Apigenin ameliorates chronic mild stress-induced depressive behavior by inhibiting interleukin-1β production and NLRP3 inflammasome activation in the rat brain.

PubMed

Li, Ruipeng; Wang, Xiangxiang; Qin, Tingting; Qu, Rong; Ma, Shiping

2016-01-01

Increasing evidence suggests that inflammation and oxidative stress may contribute to the development of major depressive disorder (MDD). Apigenin, a type of bioflavonoid widely found in citrus fruits, has a number of biological actions including anti-inflammatory and antioxidant effects. Although apigenin has potential antidepressant activity, the mechanisms of this effect remain unclear. The present study aims to investigate the effects of apigenin on behavioral changes and inflammatory responses induced by chronic unpredictable mild stress (CUMS) in rats. GW9662, a selective peroxisome proliferator-activated receptor gamma (PPARγ) inhibitor, was administered 30 min before apigenin. We found that treatment with apigenin (20mg/kg, intragastrically) for three weeks remarkably ameliorated CUMS-induced behavioral abnormalities, such as decreased locomotor activity and reduced sucrose consumption. In response to oxidative stress, the NLRP3 inflammasome was activated and IL-1β secretion increased in the prefrontal cortex (PFC) of CUMS rats. However, apigenin treatment upregulated PPARγ expression and downregulated the expression of NLRP3, which subsequently downregulated the production of IL-1β. In addition, GW9662 diminished the inhibitory effects of apigenin on the NLRP3 inflammasome. In conclusion, our results demonstrate that apigenin exhibits antidepressant-like effects in CUMS rats, possibly by inhibiting IL-1β production and NLRP3 inflammasome expression via the up-regulation of PPARγ expression. Copyright © 2015. Published by Elsevier B.V.

Sensorimotor Plasticity after Music-Supported Therapy in Chronic Stroke Patients Revealed by Transcranial Magnetic Stimulation

PubMed Central

Amengual, Julià L.; Rojo, Nuria; Veciana de las Heras, Misericordia; Marco-Pallarés, Josep; Grau-Sánchez, Jennifer; Schneider, Sabine; Vaquero, Lucía; Juncadella, Montserrat; Montero, Jordi; Mohammadi, Bahram; Rubio, Francisco; Rueda, Nohora; Duarte, Esther; Grau, Carles; Altenmüller, Eckart; Münte, Thomas F.; Rodríguez-Fornells, Antoni

2013-01-01

Background Several recently developed therapies targeting motor disabilities in stroke sufferers have shown to be more effective than standard neurorehabilitation approaches. In this context, several basic studies demonstrated that music training produces rapid neuroplastic changes in motor-related brain areas. Music-supported therapy has been recently developed as a new motor rehabilitation intervention. Methods and Results In order to explore the plasticity effects of music-supported therapy, this therapeutic intervention was applied to twenty chronic stroke patients. Before and after the music-supported therapy, transcranial magnetic stimulation was applied for the assessment of excitability changes in the motor cortex and a 3D movement analyzer was used for the assessment of motor performance parameters such as velocity, acceleration and smoothness in a set of diadochokinetic movement tasks. Our results suggest that the music-supported therapy produces changes in cortical plasticity leading the improvement of the subjects' motor performance. Conclusion Our findings represent the first evidence of the neurophysiological changes induced by this therapy in chronic stroke patients, and their link with the amelioration of motor performance. Further studies are needed to confirm our observations. PMID:23613966

Impaired Auditory and Contextual Fear Conditioning in Soman-Exposed Rats

DTIC Science & Technology

2011-01-01

include the piriform cortex, amygdala, thalamus and hippocampus (Carpentier et al., 1990; Petras , 1994; Shih et al., 2003). Often the resulting... Martin M, Shah R, Bertchume A, Colvin J, Dong H. Cholinesterase inhibitors ameliorate behavioral deficits induced by MK-801 in mice. Neuropsy...Csernansky CA, Martin MV, Bertchume A, Vallera D, Csernansky JG. Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse

Guanfacine ameliorates hypobaric hypoxia induced spatial working memory deficits.

PubMed

Kauser, H; Sahu, S; Kumar, S; Panjwani, U

2014-01-17

Hypobaric hypoxia (HH) observed at high altitude causes mild cognitive impairment specifically affecting attention and working memory. Adrenergic dysregulation and neuronal damage in prefrontal cortex (PFC) has been implicated in hypoxia induced memory deficits. Optimal stimulation of alpha 2A adrenergic receptor in PFC facilitates the spatial working memory (SWM) under the conditions of adrenergic dysregulation. Therefore the present study was designed to test the efficacy of alpha 2A adrenergic agonist, Guanfacine (GFC), to restore HH induced SWM deficits and PFC neuronal damage. The rats were exposed to chronic HH equivalent to 25,000ft for 7days in an animal decompression chamber and received daily treatment of GFC at a dose of 1mg/kg body weight via the intramuscular route during the period of exposure. The cognitive performance was assessed by Delayed Alternation Task (DAT) using T-Maze and PFC neuronal damage was studied by apoptotic and neurodegenerative markers. Percentage of correct choice decreased significantly while perseverative errors showed a significant increase after 7days HH exposure, GFC significantly ameliorated the SWM deficits and perseveration. There was a marked and significant increase in chromatin condensation, DNA fragmentation, neuronal pyknosis and fluoro Jade positive cells in layer II of the medial PFC in hypoxia exposed group, administration of GFC significantly reduced the magnitude of these changes. Modulation of adrenergic mechanisms by GFC may serve as an effective countermeasure in amelioration of prefrontal deficits and neurodegenerative changes during HH. © 2013.

Cardiac and renal antioxidant enzymes and effects of tempol in hyperthyroid rats.

PubMed

Moreno, Juan Manuel; Rodríguez Gómez, Isabel; Wangensteen, Rosemary; Osuna, Antonio; Bueno, Pablo; Vargas, Félix

2005-11-01

This study evaluated the activity of cardiac and renal antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and glutathione reductase (GR)] and whether chronic treatment with tempol, a cell membrane-permeable SOD mimetic, ameliorates the hypertension of hyperthyroidism. Two experiments were performed. In experiment I, the following four groups of male Wistar rats were used: control group and three groups that received thyroxine (T4) at 10, 50, or 75 microg x rat(-1) x day(-1). In experiment II, tempol was orally administered (18 mg x kg(-1) x day(-1)) to control and T4-treated (75 microg x rat(-1) x day(-1)) rats. All treatments were maintained for 6 wk. Body weight, tail systolic blood pressure (BP), and heart rate were measured one time a week, and direct BP and morphological, metabolic, plasma, and renal variables were measured at the end of the experiment. Enzymatic activities were measured in renal cortex and medulla and right and left ventricles. In renal cortex, SOD activity was decreased in the T4-75 group, and there was a dose-related increase in CAT activity and decrease in GPX and GR activities in T4-treated groups. Activity of all antioxidant enzymes was reduced in left ventricle in T4-50 and T4-75 groups and in right ventricle in the T4-75 group. Tempol reduced BP, plasma malondialdehyde, and total urinary excretion of F2 isoprostanes in hypertensive hyperthyroid rats but not in controls. Tempol did not improve cardiac hypertrophy, proteinuria, or creatinine clearance in hyperthyroid rats. In conclusion, the results obtained indicate that the activity of SOD, GPX, and GR in renal and cardiac tissues is decreased in hyperthyroidism and that antioxidant treatment with tempol ameliorates T4-induced hypertension.

Transcription factor Nrf2 hyperactivation in early-phase renal ischemia-reperfusion injury prevents tubular damage progression.

PubMed

Nezu, Masahiro; Souma, Tomokazu; Yu, Lei; Suzuki, Takafumi; Saigusa, Daisuke; Ito, Sadayoshi; Suzuki, Norio; Yamamoto, Masayuki

2017-02-01

Acute kidney injury is a devastating disease with high morbidity in hospitalized patients and contributes to the pathogenesis of chronic kidney disease. An underlying mechanism of acute kidney injury involves ischemia-reperfusion injury which, in turn, induces oxidative stress and provokes organ damage. Nrf2 is a master transcription factor that regulates the cellular response to oxidative stress. Here, we examined the role of Nrf2 in the progression of ischemia-reperfusion injury-induced kidney damage in mice using genetic and pharmacological approaches. Both global and tubular-specific Nrf2 activation enhanced gene expression of antioxidant and NADPH synthesis enzymes, including glucose-6-phosphate dehydrogenase, and ameliorated both the initiation of injury in the outer medulla and the progression of tubular damage in the cortex. Myeloid-specific Nrf2 activation was ineffective. Short-term administration of the Nrf2 inducer CDDO during the initial phase of injury ameliorated the late phase of tubular damage. This inducer effectively protected the human proximal tubular cell line HK-2 from oxidative stress-mediated cell death while glucose-6-phosphate dehydrogenase knockdown increased intracellular reactive oxygen species. These findings demonstrate that tubular hyperactivation of Nrf2 in the initial phase of injury prevents the progression of reactive oxygen species-mediated tubular damage by inducing antioxidant enzymes and NADPH synthesis. Thus, Nrf2 may be a promising therapeutic target for preventing acute kidney injury to chronic kidney disease transition. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Environmental Enrichment Alters Neurotrophin Levels After Fetal Alcohol Exposure in Rats

PubMed Central

Parks, Elizabeth A.; McMechan, Andrew P.; Hannigan, John H.; Berman, Robert F.

2014-01-01

Background Prenatal alcohol exposure causes abnormal brain development, leading to behavioral deficits, some of which can be ameliorated by environmental enrichment. As both environmental enrichment and prenatal alcohol exposure can individually alter neurotrophin expression, we studied the interaction of prenatal alcohol and postweaning environmental enrichment on brain neurotrophin levels in rats. Methods Pregnant rats received alcohol by gavage, 0, 4, or 6 g / kg / d (Zero, Low, or High groups), or no treatment (Naïve group), on gestational days 8 to 20. After weaning on postnatal day 21, offspring were housed for 6 weeks in Isolated, Social, or Enriched conditions. Levels of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) were then measured in frontal cortex, occipital cortex, hippocampus, and cerebellar vermis. Results Prenatal alcohol exposure increased NGF levels in frontal cortex (High-dose group) and cerebellar vermis (High- and Low-dose groups); increased BDNF in frontal cortex, occipital cortex and hippocampus (Low-dose groups), and increased NT-3 in hippocampus and cerebellar vermis (High-dose). Environmental enrichment resulted in lower NGF, BDNF, and NT-3 levels in occipital cortex and lower NGF in frontal cortex. The only significant interaction between prenatal alcohol treatment and environment was in cerebellar vermis where NT-3 levels were higher for enriched animals after prenatal alcohol exposure, but not for animals housed under Isolated or Social conditions. Conclusions Both prenatal alcohol exposure and postweaning housing conditions alter brain neurotrophin levels, but the effects appear to be largely independent. Although environmental enrichment can improve functional outcomes, these results do not provide strong support for the hypothesis that rearing in a complex environment ameliorates prenatal alcohol effects on brain neurotrophin levels in rats. PMID:18652597

Subtle Alterations in Brain Anatomy May Change an Individual’s Personality in Chronic Pain

PubMed Central

Gustin, Sylvia M.; McKay, Jamie G.; Petersen, Esben T.; Peck, Chris C.; Murray, Greg M.; Henderson, Luke A.

2014-01-01

It is well established that gross prefrontal cortex damage can affect an individual’s personality. It is also possible that subtle prefrontal cortex changes associated with conditions such as chronic pain, and not detectable until recent advances in human brain imaging, may also result in subtle changes in an individual’s personality. In an animal model of chronic neuropathic pain, subtle prefrontal cortex changes including altered basal dendritic length, resulted in altered decision making ability. Using multiple magnetic resonance imaging techniques, we found in humans, although gray matter volume and on-going activity were unaltered, chronic neuropathic pain was associated with reduced free and bound proton movement, indicators of subtle anatomical changes, in the medial prefrontal cortex, anterior cingulate cortex and mediodorsal thalamus. Furthermore, proton spectroscopy revealed an increase in neural integrity in the medial prefrontal cortex in neuropathic pain patients, the degree of which was significantly correlated to the personality temperament of novelty seeking. These data reveal that even subtle changes in prefrontal cortex anatomy may result in a significant change in an individual’s personality. PMID:25291361

Baclofen ameliorates spatial working memory impairments induced by chronic cerebral hypoperfusion via up-regulation of HCN2 expression in the PFC in rats.

PubMed

Luo, Pan; Chen, Cheng; Lu, Yun; Fu, TianLi; Lu, Qing; Xu, Xulin; Li, Changjun; He, Zhi; Guo, Lianjun

2016-07-15

Chronic cerebral hypoperfusion (CCH) causes memory deficits and increases the risk of vascular dementia (VD) through several biologically plausible pathways. However, whether CCH causes prefrontal cortex (PFC)-dependent spatial working memory impairments and Baclofen, a GABAB receptor agonist, could ameliorate the impairments is still not clear especially the mechanisms underlying the process. In this study, rats were subjected to permanent bilateral occlusion of the common carotid arteries (two-vessel occlusion, 2VO) to induce CCH. Two weeks later, rats were treated with 25mg/kg Baclofen (intraperitioneal injection, i.p.) for 3 weeks. Spatial working memory was evaluated in a Morris water maze using a modified delayed matching-to-place (DMP) procedure. Western blotting and immunohistochemistry were used to quantify the protein levels and protein localization. Our results showed that 2VO caused striking spatial working memory impairments, accompanied with a decreased HCN2 expression in PFC, but the protein levels of protein gene product 9.5 (PGP9.5, a neuron specific protein), glial fibrillary acidic protein (GFAP), synaptophysin (SYP), brain-derived neurotrophic factor (BDNF), parvalbumin (PV) and HCN1 were not distinguishably changed as compared with sham-operated rats. Baclofen treatment significantly improved the spatial working memory impairments caused by 2VO, accompanied with a reversion of 2VO-induced down-regulation of HCN2. Furthermore, there was a co-localization of HCN2 subunits and parvalbumin-positive neurons in PFC. Therefore, HCN2 may target inhibitory interneurons that is implicated in working memory processes, which may be a possible mechanism of the up-regulation of HCN2 by Baclofen treatment that reliefs spatial working memory deficits in rats with CCH. Copyright © 2016 Elsevier B.V. All rights reserved.

Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice

PubMed Central

Kishi, Noriyuki; MacDonald, Jessica L.; Ye, Julia; Molyneaux, Bradley J.; Azim, Eiman; Macklis, Jeffrey D.

2016-01-01

Mutations in the transcriptional regulator Mecp2 cause the severe X-linked neurodevelopmental disorder Rett syndrome (RTT). In this study, we investigate genes that function downstream of MeCP2 in cerebral cortex circuitry, and identify upregulation of Irak1, a central component of the NF-κB pathway. We show that overexpression of Irak1 mimics the reduced dendritic complexity of Mecp2-null cortical callosal projection neurons (CPN), and that NF-κB signalling is upregulated in the cortex with Mecp2 loss-of-function. Strikingly, we find that genetically reducing NF-κB signalling in Mecp2-null mice not only ameliorates CPN dendritic complexity but also substantially extends their normally shortened lifespan, indicating broader roles for NF-κB signalling in RTT pathogenesis. These results provide new insight into both the fundamental neurobiology of RTT, and potential therapeutic strategies via NF-κB pathway modulation. PMID:26821816

Lithium ameliorates lipopolysaccharide-induced neurotoxicity in the cortex and hippocampus of the adult rat brain.

PubMed

Khan, Muhammad Sohail; Ali, Tahir; Abid, Muhammad Noman; Jo, Myeung Hoon; Khan, Amjad; Kim, Min Woo; Yoon, Gwang Ho; Cheon, Eun Woo; Rehman, Shafiq Ur; Kim, Myeong Ok

2017-09-01

Lithium an effective mood stabilizer, primary used in the treatment of bipolar disorders, has been reported as a protective agent in various neurological disorders. In this study, we examined the neuroprotective role of lithium chloride (LiCl) against lipopolysaccharide (LPS) in the cortex and hippocampus of the adult rat brain. We determined that LiCl -attenuated LPS-induced activated toll-like receptor 4 (TLR4) signalling and significantly reduced the nuclear factor- k B (NF- K B) translation factor and various other inflammatory mediators such as interleukin-1 beta (IL-1β) and tumour necrosis factor alpha (TNF-α). We also analyzed that LiCl significantly abrogated activated gliosis via attenuation of specific markers for activated microglia, ionized calcium-binding adaptor molecule (Iba-1) and astrocytes, glial fibrillary acidic protein (GFAP) in both the cortex and hippocampus of the adult rat brain. Furthermore, we also observed that LiCl treatment significantly ameliorated the increase expression level of apoptotic neurodegeneration protein markers Bax/Bcl2, activated caspase-3 and poly (ADP-ribose) polymerase-1 (PARP-1) in the cortex and hippocampus regions of the LPS-treated adult rat brain. In addition, the morphological results of the fluoro-jade B (FJB) and Nissl staining showed that LiCl attenuated the neuronal degeneration in the cortex and hippocampus regions of the LPS-treated adult rat brain. Taken together, our Western blot and morphological results indicated that LiCl significantly prevents the LPS-induced neurotoxicity via attenuation of neuroinflammation and apoptotic neurodegeneration in the cortex and hippocampus of the adult rat brain. Copyright © 2017 Elsevier Ltd. All rights reserved.

Abnormal Resting-State Functional Connectivity of the Anterior Cingulate Cortex in Unilateral Chronic Tinnitus Patients

PubMed Central

Chen, Yu-Chen; Liu, Shenghua; Lv, Han; Bo, Fan; Feng, Yuan; Chen, Huiyou; Xu, Jin-Jing; Yin, Xindao; Wang, Shukui; Gu, Jian-Ping

2018-01-01

Purpose: The anterior cingulate cortex (ACC) has been suggested to be involved in chronic subjective tinnitus. Tinnitus may arise from aberrant functional coupling between the ACC and cerebral cortex. To explore this hypothesis, we used resting-state functional magnetic resonance imaging (fMRI) to illuminate the functional connectivity (FC) network of the ACC subregions in chronic tinnitus patients. Methods: Resting-state fMRI scans were obtained from 31 chronic right-sided tinnitus patients and 40 healthy controls (age, sex, and education well-matched) in this study. Rostral ACC and dorsal ACC were selected as seed regions to investigate the intrinsic FC with the whole brain. The resulting FC patterns were correlated with clinical tinnitus characteristics including the tinnitus duration and tinnitus distress. Results: Compared with healthy controls, chronic tinnitus patients showed disrupted FC patterns of ACC within several brain networks, including the auditory cortex, prefrontal cortex, visual cortex, and default mode network (DMN). The Tinnitus Handicap Questionnaires (THQ) scores showed positive correlations with increased FC between the rostral ACC and left precuneus (r = 0.507, p = 0.008) as well as the dorsal ACC and right inferior parietal lobe (r = 0.447, p = 0.022). Conclusions: Chronic tinnitus patients have abnormal FC networks originating from ACC to other selected brain regions that are associated with specific tinnitus characteristics. Resting-state ACC-cortical FC disturbances may play an important role in neuropathological features underlying chronic tinnitus. PMID:29410609

Cotinine reduces depressive-like behavior, working memory deficits, and synaptic loss associated with chronic stress in mice.

PubMed

Grizzell, J Alex; Iarkov, Alexandre; Holmes, Rosalee; Mori, Takahashi; Echeverria, Valentina

2014-07-15

Chronic stress underlies and/or exacerbates many psychiatric conditions and often results in memory impairment as well as depressive symptoms. Such afflicted individuals use tobacco more than the general population and this has been suggested as a form of self-medication. Cotinine, the predominant metabolite of nicotine, may underlie such behavior as it has been shown to ameliorate anxiety and memory loss in animal models. In this study, we sought to investigate the effects of cotinine on working memory and depressive-like behavior in mice subjected to prolonged restraint. Cotinine-treated mice displayed better performance than vehicle-treated cohorts on the working memory task, the radial arm water maze test. In addition, with or without chronic stress exposure, cotinine-treated mice engaged in fewer depressive-like behaviors as assessed using the tail suspension and Porsolt's forced swim tests. These antidepressant and nootropic effects of cotinine were associated with an increase in the synaptophysin expression, a commonly used marker of synaptic density, in the hippocampus as well as the prefrontal and entorhinal cortices of restrained mice. The beneficial effects of cotinine in preventing various consequences of chronic stress were underscored by the inhibition of the glycogen synthase kinase 3 β in the hippocampus and prefrontal cortex. Taken together, our results show for the first time that cotinine reduces the negative effects of stress on mood, memory, and the synapse. Published by Elsevier B.V.

Increased Neuronal DNA/RNA Oxidation in the Frontal Cortex of Mice Subjected to Unpredictable Chronic Mild Stress.

PubMed

Maluach, Alfred M; Misquitta, Keith A; Prevot, Thomas D; Fee, Corey; Sibille, Etienne; Banasr, Mounira; Andreazza, Ana C

2017-01-01

Chronic stress is implicated in the development of various psychiatric illnesses including major depressive disorder. Previous reports suggest that patients with major depressive disorder have increased levels of oxidative stress, including higher levels of DNA/RNA oxidation found in postmortem studies, especially within brain regions responsible for the cognitive and emotional processes disrupted in the disorder. Here, we aimed to investigate whether unpredictable chronic mild stress in mice induces neuronal DNA/RNA oxidation in the prelimbic, infralimbic, and cingulate cortices of the frontal cortex and the basolateral amygdala and to explore potential associations with depressive-like behaviors. We expected that animals subjected to unpredictable chronic mild stress will present higher levels of DNA/RNA oxidation, which will be associated with anxiety-/depressive-like behaviors. C57BL/6J mice were assigned to unpredictable chronic mild stress or nonstress conditions (n = 10/group, 50% females). Following five weeks of unpredictable chronic mild stress exposure, mice were tested in a series of behavioral tests measuring anxiety- and depressive-like behaviors. Frontal cortex and amygdala sections were then immunolabeled for neuronal nuclei, a marker of post-mitotic neurons and anti-8-hydroxy-2-deoxyguanosine/8-oxo-7,8-dihydroguanosine, which reflects both DNA and RNA oxidation. Levels of neuronal DNA/RNA oxidation were increased in the frontal cortex of mice subjected to unpredictable chronic mild stress ( p = 0.0207). Levels of neuronal DNA/RNA oxidation in the frontal cortex were positively correlated with z-emotionality scores for latency to feed in the novelty-suppressed feeding test ( p = 0.0031). Statistically significant differences were not detected in basolateral amygdala levels of neuronal DNA/RNA oxidation between nonstress- and unpredictable chronic mild stress-exposed mice, nor were correlations found with behavioral performances for this region. Our results demonstrate that unpredictable chronic mild stress induces a significant increase in neuronal DNA/RNA oxidation in the frontal cortex that correlate with behavioral readouts of the stress response. A lack of DNA/RNA oxidation alterations in the basolateral amygdala suggests greater vulnerability of frontal cortex neurons to DNA/RNA oxidation in response to unpredictable chronic mild stress. These findings add support to the hypothesis that chronic stress-induced damage to DNA/RNA may be an additional molecular mechanism underlying cellular dysfunctions associated with chronic stress and present in stress-related disorders.

Captodiamine, a putative antidepressant, enhances hypothalamic BDNF expression in vivo by synergistic 5-HT2c receptor antagonism and sigma-1 receptor agonism.

PubMed

Ring, Rebecca M; Regan, Ciaran M

2013-10-01

The putative antidepressant captodiamine is a 5-HT2c receptor antagonist and agonist at sigma-1 and D3 dopamine receptors, exerts an anti-immobility action in the forced swim paradigm, and enhances dopamine turnover in the frontal cortex. Captodiamine has also been found to ameliorate stress-induced anhedonia, reduce the associated elevations of hypothalamic corticotrophin-releasing factor (CRF) and restore the reductions in hypothalamic BDNF expression. Here we demonstrate chronic administration of captodiamine to have no significant effect on hypothalamic CRF expression through sigma-1 receptor agonism; however, both sigma-1 receptor agonism or 5-HT2c receptor antagonism were necessary to enhance BDNF expression. Regulation of BDNF expression by captodiamine was associated with increased phosphorylation of transcription factor CREB and mediated through sigma-1 receptor agonism but blocked by 5-HT2c receptor antagonism. The existence of two separate signalling pathways was confirmed by immunolocalisation of each receptor to distinct cell populations in the paraventricular nucleus of the hypothalamus. Increased BDNF induced by captodiamine was also associated with enhanced expression of synapsin, but not PSD-95, suggesting induction of long-term structural plasticity between hypothalamic synapses. These unique features of captodiamine may contribute to its ability to ameliorate stress-induced anhedonia as the hypothalamus plays a prominent role in regulating HPA axis activity.

A proof-of-concept study on the combination of repetitive transcranial magnetic stimulation and relaxation techniques in chronic tinnitus.

PubMed

Kreuzer, Peter M; Poeppl, Timm B; Bulla, Jan; Schlee, Winfried; Lehner, Astrid; Langguth, Berthold; Schecklmann, Martin

2016-10-01

Interference of ongoing neuronal activity and brain stimulation motivated this study to combine repetitive transcranial magnetic stimulation (rTMS) and relaxation techniques in tinnitus patients. Forty-two patients were enrolled in this one-arm proof-of-concept study to receive ten sessions of rTMS applied to the left dorsolateral prefrontal cortex and temporo-parietal cortex. During stimulation, patients listened to five different kinds of relaxation audios. Variables of interest were tinnitus questionnaires, tinnitus numeric rating scales, depressivity, and quality of life. Results were compared to results of historical control groups having received the same rTMS protocol (active control) and sham treatment (placebo) without relaxation techniques. Thirty-eight patients completed the treatment, drop-out rates and adverse events were low. Responder rates (reduction in tinnitus questionnaire (TQ) score ≥5 points 10 weeks after treatment) were 44.7 % in the study, 27.8 % in the active control group, and 21.7 % in the placebo group, differing between groups on a near significant level. For the tinnitus handicap inventory (THI), the main effect of group was not significant. However, linear mixed model analyses showed that the relaxation/rTMS group differed significantly from the active control group showing steeper negative THI trend for the relaxation/rTMS group indicating better amelioration over the course of the trial. Deepness of relaxation during rTMS and selection of active relaxation vs. passive listening to music predicted larger TQ. All remaining secondary outcomes turned out non-significant. This combined treatment proved to be a safe, feasible and promising approach to enhance rTMS treatment effects in chronic tinnitus.

Protective Effects of Cornel Iridoid Glycoside in Rats After Traumatic Brain Injury.

PubMed

Ma, Denglei; Wang, Na; Fan, Xiaotong; Zhang, Lan; Luo, Yi; Huang, Rui; Zhang, Li; Li, Yali; Zhao, Guoguang; Li, Lin

2018-04-01

Cornel iridoid glycoside (CIG) is the active ingredient extracted from Cornus officinalis. Our previous studies showed that CIG had protective effects on several brain injury models. In the present study, we aimed to examine the effects and elucidate the mechanisms of CIG against traumatic brain injury (TBI). TBI was induced in the right cerebral cortex of male adult rats. The neurological and cognitive functions were evaluated by modified neurological severity score (mNSS) and object recognition test (ORT), respectively. The level of serum S100β was measured by an ELISA method. Nissl staining was used to estimate the neuron survival in the brain. The expression of proteins was determined by western blot and/or immunohistochemical staining. We found that intragastric administration of CIG in TBI rats ameliorated the neurological defects and cognitive impairment, and alleviated the neuronal loss in the injured brain. In the acute stage of TBI (24-72 h), CIG decreased the level of S100β in the serum and brain, increased the ratio of Bcl-2/Bax and decreased the expression of caspase-3 in the injured cortex. Moreover, the treatment with CIG for 30 days increased the levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), enhanced the expression of synapsin I, synaptophysin and postsynaptic density protein 95 (PSD-95), and inhibited the apoptosis-regulating factors in the chronic stage of TBI. The present study demonstrated that CIG had neuroprotective effects against TBI through inhibiting apoptosis in the acute stage and promoting neurorestoration in the chronic stage. The results suggest that CIG may be beneficial to TBI therapy.

Evaluation of Krebs cycle enzymes in the brain of rats after chronic administration of antidepressants.

PubMed

Scaini, Giselli; Santos, Patricia M; Benedet, Joana; Rochi, Natália; Gomes, Lara M; Borges, Lislaine S; Rezin, Gislaine T; Pezente, Daiana P; Quevedo, João; Streck, Emilio L

2010-05-31

Several works report brain impairment of metabolism as a mechanism underlying depression. Citrate synthase and succinate dehydrogenase are enzymes localized within cells in the mitochondrial matrix and are important steps of Krebs cycle. In addition, citrate synthase has been used as a quantitative enzyme marker for the presence of intact mitochondria. Thus, we investigated citrate synthase and succinate dehydrogenase activities from rat brain after chronic administration of paroxetine, nortriptiline and venlafaxine. Adult male Wistar rats received daily injections of paroxetine (10mg/kg), nortriptiline (15mg/kg), venlafaxine (10mg/kg) or saline in 1.0mL/kg volume for 15 days. Twelve hours after the last administration, the rats were killed by decapitation, the hippocampus, striatum and prefrontal cortex were immediately removed, and activities of citrate synthase and succinate dehydrogenase were measured. We verified that chronic administration of paroxetine increased citrate synthase activity in the prefrontal cortex, hippocampus, striatum and cerebral cortex of adult rats; cerebellum was not affected. Chronic administration of nortriptiline and venlafaxine did not affect the enzyme activity in these brain areas. Succinate dehydrogenase activity was increased by chronic administration of paroxetine and nortriptiline in the prefrontal cortex, hippocampus, striatum and cerebral cortex of adult rats; cerebellum was not affected either. Chronic administration of venlafaxine increased succinate dehydrogenase activity in prefrontal cortex, but did not affect the enzyme activity in cerebellum, hippocampus, striatum and cerebral cortex. Considering that metabolism impairment is probably involved in the pathophysiology of depressive disorders, an increase in these enzymes by antidepressants may be an important mechanism of action of these drugs. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Motor Cortex Stimulation for Pain Relief: Do Corollary Discharges Play a Role?

PubMed

Brasil-Neto, Joaquim P

2016-01-01

Both invasive and non-invasive motor cortex stimulation techniques have been successfully employed in the treatment of chronic pain, but the precise mechanism of action of such treatments is not fully understood. It has been hypothesized that a mismatch of normal interaction between motor intention and sensory feedback may result in central pain. Sensory feedback may come from peripheral nerves, vision and also from corollary discharges originating from the motor cortex itself. Therefore, a possible mechanism of action of motor cortex stimulation might be corollary discharge reinforcement, which could counterbalance sensory feedback deficiency. In other instances, primary deficiency in the production of corollary discharges by the motor cortex might be the culprit and stimulation of cortical motor areas might then be beneficial by enhancing production of such discharges. Here we review evidence for a possible role of motor cortex corollary discharges upon both the pathophysiology and the response to motor cortex stimulation of different types of chronic pain. We further suggest that the right dorsolateral prefrontal cortex (DLPC), thought to constantly monitor incongruity between corollary discharges, vision and proprioception, might be an interesting target for non-invasive neuromodulation in cases of chronic neuropathic pain.

Citalopram Ameliorates Synaptic Plasticity Deficits in Different Cognition-Associated Brain Regions Induced by Social Isolation in Middle-Aged Rats.

PubMed

Gong, Wei-Gang; Wang, Yan-Juan; Zhou, Hong; Li, Xiao-Li; Bai, Feng; Ren, Qing-Guo; Zhang, Zhi-Jun

2017-04-01

Our previous experiments demonstrated that social isolation (SI) caused AD-like tau hyperphosphorylation and spatial memory deficits in middle-aged rats. However, the underlying mechanisms of SI-induced spatial memory deficits remain elusive. Middle-aged rats (10 months) were group or isolation reared for 8 weeks. Following the initial 4-week period of rearing, citalopram (10 mg/kg i.p.) was administered for 28 days. Then, pathophysiological changes were assessed by performing behavioral, biochemical, and pathological analyses. We found that SI could cause cognitive dysfunction and decrease synaptic protein (synaptophysin or PSD93) expression in different brain regions associated with cognition, such as the prefrontal cortex, dorsal hippocampus, ventral hippocampus, amygdala, and caudal putamen, but not in the entorhinal cortex or posterior cingulate. Citalopram could significantly improve learning and memory and partially restore synaptophysin or PSD93 expression in the prefrontal cortex, hippocampus, and amygdala in SI rats. Moreover, SI decreased the number of dendritic spines in the prefrontal cortex, dorsal hippocampus, and ventral hippocampus, which could be reversed by citalopram. Furthermore, SI reduced the levels of BDNF, serine-473-phosphorylated Akt (active form), and serine-9-phosphorylated GSK-3β (inactive form) with no significant changes in the levels of total GSK-3β and Akt in the dorsal hippocampus, but not in the posterior cingulate. Our results suggest that decreased synaptic plasticity in cognition-associated regions might contribute to SI-induced cognitive deficits, and citalopram could ameliorate these deficits by promoting synaptic plasticity mainly in the prefrontal cortex, dorsal hippocampus, and ventral hippocampus. The BDNF/Akt/GSK-3β pathway plays an important role in regulating synaptic plasticity in SI rats.

Near-Infrared Spectroscopy – Electroencephalography-Based Brain-State-Dependent Electrotherapy: A Computational Approach Based on Excitation–Inhibition Balance Hypothesis

PubMed Central

Dagar, Snigdha; Chowdhury, Shubhajit Roy; Bapi, Raju Surampudi; Dutta, Anirban; Roy, Dipanjan

2016-01-01

Stroke is the leading cause of severe chronic disability and the second cause of death worldwide with 15 million new cases and 50 million stroke survivors. The poststroke chronic disability may be ameliorated with early neuro rehabilitation where non-invasive brain stimulation (NIBS) techniques can be used as an adjuvant treatment to hasten the effects. However, the heterogeneity in the lesioned brain will require individualized NIBS intervention where innovative neuroimaging technologies of portable electroencephalography (EEG) and functional-near-infrared spectroscopy (fNIRS) can be leveraged for Brain State Dependent Electrotherapy (BSDE). In this hypothesis and theory article, we propose a computational approach based on excitation–inhibition (E–I) balance hypothesis to objectively quantify the poststroke individual brain state using online fNIRS–EEG joint imaging. One of the key events that occurs following Stroke is the imbalance in local E–I (that is the ratio of Glutamate/GABA), which may be targeted with NIBS using a computational pipeline that includes individual “forward models” to predict current flow patterns through the lesioned brain or brain target region. The current flow will polarize the neurons, which can be captured with E–I-based brain models. Furthermore, E–I balance hypothesis can be used to find the consequences of cellular polarization on neuronal information processing, which can then be implicated in changes in function. We first review the evidence that shows how this local imbalance between E–I leading to functional dysfunction can be restored in targeted sites with NIBS (motor cortex and somatosensory cortex) resulting in large-scale plastic reorganization over the cortex, and probably facilitating recovery of functions. Second, we show evidence how BSDE based on E–I balance hypothesis may target a specific brain site or network as an adjuvant treatment. Hence, computational neural mass model-based integration of neurostimulation with online neuroimaging systems may provide less ambiguous, robust optimization of NIBS, and its application in neurological conditions and disorders across individual patients. PMID:27551273

Withdrawal From Chronic Nicotine Reduces Thyroid Hormone Levels and Levothyroxine Treatment Ameliorates Nicotine Withdrawal-Induced Deficits in Hippocampus-Dependent Learning in C57BL/6J Mice

PubMed Central

Leach, Prescott T.; Holliday, Erica; Kutlu, Munir G.

2015-01-01

Introduction: Cigarette smoking alters a variety of endocrine systems including thyroid hormones. Altered thyroid hormone signaling may lead to a subclinical or overt hypothyroid condition that could contribute to nicotine withdrawal-related symptoms, such as cognitive deficits. Thus, normalizing thyroid hormone levels may represent a novel therapeutic target for ameliorating nicotine withdrawal-associated cognitive deficits. Methods: The current studies conducted an analysis of serum thyroid hormone levels after chronic and withdrawal from chronic nicotine treatment in C57BL/6J mice using an enzyme-linked immunosorbent assay. The present studies also evaluated the effect of synthetic thyroid hormone (levothyroxine) on contextual and cued memory. Results: The current studies found that nicotine withdrawal reduces secreted thyroid hormone levels by 9% in C57BL/6J mice. Further, supplemental thyroid hormone not only enhanced memory in naïve animals, but also ameliorated deficits in hippocampus-dependent learning associated with nicotine withdrawal. Conclusions: These results suggest that smokers attempting to quit should be monitored closely for changes in thyroid function. If successfully treated, normalization of thyroid hormone levels may ameliorate some deficits associated with nicotine withdrawal and this may lead to higher rates of successful abstinence. PMID:25358661

Schisandra chinensis produces the antidepressant-like effects in repeated corticosterone-induced mice via the BDNF/TrkB/CREB signaling pathway.

PubMed

Yan, Tingxu; Xu, Mengjie; Wan, Shutong; Wang, Mengshi; Wu, Bo; Xiao, Feng; Bi, Kaishun; Jia, Ying

2016-09-30

The present study aimed to examine the antidepressant-like effects and the possible mechanisms of Schisandra chinensis on depressive-like behavior induced by repeated corticosterone injections in mice. Here we evaluated the effect of an ethanol extract of the dried fruit of S. chinensis (EESC) on BDNF/TrkB/CREB signaling in the hippocampus and the prefrontal cortex. Three weeks of corticosterone injections in mice resulted in depressive-like behavior, as indicated by the significant decrease in sucrose consumption and increase the immobility time in the forced swim test, but without any influence on the locomotor activity. Further, there was a significant increase in serum corticosterone level and a significant downregulation of BDNF/TrkB/CREB signaling pathway in the hippocampus and prefrontal cortex in CORT-treated mice. Treatment of mice with EESC (600mg/kg) significantly ameliorated all the behavioral and biochemical changes induced by corticosterone. Moreover, pharmacological inhibition of BDNF signaling by K252a abolished entirely the antidepressant-like effect triggered by chronic EESC treatment. These results suggest that EESC produces an antidepressant-like effect in CORT-induced depression in mice, which is possibly mediated, at least in part, by rectifying the stress-based hypothalamic-pituitary-adrenal (HPA) axis dysfunction paradigm and upregulation of BDNF/TrkB/CREB signaling pathway. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Magnolol treatment reversed the glial pathology in an unpredictable chronic mild stress-induced rat model of depression.

PubMed

Li, Lu-Fan; Yang, Jie; Ma, Shi-Ping; Qu, Rong

2013-07-05

Growing evidence indicates that glia atrophy contributes to the pathophysiology and the pathogenesis of major depressive disorder. Magnolol is the main constituent identified in the bark of Magnolia officinalis, which has been used for the treatment of mental disorders, including depression, in Asian countries. In this study, we investigated the antidepressant-like effect and the possible mechanisms of magnolol in rats subjected to unpredictable chronic mild stress (UCMS). The ameliorative effect of magnolol on depression symptoms was investigated through behavior tests, including sucrose preference test, open-field test and forced-swimming test. In addition, the levels of glial fibrillary acidic protein (GFAP), an astrocyte marker, in the hippocampus and prefrontal cortex were determined by immunohistochemistry, Western blot, and reverse transcription-polymerase chain reaction (RT-PCR). Exposure to UCMS resulted in a decrease of behavioral activity, whereas magnolol (20, 40 mg/kg) and fluoxetine (20mg/kg) administration significantly reversed the depressive-like behaviors (P<0.05).Moreover, treatment with magnolol effectively increased GFAP mRNA and protein levels in UCMS rats. These results confirmed the antidepressant-like effect of magnolol, which maybe primarily mediated by reversing the glial atrophy in the UCMS rat brain. Copyright © 2013 Elsevier B.V. All rights reserved.

Curcumin attenuates chronic intermittent hypoxia-induced brain injuries by inhibiting AQP4 and p38 MAPK pathway.

PubMed

Wang, Bo; Li, Wenyang; Jin, Hongyu; Nie, Xinshi; Shen, Hui; Li, Erran; Wang, Wei

2018-09-01

Chronic intermittent hypoxia (CIH) is one of the main features of obstructive sleep apnea (OSA), which is also commonly associated with neurocognitive impairments. The present study aimed to elucidate the beneficial effect of curcumin on CIH-induced brain injuries. Male balb/c mice (6 ∼ 8 weeks) were exposed to normoxia or a pattern of CIH (8 h/day, cycles of 180 s each, hypoxia: 5% O 2 for 50 s, reoxygenation: 21% O 2 for 50 s) for 10 weeks, along with daily curcumin treatment (50, 100, or 200 mg/kg, intragastrically) or its vehicle. The results showed that CIH induced significant brain edema, as well as neuronal apoptosis and astrogliosis in the cerebral cortex, brainstem, and cerebellum regions of brain. In addition, increased astrocytic AQP4 expression and activation of p38 MAPK pathway were observed after CIH exposure. Curcumin dose-dependently mitigated the brain edema and relevant cell alterations, showing a neuroprotective effect in CIH-induced brain injury. Together, these results suggest curcumin ameliorates the CIH-induced brain injuries, including brain edema, neuronal death and astrogliosis. The beneficial role of curcumin is mediated partially by regulating AQP4 and p38 MAPK pathway. Copyright © 2018 Elsevier B.V. All rights reserved.

Behavioral training enhances cortical temporal processing in neonatally deafened juvenile cats

PubMed Central

Vollmer, Maike; Raggio, Marcia W.; Schreiner, Christoph E.

2011-01-01

Deaf humans implanted with a cochlear prosthesis depend largely on temporal cues for speech recognition because spectral information processing is severely impaired. Training with a cochlear prosthesis is typically required before speech perception shows improvement, suggesting that relevant experience modifies temporal processing in the central auditory system. We tested this hypothesis in neonatally deafened cats by comparing temporal processing in the primary auditory cortex (AI) of cats that received only chronic passive intracochlear electric stimulation (ICES) with cats that were also trained with ICES to detect temporally challenging trains of electric pulses. After months of chronic passive stimulation and several weeks of detection training in behaviorally trained cats, multineuronal AI responses evoked by temporally modulated ICES were recorded in anesthetized animals. The stimulus repetition rates that produced the maximum number of phase-locked spikes (best repetition rate) and 50% cutoff rate were significantly higher in behaviorally trained cats than the corresponding rates in cats that received only chronic passive ICES. Behavioral training restored neuronal temporal following ability to levels comparable with those recorded in naïve prior normal-hearing adult deafened animals. Importantly, best repetitition rates and cutoff rates were highest for neuronal clusters activated by the electrode configuration used in behavioral training. These results suggest that neuroplasticity in the AI is induced by behavioral training and perceptual learning in animals deprived of ordinary auditory experience during development and indicate that behavioral training can ameliorate or restore temporal processing in the AI of profoundly deaf animals. PMID:21543753

Cysteamine treatment ameliorates alterations in GAD67 expression and spatial memory in heterozygous reeler mice

PubMed Central

Kutiyanawalla, Ammar; Promsote, Wanwisa; Terry, Alvin; Pillai, Anilkumar

2011-01-01

Brain derived neurotrophic factor (BDNF) signaling through its receptor, TrkB is known to regulate GABAergic function and glutamic acid decarboxylase (GAD) 67 expression in neurons. Alterations in BDNF signaling have been implicated in the pathophysiology of schizophrenia and as a result, they are a potential therapeutic target. Interestingly, heterozygous reeler mice (HRM) have decreased GAD67 expression in the frontal cortex and hippocampus and they exhibit many behavioral and neurochemical abnormalities similar to schizophrenia. In the present study, we evaluated the potential of cysteamine, a neuroprotective compound to improve the deficits in GAD67 expression and cognitive function in HRM. We found that cysteamine administration (150 mg/kg/day, through drinking water) for 30 days significantly ameliorated the decreases in GAD67, mature BDNF and full-length TrkB protein levels found in frontal cortex and hippocampus of HRM. A significant attenuation of the increased levels of truncated BDNF in frontal cortex and hippocampus, as well as truncated TrkB in frontal cortex of HRM was also observed following cysteamine treatment. In behavioral studies, HRM were impaired in a Y-maze spatial recognition memory task, but not in a spontaneous alternation task or a sensorimotor, prepulse inhibition (PPI) procedure. Cysteamine improved Y-maze spatial recognition in HRM to the level of wide-type controls and it improved PPI in both wild-type and HRM. Finally, mice deficient in TrkB, showed a reduced response to cysteamine in GAD67 expression suggesting that TrkB signaling plays an important role in GAD67 regulation by cysteamine. PMID:21777509

Ameliorating effect and potential mechanism of Rehmannia glutinosa oligosaccharides on the impaired glucose metabolism in chronic stress rats fed with high-fat diet.

PubMed

Zhang, Ruxue; Zhou, Jun; Li, Maoxing; Ma, Haigang; Qiu, Jianguo; Luo, Xiaohong; Jia, Zhengping

2014-04-15

The aim of this study was to determine whether the Rehmannia glutinosa oligosaccharides (ROS) ameliorate the impaired glucose metabolism and the potential mechanism in chronic stress rats fed with high-fat diet. The rats were fed by a high-fat diet and simultaneously stimulated by chronic stress over 5 weeks. Body weight, fasting plasma glucose, intraperitoneal glucose tolerance test (IPGTT), plasma lipids, gluconeogenesis test (GGT), glycogen content, and corticosterone, insulin and leptin levels were measured. The results showed that ROS administration (100, 200 mg/kg, i.g.) for 5 weeks exerted the effects of increasing the organ weights of thymus and spleen, lowering the fasting plasma glucose level, improving impaired glucose tolerance, increasing the contents of liver and muscle glycogen, decreasing the gluconeogenesis ability, plasma-free fatty acid's level, as well as plasma triglyceride and total cholesterol levels in chronic stress and high-fat fed rats, especially in the group of 200mg/kg; while the plasma corticosterone level was decreased, and plasma leptin level was increased. These results suggest that ROS exert an ameliorating effect of impaired glucose metabolism in chronic stress rats fed with high-fat diet, and the potential mechanism may be mediated through rebuilding the glucose homeostasis in the neuroendocrine immuno-modulation (NIM) network through multilinks and multitargets. Copyright © 2013 Elsevier GmbH. All rights reserved.

Amygdala functional disconnection with the prefrontal-cingulate-temporal circuit in chronic tinnitus patients with depressive mood.

PubMed

Chen, Yu-Chen; Bo, Fan; Xia, Wenqing; Liu, Shenghua; Wang, Peng; Su, Wen; Xu, Jin-Jing; Xiong, Zhenyu; Yin, Xindao

2017-10-03

Chronic tinnitus is often accompanied with depressive symptom, which may arise from aberrant functional coupling between the amygdala and cerebral cortex. To explore this hypothesis, resting-state functional magnetic resonance imaging (fMRI) was used to investigate the disrupted amygdala-cortical functional connectivity (FC) in chronic tinnitus patients with depressive mood. Chronic tinnitus patients with depressive mood (n=20), without depressive mood (n=20), and well-matched healthy controls (n=23) underwent resting-state fMRI scanning. Amygdala-cortical FC was characterized using a seed-based whole-brain correlation method. The bilateral amygdala FC was compared among the three groups. Compared to non-depressed patients, depressive tinnitus patients showed decreased amygdala FC with the prefrontal cortex and anterior cingulate cortex as well as increased amygdala FC with the postcentral gyrus and lingual gyrus. Relative to healthy controls, depressive tinnitus patients revealed decreased amygdala FC with the superior and middle temporal gyrus, anterior and posterior cingulate cortex, and prefrontal cortex, as well as increased amygdala FC with the postcentral gyrus and lingual gyrus. The current study identified for the first time abnormal resting-state amygdala-cortical FC with the prefrontal-cingulate-temporal circuit in chronic tinnitus patients with depressive mood, which will provide novel insight into the underlying neuropathological mechanisms of tinnitus-induced depressive disorder. Copyright © 2017 Elsevier Inc. All rights reserved.

Development of tolerance to the effects of vigabatrin (gamma-vinyl-GABA) on GABA release from rat cerebral cortex, spinal cord and retina.

PubMed Central

Neal, M. J.; Shah, M. A.

1990-01-01

1. The effects of acute and chronic vigabatrin (gamma-vinyl-GABA) (GVG) administration on gamma-aminobutyric acid (GABA) levels and release in rat cortical slices, spinal cord slices and retinas were studied. 2. GVG (250 mgkg-1 i.p.) administered to rats 18 h before death (acute administration) produced an almost 3 fold increase in GABA levels of the cortex and spinal cord and a 6 fold increase in retinal GABA. The levels of glutamate, aspartate, glycine and taurine were unaffected. 3. When GVG (250 mgkg-1 i.p.) was administered daily for 17 days (chronic administration) a similar (almost 3 fold) increase in cortical GABA occurred but the increases in spinal and retinal GABA were reduced by approximately 40%. 4. Acute administration of GVG strikingly increased the potassium-evoked release (KCl 50 mM) of GABA from all three tissues. This enhanced evoked release was reduced by about 50% in tissues taken from rats that had been chronically treated with GVG. 5. Acute administration of GVG reduced GABA-transaminase (GABA-T) activity by approximately 80% in cortex and cord and by 98% in the retina. Following the chronic administration of GVG, there was a trend for GABA-T activities to recover (significant only in cortex). Acute administration of GVG had no effect on glutamic acid decarboxylase (GAD) activity in cortex or spinal cord. However, chronic treatment resulted in significant decreases in GAD activity in both the cortex and cord (35% and 50% reduction respectively).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2379037

New therapeutic aspect for carvedilol: Antifibrotic effects of carvedilol in chronic carbon tetrachloride-induced liver damage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hamdy, Nadia; El-Demerdash, Ebtehal, E-mail: ebtehal_dm@yahoo.com

2012-06-15

Portal hypertension is a common complication of chronic liver diseases associated with liver fibrosis and cirrhosis. At present, beta-blockers such as carvedilol remain the medical treatment of choice for protection against variceal bleeding and other complications. Since carvedilol has powerful antioxidant properties we assessed the potential antifibrotic effects of carvedilol and the underlying mechanisms that may add further benefits for its clinical usefulness using a chronic model of carbon tetrachloride (CCl4)-induced hepatotoxicity. Two weeks after CCl4 induction of chronic hepatotoxicity, rats were co-treated with carvedilol (10 mg/kg, orally) daily for 6 weeks. It was found that treatment of animals withmore » carvedilol significantly counteracted the changes in liver function and histopathological lesions induced by CCl4. Also, carvedilol significantly counteracted lipid peroxidation, GSH depletion, and reduction in antioxidant enzyme activities; glutathione-S-transferase and catalase that was induced by CCl4. In addition, carvedilol ameliorated the inflammation induced by CCl4 as indicated by reducing the serum level of acute phase protein marker; alpha-2-macroglobulin and the liver expression of nuclear factor-kappa B (NF-κB). Finally, carvedilol significantly reduced liver fibrosis markers including hydroxyproline, collagen accumulation, and the expression of the hepatic stellate cell (HSC) activation marker; alpha smooth muscle actin. In conclusion, the present study provides evidences for the promising antifibrotic effects of carvedilol that can be explained by amelioration of oxidative stress through mainly, replenishment of GSH, restoration of antioxidant enzyme activities and reduction of lipid peroxides as well as amelioration of inflammation and fibrosis by decreasing collagen accumulation, acute phase protein level, NF-κB expression and finally HSC activation. -- Highlights: ► Carvedilol is a beta blocker with antioxidant and antifibrotic properties. ► It restores GSH and antioxidant enzyme activities and reduces lipid peroxidation. ► It ameliorates inflammation and nuclear factor kappa-B expression. ► It ameliorates fibrosis by decreasing collagen accumulation and HSC activation.« less

Abnormal neural activation patterns underlying working memory impairment in chronic phencyclidine-treated mice.

PubMed

Arime, Yosefu; Akiyama, Kazufumi

2017-01-01

Working memory impairment is a hallmark feature of schizophrenia and is thought be caused by dysfunctions in the prefrontal cortex (PFC) and associated brain regions. However, the neural circuit anomalies underlying this impairment are poorly understood. The aim of this study is to assess working memory performance in the chronic phencyclidine (PCP) mouse model of schizophrenia, and to identify the neural substrates of working memory. To address this issue, we conducted the following experiments for mice after withdrawal from chronic administration (14 days) of either saline or PCP (10 mg/kg): (1) a discrete paired-trial variable-delay task in T-maze to assess working memory, and (2) brain-wide c-Fos mapping to identify activated brain regions relevant to this task performance either 90 min or 0 min after the completion of the task, with each time point examined under working memory effort and basal conditions. Correct responses in the test phase of the task were significantly reduced across delays (5, 15, and 30 s) in chronic PCP-treated mice compared with chronic saline-treated controls, suggesting delay-independent impairments in working memory in the PCP group. In layer 2-3 of the prelimbic cortex, the number of working memory effort-elicited c-Fos+ cells was significantly higher in the chronic PCP group than in the chronic saline group. The main effect of working memory effort relative to basal conditions was to induce significantly increased c-Fos+ cells in the other layers of prelimbic cortex and the anterior cingulate and infralimbic cortex regardless of the different chronic regimens. Conversely, this working memory effort had a negative effect (fewer c-Fos+ cells) in the ventral hippocampus. These results shed light on some putative neural networks relevant to working memory impairments in mice chronically treated with PCP, and emphasize the importance of the layer 2-3 of the prelimbic cortex of the PFC.

Abnormal neural activation patterns underlying working memory impairment in chronic phencyclidine-treated mice

PubMed Central

Akiyama, Kazufumi

2017-01-01

Working memory impairment is a hallmark feature of schizophrenia and is thought be caused by dysfunctions in the prefrontal cortex (PFC) and associated brain regions. However, the neural circuit anomalies underlying this impairment are poorly understood. The aim of this study is to assess working memory performance in the chronic phencyclidine (PCP) mouse model of schizophrenia, and to identify the neural substrates of working memory. To address this issue, we conducted the following experiments for mice after withdrawal from chronic administration (14 days) of either saline or PCP (10 mg/kg): (1) a discrete paired-trial variable-delay task in T-maze to assess working memory, and (2) brain-wide c-Fos mapping to identify activated brain regions relevant to this task performance either 90 min or 0 min after the completion of the task, with each time point examined under working memory effort and basal conditions. Correct responses in the test phase of the task were significantly reduced across delays (5, 15, and 30 s) in chronic PCP-treated mice compared with chronic saline-treated controls, suggesting delay-independent impairments in working memory in the PCP group. In layer 2–3 of the prelimbic cortex, the number of working memory effort-elicited c-Fos+ cells was significantly higher in the chronic PCP group than in the chronic saline group. The main effect of working memory effort relative to basal conditions was to induce significantly increased c-Fos+ cells in the other layers of prelimbic cortex and the anterior cingulate and infralimbic cortex regardless of the different chronic regimens. Conversely, this working memory effort had a negative effect (fewer c-Fos+ cells) in the ventral hippocampus. These results shed light on some putative neural networks relevant to working memory impairments in mice chronically treated with PCP, and emphasize the importance of the layer 2–3 of the prelimbic cortex of the PFC. PMID:29253020

The Neural Correlates of Chronic Symptoms of Vertigo Proneness in Humans

PubMed Central

Alsalman, Ola; Ost, Jan; Vanspauwen, Robby; Blaivie, Catherine; De Ridder, Dirk; Vanneste, Sven

2016-01-01

Vestibular signals are of significant importance for variable functions including gaze stabilization, spatial perception, navigation, cognition, and bodily self-consciousness. The vestibular network governs functions that might be impaired in patients affected with vestibular dysfunction. It is currently unclear how different brain regions/networks process vestibular information and integrate the information into a unified spatial percept related to somatosensory awareness and whether people with recurrent balance complaints have a neural signature as a trait affecting their development of chronic symptoms of vertigo. Pivotal evidence points to a vestibular-related brain network in humans that is widely distributed in nature. By using resting state source localized electroencephalography in non-vertiginous state, electrophysiological changes in activity and functional connectivity of 23 patients with balance complaints where chronic symptoms of vertigo and dizziness are among the most common reported complaints are analyzed and compared to healthy subjects. The analyses showed increased alpha2 activity within the posterior cingulate cortex and the precuneues/cuneus and reduced beta3 and gamma activity within the pregenual and subgenual anterior cingulate cortex for the subjects with balance complaints. These electrophysiological variations were correlated with reported chronic symptoms of vertigo intensity. A region of interest analysis found reduced functional connectivity for gamma activity within the vestibular cortex, precuneus, frontal eye field, intra-parietal sulcus, orbitofrontal cortex, and the dorsal anterior cingulate cortex. In addition, there was a positive correlation between chronic symptoms of vertigo intensity and increased alpha-gamma nesting in the left frontal eye field. When compared to healthy subjects, there is evidence of electrophysiological changes in the brain of patients with balance complaints even outside chronic symptoms of vertigo episodes. This suggests that these patients have a neural signature or trait that makes them prone to developing chronic balance problems. PMID:27089185

The Neural Correlates of Chronic Symptoms of Vertigo Proneness in Humans.

PubMed

Alsalman, Ola; Ost, Jan; Vanspauwen, Robby; Blaivie, Catherine; De Ridder, Dirk; Vanneste, Sven

2016-01-01

Vestibular signals are of significant importance for variable functions including gaze stabilization, spatial perception, navigation, cognition, and bodily self-consciousness. The vestibular network governs functions that might be impaired in patients affected with vestibular dysfunction. It is currently unclear how different brain regions/networks process vestibular information and integrate the information into a unified spatial percept related to somatosensory awareness and whether people with recurrent balance complaints have a neural signature as a trait affecting their development of chronic symptoms of vertigo. Pivotal evidence points to a vestibular-related brain network in humans that is widely distributed in nature. By using resting state source localized electroencephalography in non-vertiginous state, electrophysiological changes in activity and functional connectivity of 23 patients with balance complaints where chronic symptoms of vertigo and dizziness are among the most common reported complaints are analyzed and compared to healthy subjects. The analyses showed increased alpha2 activity within the posterior cingulate cortex and the precuneues/cuneus and reduced beta3 and gamma activity within the pregenual and subgenual anterior cingulate cortex for the subjects with balance complaints. These electrophysiological variations were correlated with reported chronic symptoms of vertigo intensity. A region of interest analysis found reduced functional connectivity for gamma activity within the vestibular cortex, precuneus, frontal eye field, intra-parietal sulcus, orbitofrontal cortex, and the dorsal anterior cingulate cortex. In addition, there was a positive correlation between chronic symptoms of vertigo intensity and increased alpha-gamma nesting in the left frontal eye field. When compared to healthy subjects, there is evidence of electrophysiological changes in the brain of patients with balance complaints even outside chronic symptoms of vertigo episodes. This suggests that these patients have a neural signature or trait that makes them prone to developing chronic balance problems.

Tandospirone, a 5-HT1A partial agonist, ameliorates aberrant lactate production in the prefrontal cortex of rats exposed to blockade of N-methy-D-aspartate receptors; Toward the therapeutics of cognitive impairment of schizophrenia.

PubMed

Uehara, Takashi; Matsuoka, Tadasu; Sumiyoshi, Tomiki

2014-01-01

Augmentation therapy with serotonin-1A (5-HT1A) receptor partial agonists has been suggested to improve cognitive impairment in patients with schizophrenia. Decreased activity of prefrontal cortex may provide a basis for cognitive deficits of the disease. Lactate plays a significant role in the supply of energy to the brain, and glutamatergic neurotransmission contributes to lactate production. The purposes of this study were to examine the effect of repeated administration (once a daily for 4 days) of tandospirone (0.05 or 5 mg/kg) on brain energy metabolism, as represented by extracellular lactate concentration (eLAC) in the medial prefrontal cortex (mPFC) of a rat model of schizophrenia. Four-day treatment with MK-801, an NMDA-R antagonist, prolonged eLAC elevation induced by foot-shock stress (FS). Co-administration with the high-dose tandospirone suppressed prolonged FS-induced eLAC elevation in rats receiving MK-801, whereas tandospirone by itself did not affected eLAC increment. These results suggest that stimulation of 5-HT1A receptors ameliorates abnormalities of energy metabolism in the mPFC due to blockade of NMDA receptors. These findings provide a possible mechanism, based on brain energy metabolism, by which 5-HT1A agonism improve cognitive impairment of schizophrenia and related disorders.

Capsaicin 8% patch treatment for amputation stump and phantom limb pain: a clinical and functional MRI study

PubMed Central

Privitera, Rosario; Birch, Rolfe; Sinisi, Marco; Mihaylov, Iordan R; Leech, Robert; Anand, Praveen

2017-01-01

Purpose The aim of this study was to measure the efficacy of a single 60 min application of capsaicin 8% patch in reducing chronic amputation stump and phantom limb pain, associated hypersensitivity with quantitative sensory testing, and changes in brain cortical maps using functional MRI (fMRI) scans. Methods A capsaicin 8% patch (Qutenza) treatment study was conducted on 14 patients with single limb amputation, who reported pain intensity on the Numerical Pain Rating Scale ≥4/10 for chronic stump or phantom limb pain. Pain assessments, quantitative sensory testing, and fMRI (for the lip pursing task) were performed at baseline and 4 weeks after application of capsaicin 8% patch to the amputation stump. The shift into the hand representation area of the cerebral cortex with the lip pursing task has been correlated with phantom limb pain intensity in previous studies, and was the fMRI clinical model for cortical plasticity used in this study. Results The mean reduction in spontaneous amputation stump pain, phantom limb pain, and evoked stump pain were −1.007 (p=0.028), −1.414 (p=0.018), and −2.029 (p=0.007), respectively. The areas of brush allodynia and pinprick hypersensitivity in the amputation stump showed marked decreases: −165 cm2, −80% (p=0.001) and −132 cm2, −72% (p=0.001), respectively. fMRI analyses provided objective evidence of the restoration of the brain map, that is, reversal of the shift into the hand representation of the cerebral cortex with the lip pursing task (p<0.05). Conclusion The results show that capsaicin 8% patch treatment leads to significant reduction in chronic pain and, particularly, in the area of stump hypersensitivity, which may enable patients to wear prostheses, thereby improving mobility and rehabilitation. Phantom limb pain (“central” pain) and associated brain plasticity may be modulated by peripheral inputs, as they can be ameliorated by the peripherally restricted effect of the capsaicin 8% patch. PMID:28761369

Hyperactivity and memory/learning deficits evoked by developmental exposure to nicotine and/or ethanol are mitigated by cAMP and cGMP signaling cascades activation.

PubMed

Abreu-Villaça, Yael; Carvalho-Graça, Anna C; Skinner, Gabriela; Lotufo, Bruna M; Duarte-Pinheiro, Vitor H S; Ribeiro-Carvalho, Anderson; Manhães, Alex C; Filgueiras, Claudio C

2018-05-01

Pregnant smoking women are frequently episodic drinkers. Here, we investigated whether ethanol exposure restricted to the brain growth spurt period when combined with chronic developmental exposure to nicotine aggravates memory/learning deficits and hyperactivity, and associated cAMP and cGMP signaling disruption. To further investigate the role of these signaling cascades, we verified whether vinpocetine (a phosphodiesterase inhibitor) ameliorates the neurochemical and behavioral outcomes. Swiss mice had free access to nicotine (NIC, 50 μg/ml) or water to drink during gestation and until the 8th postnatal day (PN8). Ethanol (ETOH, 5 g/kg, i.p.) or saline were injected in the pups every other day from PN2 to PN8. At PN30, animals either received vinpocetine (20 mg/kg, i.p.) or vehicle before being tested in the step-down passive avoidance or open field. Memory/learning was impaired in NIC, ETOH and NIC + ETOH mice, and vinpocetine mitigated ETOH- and NIC + ETOH-induced deficits. Locomotor hyperactivity identified in ETOH and NIC + ETOH mice was ameliorated by vinpocetine. While cyclic nucleotides levels in cerebral cortex and hippocampus were reduced by NIC, ETOH and NIC + ETOH, this outcome was more consistent in the latter group. As observed for behavior, vinpocetine normalized NIC + ETOH nucleotides levels. pCREB levels were also increased in response to vinpocetine, with stronger effects in the NIC + ETOH group. Exposure to both drugs of abuse worsens behavioral and neurochemical disruption. These findings and the amelioration of deleterious effects by vinpocetine support the idea that cAMP and cGMP signaling contribute to nicotine- and ethanol-induced hyperactivity and memory/learning deficits. Copyright © 2018 Elsevier B.V. All rights reserved.

Effect of yokukansan, a traditional Japanese medicine, on social and aggressive behaviour of para-chloroamphetamine-injected rats.

PubMed

Kanno, Hitomi; Sekiguchi, Kyoji; Yamaguchi, Takuji; Terawaki, Kiyoshi; Yuzurihara, Mitsutoshi; Kase, Yoshio; Ikarashi, Yasushi

2009-09-01

Yokukansan, a traditional Japanese medicine, has been approved by the Ministry of Health, Labour, and Welfare of Japan as a remedy for neurosis, insomnia or night crying and irritability in children. It has recently been reported to improve behavioural and psychological symptoms of dementia, such as hallucinations, agitation, and aggressiveness in patients with some forms of senile dementia. Little is known about the mechanism underlying the effectiveness of yokukansan. Our aim was to clarify the involvement of yokukansan in serotonergic function in para-chloroamphetamine (PCA)-induced aggressive behaviour in rats. The effect of yokukansan on social interactions, including social and aggressive behaviour, was examined in PCA-injected rats. Concentration and release level of serotonin (5-HT) in the hypothalamus were measured. PCA reduced not only the 5-HT concentration but also the high K(+)-induced 5-HT release in the rat hypothalamus. Social interaction tests showed a significant decrease in social behaviour and a significant increase in aggressive behaviour in the PCA-treated rats. The decrease in social behaviour was ameliorated by the 5-HT1A agonist buspirone and further decreased by a 5-HT1A antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclo-hexanecarboxamide trihydrochloride (WAY-100635), whereas it was further decreased by the 5-HT2A agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), and ameliorated by the 5-HT2A antagonist ketanserin. On the other hand, the increase in aggressive behaviour was ameliorated by buspirone but not affected by WAY-100635, whereas it was enhanced by DOI and ameliorated by ketanserin. A single injection of yokukansan ameliorated the PCA-induced decrease in social behaviour but not aggressive behaviour. Chronic treatment for 14 days with yokukansan ameliorated PCA-induced abnormal behaviour, decreased social behaviour and increased aggressive behaviour, but it did not ameliorate PCA-induced decreases in the cerebral 5-HT concentration and 5-HT release. The ameliorative effects of chronic yokukansan on behaviour were counteracted by co-administration of WAY-100635. These results suggest that yokukansan might have two different effects: an acute effect on social behaviour and a chronic effect on aggressive behaviour. One of the mechanisms of these effects of yokukansan may be related to the agonistic effect on 5-HT1A receptors.

Dysregulation of major functional genes in frontal cortex by maternal exposure to carbon black nanoparticle is not ameliorated by ascorbic acid pretreatment.

PubMed

Onoda, Atsuto; Takeda, Ken; Umezawa, Masakazu

2018-09-01

Recent cohort studies have revealed that perinatal exposure to particulate air pollution, including carbon-based nanoparticles, increases the risk of brain disorders. Although developmental neurotoxicity is currently a major issue in the toxicology of nanoparticles, critical information for understanding the mechanisms underlying the developmental neurotoxicity of airway exposure to carbon black nanoparticle (CB-NP) is still lacking. In order to investigate these mechanisms, we comprehensively analyzed fluctuations in the gene expression profile of the frontal cortex of offspring mice exposed maternally to CB-NP, using microarray analysis combined with Gene Ontology information. We also analyzed differences in the enriched function of genes dysregulated by maternal CB-NP exposure with and without ascorbic acid pretreatment to refine specific alterations in gene expression induced by CB-NP. Total of 652 and 775 genes were dysregulated by CB-NP in the frontal cortex of 6- and 12-week-old offspring mice, respectively. Among the genes dysregulated by CB-NP, those related to extracellular matrix structural constituent, cellular response to interferon-beta, muscle organ development, and cysteine-type endopeptidase inhibitor activity were ameliorated by ascorbic acid pretreatment. A large proportion of the dysregulated genes, categorized in hemostasis, growth factor, chemotaxis, cell proliferation, blood vessel, and dopaminergic neurotransmission, were, however, not ameliorated by ascorbic acid pretreatment. The lack of effects of ascorbic acid on the dysregulation of genes following maternal CB-NP exposure suggests that the contribution of oxidative stress to the effects of CB-NP on these biological functions, i.e., cell migration and proliferation, blood vessel maintenance, and dopaminergic neuron system, may be limited. At least, ascorbic acid pretreatment is hardly likely to be able to protect the brain of offspring from developmental neurotoxicity of CB-NP. The present study provides insight into the mechanisms underlying developmental neurotoxicity following maternal nanoparticle exposure. Copyright © 2018 Elsevier B.V. All rights reserved.

Rosuvastatin protects against angiotensin II-induced renal injury in a dose-dependent fashion.

PubMed

Park, Joon-Keun; Mervaala, Eero Ma; Muller, Dominik N; Menne, Jan; Fiebeler, Anette; Luft, Friedrich C; Haller, Hermann

2009-03-01

We showed earlier that statin treatment ameliorates target-organ injury in a transgenic model of angiotensin (Ang) II-induced hypertension. We now test the hypothesis that rosuvastatin (1, 10, and 50 mg/kg/day) influences leukocyte adhesion and infiltration, prevents induction of inducible nitric oxide synthase (iNOS), and ameliorates target-organ damage in a dose-dependent fashion. We treated rats harboring the human renin and human angiotensinogen genes (dTGR) from week 4 to 8 (n = 20 per group). Untreated dTGR developed severe hypertension, cardiac hypertrophy, and renal damage, with a 100-fold increased albuminuria and focal cortical necrosis. Mortality of untreated dTGR at age 8 weeks was 59%. Rosuvastatin treatment decreased mortality dose-dependently. Blood pressure was not affected. Albuminuria was reduced dose-dependently. Interstitial adhesion molecule (ICAM)-1 expression was markedly reduced by rosuvastatin, as were neutrophil and monocyte infiltration. Immunohistochemistry showed an increased endothelial and medial iNOS expression in small vessels, infiltrating cells, afferent arterioles, and glomeruli of dTGR. Immunoreactivity was stronger in cortex than medulla. Rosuvastatin markedly reduced the iNOS expression in both cortex and medulla. Finally, matrix protein (type IV collagen, fibronectin) expression was also dose- dependently reduced by rosuvastatin. Our findings indicate that rosuvastatin dose- dependently ameliorates angiotensin II-induced-organ damage and almost completely prevents inflammation at the highest dose. The data implicate 3-hydroxy-3-methylglutaryl coenzyme A function in signaling events leading to target-organ damage.

Gene Expression in Brain and Liver Produced by Three Different Regimens of Alcohol Consumption in Mice: Comparison with Immune Activation

PubMed Central

Osterndorff-Kahanek, Elizabeth; Ponomarev, Igor; Blednov, Yuri A.; Harris, R. Adron

2013-01-01

Chronically available alcohol escalates drinking in mice and a single injection of the immune activator lipopolysaccharide can mimic this effect and result in a persistent increase in alcohol consumption. We hypothesized that chronic alcohol drinking and lipopolysaccharide injections will produce some similar molecular changes that play a role in regulation of alcohol intake. We investigated the molecular mechanisms of chronic alcohol consumption or lipopolysaccharide insult by gene expression profiling in prefrontal cortex and liver of C57BL/6J mice. We identified similar patterns of transcriptional changes among four groups of animals, three consuming alcohol (vs water) in different consumption tests and one injected with lipopolysaccharide (vs. vehicle). The three tests of alcohol consumption are the continuous chronic two bottle choice (Chronic), two bottle choice available every other day (Chronic Intermittent) and limited access to one bottle of ethanol (Drinking in the Dark). Gene expression changes were more numerous and marked in liver than in prefrontal cortex for the alcohol treatments and similar in the two tissues for lipopolysaccharide. Many of the changes were unique to each treatment, but there was significant overlap in prefrontal cortex for Chronic-Chronic Intermittent and for Chronic Intermittent-lipopolysaccharide and in liver all pairs showed overlap. In silico cell-type analysis indicated that lipopolysaccharide had strongest effects on brain microglia and liver Kupffer cells. Pathway analysis detected a prefrontal cortex-based dopamine-related (PPP1R1B, DRD1, DRD2, FOSB, PDNY) network that was highly over-represented in the Chronic Intermittent group, with several genes from the network being also regulated in the Chronic and lipopolysaccharide (but not Drinking in the Dark) groups. Liver showed a CYP and GST centered metabolic network shared in part by all four treatments. We demonstrate common consequences of chronic alcohol consumption and immune activation in both liver and brain and show distinct genomic consequences of different types of alcohol consumption. PMID:23555817

Dendritic Spines in Depression: What We Learned from Animal Models

PubMed Central

Qiao, Hui; Li, Ming-Xing; Xu, Chang; Chen, Hui-Bin; An, Shu-Cheng; Ma, Xin-Ming

2016-01-01

Depression, a severe psychiatric disorder, has been studied for decades, but the underlying mechanisms still remain largely unknown. Depression is closely associated with alterations in dendritic spine morphology and spine density. Therefore, understanding dendritic spines is vital for uncovering the mechanisms underlying depression. Several chronic stress models, including chronic restraint stress (CRS), chronic unpredictable mild stress (CUMS), and chronic social defeat stress (CSDS), have been used to recapitulate depression-like behaviors in rodents and study the underlying mechanisms. In comparison with CRS, CUMS overcomes the stress habituation and has been widely used to model depression-like behaviors. CSDS is one of the most frequently used models for depression, but it is limited to the study of male mice. Generally, chronic stress causes dendritic atrophy and spine loss in the neurons of the hippocampus and prefrontal cortex. Meanwhile, neurons of the amygdala and nucleus accumbens exhibit an increase in spine density. These alterations induced by chronic stress are often accompanied by depression-like behaviors. However, the underlying mechanisms are poorly understood. This review summarizes our current understanding of the chronic stress-induced remodeling of dendritic spines in the hippocampus, prefrontal cortex, orbitofrontal cortex, amygdala, and nucleus accumbens and also discusses the putative underlying mechanisms. PMID:26881133

Behavioral tolerance to lysergic acid diethylamide is associated with reduced serotonin-2A receptor signaling in rat cortex.

PubMed

Gresch, Paul J; Smith, Randy L; Barrett, Robert J; Sanders-Bush, Elaine

2005-09-01

Tolerance is defined as a decrease in responsiveness to a drug after repeated administration. Tolerance to the behavioral effects of hallucinogens occurs in humans and animals. In this study, we used drug discrimination to establish a behavioral model of lysergic acid diethylamide (LSD) tolerance and examined whether tolerance to the stimulus properties of LSD is related to altered serotonin receptor signaling. Rats were trained to discriminate 60 microg/kg LSD from saline in a two-lever drug discrimination paradigm. Two groups of animals were assigned to either chronic saline treatment or chronic LSD treatment. For chronic treatment, rats from each group were injected once per day with either 130 microg/kg LSD or saline for 5 days. Rats were tested for their ability to discriminate either saline or 60 microg/kg LSD, 24 h after the last chronic injection. Rats receiving chronic LSD showed a 44% reduction in LSD lever selection, while rats receiving chronic vehicle showed no change in percent choice on the LSD lever. In another group of rats receiving the identical chronic LSD treatment, LSD-stimulated [35S]GTPgammaS binding, an index of G-protein coupling, was measured in the rat brain by autoradiography. After chronic LSD, a significant reduction in LSD-stimulated [35S]GTPgammaS binding was observed in the medial prefrontal cortex and anterior cingulate cortex. Furthermore, chronic LSD produced a significant reduction in 2,5-dimethoxy-4-iodoamphetamine-stimulated [35S]GTPgammaS binding in medial prefrontal cortex and anterior cingulate cortex, which was blocked by MDL 100907, a selective 5-HT2A receptor antagonist, but not SB206553, a 5-HT2C receptor antagonist, indicating a reduction in 5-HT2A receptor signaling. 125I-LSD binding to 5-HT2A receptors was reduced in cortical regions, demonstrating a reduction in 5-HT2A receptor density. Taken together, these results indicate that adaptive changes in LSD-stimulated serotonin receptor signaling may mediate tolerance to the discriminative stimulus effects of LSD.

Animal model of dementia induced by entorhinal synaptic damage and partial restoration of cognitive deficits by BDNF and carnitine.

PubMed

Ando, Susumu; Kobayashi, Satoru; Waki, Hatsue; Kon, Kazuo; Fukui, Fumiko; Tadenuma, Tomoko; Iwamoto, Machiko; Takeda, Yasuo; Izumiyama, Naotaka; Watanabe, Kazutada; Nakamura, Hiroaki

2002-11-01

A rat dementia model with cognitive deficits was generated by synapse-specific lesions using botulinum neurotoxin (BoNTx) type B in the entorhinal cortex. To detect cognitive deficits, different tasks were needed depending upon the age of the model animals. Impaired learning and memory with lesions were observed in adult rats using the Hebb-Williams maze, AKON-1 maze and a continuous alternation task in T-maze. Cognitive deficits in lesioned aged rats were detected by a continuous alternation and delayed non-matching-to-sample tasks in T-maze. Adenovirus-mediated BDNF gene expression enhanced neuronal plasticity, as revealed by behavioral tests and LTP formation. Chronic administration of carnitine over time pre- and post-lesions seemed to partially ameliorate the cognitive deficits caused by the synaptic lesion. The carnitine-accelerated recovery from synaptic damage was observed by electron microscopy. These results demonstrate that the BoNTx-lesioned rat can be used as a model for dementia and that cognitive deficits can be alleviated in part by BDNF gene transfer or carnitine administration. Copyright 2002 Wiley-Liss, Inc.

Chlorella vulgaris: A Multifunctional Dietary Supplement with Diverse Medicinal Properties.

PubMed

Panahi, Yunes; Darvishi, Behrad; Jowzi, Narges; Beiraghdar, Fatemeh; Sahebkar, Amirhossein

2016-01-01

Chlorella vulgaris is a green unicellular microalgae with biological and pharmacological properties important for human health. C. vulgaris has a long history of use as a food source and contains a unique and diverse composition of functional macro- and micro-nutrients including proteinsChlorella vulgaris is a green unicellular microalgae with biological and pharmacological properties important for human health. C. vulgaris has a long history of use as a food source and contains a unique and diverse composition of functional macro- and micro-nutrients including proteins, omega-3 polyunsaturated fatty acids, polysaccharides, vitamins and minerals. Clinical trials have suggested that supplementation with C. vulgaris can ameliorate amelioration hyperlipidemia and hyperglycemia, and protect against oxidative stress, cancer and chronic obstructive pulmonary disease. In this review, we summarize the findings on the health benefits of Chlorella supplementation and the molecular mechanisms underlying these effects., omega-3 polyunsaturated fatty acids, polysaccharides, vitamins and minerals. Clinical trials have suggested that supplementation with C. vulgaris can ameliorate amelioration hyperlipidemia and hyperglycemia, and protect against oxidative stress, cancer and chronic obstructive pulmonary disease. In this review, we summarize the findings on the health benefits of Chlorella supplementation and the molecular mechanisms underlying these effects.

Two Chronic Stress Models Based on Movement Restriction in Rats Respond Selectively to Antidepressant Drugs: Aldolase C As a Potential Biomarker.

PubMed

Ampuero, Estibaliz; Luarte, Alejandro; Santibañez, Marcos; Varas-Godoy, Manuel; Toledo, Jorge; Diaz-Veliz, Gabriela; Cavada, Gabriel; Rubio, F Javier; Wyneken, Ursula

2015-03-26

Clinically depressed individuals respond to different types of antidepressants, suggesting that different neurobiological mechanisms may be responsible for their depression. However, animal models to characterize this are not yet available. We induced depressive-like behaviors in rats using 2 different chronic stress models: restraint in small cages or immobilization in adaptable plastic cones. Both models increased anxiety responses evaluated by novelty-suppressed feeding and the elevated plus-maze; increased learned helplessness evaluated by the tail suspension and forced swimming tests; and increased anhedonia evaluated by the sucrose preference test. We assessed the ability of 2 different types of antidepressants to ameliorate depressive-like behaviors. We administered the serotonin reuptake inhibitor fluoxetine or the noradrenaline reuptake inhibitor reboxetine once daily for 28 days to rats that received either chronic restraint or immobilization stress, or no stress. Behavioral analysis revealed that fluoxetine ameliorated depressive-like behaviors when induced by chronic restraint stress, whereas reboxetine ameliorated these behaviors when induced by chronic immobilization stress. To further test biological differences between both models, we evaluated the levels of Aldolase C, an enzyme expressed by forebrain astrocytes that is regulated by antidepressant treatment, in the cerebrospinal fluid: chronic restraint stress, but not immobilization stress, increased the levels of Aldolase C. Moreover, the presence of astrocyte-derived Aldolase C-GFP in the cerebrospinal fluid indicates its central origin. Two stress paradigms induced depressive-like behaviors that were sensitive to different antidepressant treatments. Biomarkers such as Aldolase C could help determine optimal antidepressant treatments for clinically depressed patients. © The Author 2015. Published by Oxford University Press on behalf of CINP.

Effect of Different Forms of Hypokinesia on the Ultrastructure of Limbic, Extrapyramidal and Neocortical Areas of the Rat Brain: Electron Microscopic Study

NASA Astrophysics Data System (ADS)

Zhvania, Mzia G.; Japaridze, Nadezhda J.; Ksovreli, Mariam G.

The effect of chronic restraint stress and chronic hypokinesia "without stress" on the ultrastructure of central and lateral nuclei of amygdala, CA1 and CA3 area of the hippocampus, cingular cortex, nucleus caudatus and motor cortex of adult male rats were elucidated. In some neurons and synapses of abovementioned regions pathological modifications were revealed. More significant alterations provokes chronic restraint stress. Alterations are mostly concentrated: first—in the nuclei of amygdala, then in the CA1 and CA3 areas. Moderate alterations were observed in cingular cortex and nucleus caudatus. In comparing with it, hypokinesia "without stress" provokes only moderate modifications: predominantly in the nucleus caudatus, in lesser degree—in the hippocampus and amygdalae.

Reduced Synapse and Axon Numbers in the Prefrontal Cortex of Rats Subjected to a Chronic Stress Model for Depression

PubMed Central

Csabai, Dávid; Wiborg, Ove; Czéh, Boldizsár

2018-01-01

Stressful experiences can induce structural changes in neurons of the limbic system. These cellular changes contribute to the development of stress-induced psychopathologies like depressive disorders. In the prefrontal cortex of chronically stressed animals, reduced dendritic length and spine loss have been reported. This loss of dendritic material should consequently result in synapse loss as well, because of the reduced dendritic surface. But so far, no one studied synapse numbers in the prefrontal cortex of chronically stressed animals. Here, we examined synaptic contacts in rats subjected to an animal model for depression, where animals are exposed to a chronic stress protocol. Our hypothesis was that long term stress should reduce the number of axo-spinous synapses in the medial prefrontal cortex. Adult male rats were exposed to daily stress for 9 weeks and afterward we did a post mortem quantitative electron microscopic analysis to quantify the number and morphology of synapses in the infralimbic cortex. We analyzed asymmetric (Type I) and symmetric (Type II) synapses in all cortical layers in control and stressed rats. We also quantified axon numbers and measured the volume of the infralimbic cortex. In our systematic unbiased analysis, we examined 21,000 axon terminals in total. We found the following numbers in the infralimbic cortex of control rats: 1.15 × 109 asymmetric synapses, 1.06 × 108 symmetric synapses and 1.00 × 108 myelinated axons. The density of asymmetric synapses was 5.5/μm3 and the density of symmetric synapses was 0.5/μm3. Average synapse membrane length was 207 nm and the average axon terminal membrane length was 489 nm. Stress reduced the number of synapses and myelinated axons in the deeper cortical layers, while synapse membrane lengths were increased. These stress-induced ultrastructural changes indicate that neurons of the infralimbic cortex have reduced cortical network connectivity. Such reduced network connectivity is likely to form the anatomical basis for the impaired functioning of this brain area. Indeed, impaired functioning of the prefrontal cortex, such as cognitive deficits are common in stressed individuals as well as in depressed patients. PMID:29440995

Reducing the harm of stress: medications to rescue the prefrontal cortex and overcome bad habits: the science of stress: focus on the brain, breaking bad habits, and chronic disease.

PubMed

Jin, Lu E

2011-12-01

Our brain is sensitive to stress. Both acute and chronic stress cause cognitive deficits and induce chronic disorders such as drug addiction. In a June 2011 conference at Yale entitled "The Science of Stress: Focus on the Brain, Breaking Bad Habits, and Chronic Disease," Drs. Amy Arnsten and Sherry Mckee discussed the roles of prefrontal cortex in the treatment of stress impairments and addiction. Medications to strengthen the prefrontal function, such as prazosin and guanfacine, may reduce the harm of stress and help overcome smoking and alcohol abuse.

Serial protocol biopsies to quantify the progression of chronic transplant nephropathy in stable renal allografts.

PubMed

Moreso, F; Lopez, M; Vallejos, A; Giordani, C; Riera, L; Fulladosa, X; Hueso, M; Alsina, J; Grinyó, J M; Serón, D

2001-05-01

To evaluate the utility of intimal thickness and interstitial width as a primary efficacy variable in the design of clinical trials aimed to modify the natural history of chronic allograft nephropathy. A donor and a 4-month protocol biopsy were evaluated in 40 stable grafts according to the Banff schema. In 27 patients, a second protocol biopsy was done at 1 yr. Arterial intimal volume fraction (Vvintima/artery) and cortical interstitial volume fraction (Vvinterstitium/cortex) were estimated with a point counting technique. Chronic Banff scores increased during follow-up, while acute scores reached its peak at 4 months. Vvintima/artery and Vvinterstitium/cortex significantly increased at 4 months, but not at 1 yr. Vvintima/artery at 4 months correlated with donor Vvintima/artery (r = 0.57, p < 0.001), histocompatibility (r = 0.38, p = 0.01) and serum cholesterol (r = 0.31, p = 0.047). Vvinterstitium/cortex at 4 months correlated with recipient body surface area (r = 0.44, p = 0.004) and delayed graft function (p = 0.016). Power calculations showed that Vvintima/artery and Vvinterstitium/cortex allow an important reduction in minimum sample size of a hypothetical trial aimed to prevent chronic allograft nephropathy. Intimal thickening and interstitial widening progresses rapidly during the first 4 months after transplantation and slowly thereafter. These parameters can be considered as a primary efficacy variable in trials aimed to prevent chronic allograft nephropathy.

Multitarget transcranial direct current stimulation for freezing of gait in Parkinson's disease.

PubMed

Dagan, Moria; Herman, Talia; Harrison, Rachel; Zhou, Junhong; Giladi, Nir; Ruffini, Giulio; Manor, Brad; Hausdorff, Jeffrey M

2018-04-01

Recent findings suggest that transcranial direct current stimulation of the primary motor cortex may ameliorate freezing of gait. However, the effects of multitarget simultaneous stimulation of motor and cognitive networks are mostly unknown. The objective of this study was to evaluate the effects of multitarget transcranial direct current stimulation of the primary motor cortex and left dorsolateral prefrontal cortex on freezing of gait and related outcomes. Twenty patients with Parkinson's disease and freezing of gait received 20 minutes of transcranial direct current stimulation on 3 separate visits. Transcranial direct current stimulation targeted the primary motor cortex and left dorsolateral prefrontal cortex simultaneously, primary motor cortex only, or sham stimulation (order randomized and double-blinded assessments). Participants completed a freezing of gait-provoking test, the Timed Up and Go, and the Stroop test before and after each transcranial direct current stimulation session. Performance on the freezing of gait-provoking test (P = 0.010), Timed Up and Go (P = 0.006), and the Stroop test (P = 0.016) improved after simultaneous stimulation of the primary motor cortex and left dorsolateral prefrontal cortex, but not after primary motor cortex only or sham stimulation. Transcranial direct current stimulation designed to simultaneously target motor and cognitive regions apparently induces immediate aftereffects in the brain that translate into reduced freezing of gait and improvements in executive function and mobility. © 2018 International Parkinson and Movement Disorder Society. © 2018 International Parkinson and Movement Disorder Society.

Chronic restraint stress promotes learning and memory impairment due to enhanced neuronal endoplasmic reticulum stress in the frontal cortex and hippocampus in male mice.

PubMed

Huang, Rong-Rong; Hu, Wen; Yin, Yan-Yan; Wang, Yu-Chan; Li, Wei-Ping; Li, Wei-Zu

2015-02-01

Chronic stress has been implicated in many types of neurodegenerative diseases, such as Alzheimer's disease (AD). In our previous study, we demonstrated that chronic restraint stress (CRS) induced reactive oxygen species (ROS) overproduction and oxidative damage in the frontal cortex and hippocampus in mice. In the present study, we investigated the effects of CRS (over a period of 8 weeks) on learning and memory impairment and endoplasmic reticulum (ER) stress in the frontal cortex and hippocampus in male mice. The Morris water maze was used to investigate the effects of CRS on learning and memory impairment. Immunohistochemistry and immunoblot analysis were also used to determine the expression levels of protein kinase C α (PKCα), 78 kDa glucose-regulated protein (GRP78), C/EBP-homologous protein (CHOP) and mesencephalic astrocyte-derived neurotrophic factor (MANF). The results revealed that CRS significantly accelerated learning and memory impairment, and induced neuronal damage in the frontal cortex and hippocampus CA1 region. Moreover, CRS significantly increased the expression of PKCα, CHOP and MANF, and decreased that of GRP78 in the frontal cortex and hippocampus. Our data suggest that exposure to CRS (for 8 weeks) significantly accelerates learning and memory impairment, and the mechanisms involved may be related to ER stress in the frontal cortex and hippocampus.

Oxotremorine treatment restores hippocampal neurogenesis and ameliorates depression-like behaviour in chronically stressed rats.

PubMed

Veena, J; Srikumar, B N; Mahati, K; Raju, T R; Shankaranarayana Rao, B S

2011-09-01

Chronic stress results in cognitive impairment, affects hippocampal neurogenesis and is known to precipitate affective disorders such as depression. In addition to stress, neurotransmitters such as acetylcholine (ACh) modulate adult neurogenesis. Earlier, we have shown that oxotremorine, a cholinergic muscarinic agonist, ameliorates stress-induced cognitive impairment and restores cholinergic function. In the current study, we have looked into the possible involvement of adult neurogenesis in cognitive restoration by oxotremorine. Further, we have assessed the effect of oxotremorine treatment on depression-like behaviour and hippocampal volumes in stressed animals. Chronic restraint stressed rats were treated with either vehicle or oxotremorine. For neurogenesis studies, proliferation, survival and differentiation of the progenitor cells in the hippocampus were examined using 5'-bromo-2-deoxyuridine immunohistochemistry. Depression-like behaviour was evaluated using forced swim test (FST) and sucrose consumption test (SCT). Volumes were estimated using Cavalieri's estimator. Hippocampal neurogenesis was severely decreased in stressed rats. Ten days of oxotremorine treatment to stressed animals partially restored proliferation and survival, while it completely restored the differentiation of the newly formed cells. Stressed rats showed increased immobility and decreased sucrose preference in the FST and SCT, respectively, and oxotremorine ameliorated this depression-like behaviour. In addition, oxotremorine treatment recovered the stress-induced decrease in hippocampal volume. These results indicate that the restoration of impaired neurogenesis and hippocampal volume could be associated with the behavioural recovery by oxotremorine. Our results imply the muscarinic regulation of adult neurogenesis and incite the potential utility of cholinomimetics in ameliorating cognitive dysfunction in stress-related disorders.

NGFI-B and nor1 mRNAs are upregulated in brain reward pathways by drugs of abuse: different effects in Fischer and Lewis rats.

PubMed

Werme, M; Olson, L; Brené, S

2000-03-10

The two inbred Fischer and Lewis rat strains display differences in acquisition of drug self-administration, suggesting genetic factors controlling the vulnerability to drugs of abuse. In this study, we analyzed the effects of acute and chronic cocaine and morphine on mRNAs encoding the NGFI-B/Nur77 family of nuclear orphan receptors in reward pathways in Fischer and Lewis rats. After a single injection of cocaine, a similar upregulation of NGFI-B mRNA in striatal subregions and cortex cinguli was seen in both Fischer and Lewis rats. In contrast, Nor1 mRNA was only significantly upregulated by cocaine in the Fischer rats. Morphine increased NGFI-B mRNA in medial caudate putamen and cortex cinguli in Lewis rats and Nor1 mRNA in medial caudate putamen in Fischer rats. Chronic cocaine upregulated NGFI-B mRNA in nucleus accumbens core, lateral caudate putamen and cingulate cortex in Fischer rats, whereas no effect was seen in Lewis rats. In contrast, Nor1 mRNA levels were upregulated in Lewis rats in medial caudate putamen and cingulate cortex after chronic cocaine and in cingulate cortex after chronic morphine. No effect on Nor1 mRNA levels was seen in Fischer rats after chronic treatments. Our results demonstrate different responses in addiction-prone Lewis rats as compared to the less addiction-prone Fischer rats with respect to NGFI-B and Nor1 mRNA regulation after acute and repeated administration of cocaine and morphine. Thus, we suggest that the transcription factors NGFI-B and Nor1 might be involved in the control of behaviors such as sensitized locomotor response, craving and aversion that appears after repeated administration of abused drugs.

Effects of Crocin on Learning and Memory in Rats Under Chronic Restraint Stress with Special Focus on the Hippocampal and Frontal Cortex Corticosterone Levels

PubMed Central

Dastgerdi, Azadehalsadat Hosseini; Radahmadi, Maryam; Pourshanazari, Ali Asghar; Dastgerdi, Hajaralsadat Hosseini

2017-01-01

Background: Chronic stress adversely influences brain functions while crocin, as an effective component of saffron, exhibits positive effects on memory processes. This study investigated the effects of different doses of crocin on the improvement of learning and memory as well as corticosterone (CORT) levels in the hippocampus and frontal cortex of rats subjected to chronic stress. Materials and Methods: Forty male rats were randomly allocated to five different groups (n = 8): Control, sham; stress (6 h/day for 21 days) groups, and two groups receiving daily intraperitoneal injections of one of two doses (30 and 60 mg/kg) of crocin accompanied by 21 days of restraint stress. Latency was evaluated as a brain function using the passive avoidance test before and one-day after a foot shock. CORT levels were measured in the homogenized hippocampus and frontal cortex. Results: Results revealed that chronic stress had a significantly (P < 0.01) negative effect on memory. Crocin (30 and 60 mg/kg), however, gave increase to significantly (P < 0.01 and P < 0.05; respectively) improved memory functions in the stressed rats. Furthermore, the CORT levels in the hippocampus and frontal cortex declined significantly (P < 0.05) in the stress group compared to the control. Only a crocin dose of 30 mg/kg was observed modulate significantly (P < 0.05) the CORT levels in the hippocampus and frontal cortex in the stressed group. Conclusions: It was found that the lower crocin dose (30 mg/kg) had more beneficial effects than its higher (60 mg/kg) dose on learning and memory under chronic stress conditions. Moreover, it was speculated that different doses of crocin act on different neurotransmitters and biochemical factors in the brain. PMID:29387668

Effects of Crocin on Learning and Memory in Rats Under Chronic Restraint Stress with Special Focus on the Hippocampal and Frontal Cortex Corticosterone Levels.

PubMed

Dastgerdi, Azadehalsadat Hosseini; Radahmadi, Maryam; Pourshanazari, Ali Asghar; Dastgerdi, Hajaralsadat Hosseini

2017-01-01

Chronic stress adversely influences brain functions while crocin, as an effective component of saffron, exhibits positive effects on memory processes. This study investigated the effects of different doses of crocin on the improvement of learning and memory as well as corticosterone (CORT) levels in the hippocampus and frontal cortex of rats subjected to chronic stress. Forty male rats were randomly allocated to five different groups ( n = 8): Control, sham; stress (6 h/day for 21 days) groups, and two groups receiving daily intraperitoneal injections of one of two doses (30 and 60 mg/kg) of crocin accompanied by 21 days of restraint stress. Latency was evaluated as a brain function using the passive avoidance test before and one-day after a foot shock. CORT levels were measured in the homogenized hippocampus and frontal cortex. Results revealed that chronic stress had a significantly ( P < 0.01) negative effect on memory. Crocin (30 and 60 mg/kg), however, gave increase to significantly ( P < 0.01 and P < 0.05; respectively) improved memory functions in the stressed rats. Furthermore, the CORT levels in the hippocampus and frontal cortex declined significantly ( P < 0.05) in the stress group compared to the control. Only a crocin dose of 30 mg/kg was observed modulate significantly ( P < 0.05) the CORT levels in the hippocampus and frontal cortex in the stressed group. It was found that the lower crocin dose (30 mg/kg) had more beneficial effects than its higher (60 mg/kg) dose on learning and memory under chronic stress conditions. Moreover, it was speculated that different doses of crocin act on different neurotransmitters and biochemical factors in the brain.

Methylphenidate increases glucose uptake in the brain of young and adult rats.

PubMed

Réus, Gislaine Z; Scaini, Giselli; Titus, Stephanie E; Furlanetto, Camila B; Wessler, Leticia B; Ferreira, Gabriela K; Gonçalves, Cinara L; Jeremias, Gabriela C; Quevedo, João; Streck, Emilio L

2015-10-01

Methylphenidate (MPH) is the drug of choice for pharmacological treatment of attention deficit hyperactivity disorder. Studies have pointed to the role of glucose and lactate as well as in the action mechanisms of drugs used to treat these neuropsychiatric diseases. Thus, this study aims to evaluate the effects of MPH administration on lactate release and glucose uptake in the brains of young and adult rats. MPH (1.0, 2.0 and 10.0mg/kg) or saline was injected in young and adult Wistar male rats either acutely (once) or chronically (once daily for 28 days). Then, the levels of lactate release and glucose uptake were assessed in the prefrontal cortex, hippocampus, striatum, cerebellum and cerebral cortex. Chronic MPH treatment increased glucose uptake at the dose of 10.0mg/kg in the prefrontal cortex and striatum, and at the dose of 2.0mg/kg in the cerebral cortex of young rats. In adult rats, an increase in glucose uptake was observed after acute administration of MPH at the dose of 10.0mg/kg in the prefrontal cortex. After chronic treatment, there was an increase in glucose uptake with MPH doses of 2.0 and 10.0mg/kg in the prefrontal cortex, and at an MPH dose of 2.0mg/kg in the striatum of adult rats. The lactate release did not change with either acute or chronic treatments in young or adult rats. These findings indicate that MPH increases glucose consumption in the brain, and that these changes are dependent on age and posology. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Mesenchymal stem cells ameliorate the histopathological changes in a murine model of chronic asthma.

PubMed

Firinci, Fatih; Karaman, Meral; Baran, Yusuf; Bagriyanik, Alper; Ayyildiz, Zeynep Arikan; Kiray, Muge; Kozanoglu, Ilknur; Yilmaz, Osman; Uzuner, Nevin; Karaman, Ozkan

2011-08-01

Asthma therapies are effective in reducing inflammation but airway remodeling is poorly responsive to these agents. New therapeutic options that have fewer side effects and reverse chronic changes in the lungs are essential. Mesenchymal stem cells (MSCs) are promising for the development of novel therapies in regenerative medicine. This study aimed to examine the efficacy of MSCs on lung histopathology in a murine model of chronic asthma. BALB/c mice were divided into four groups: Group 1 (control group, n=6), Group 2 (ovalbumin induced asthma only, n=10), Group 3 (ovalbumin induced asthma + MSCs, n=10), and Group 4 (MSCs only, n=10). Histological findings (basement membrane, epithelium, subepithelial smooth muscle thickness, numbers of goblet and mast cells) of the airways and MSC migration were evaluated by light, electron, and confocal microscopes. In Group 3, all early histopathological changes except epithelial thickness and all of the chronic changes were significantly ameliorated when compared with Group 2. Evaluation with confocal microscopy showed that no noteworthy amount of MSCs were present in the lung tissues of Group 4 while significant amount of MSCs was detected in Group 3. Serum NO levels in Group 3, were significantly lower than Group 2. The results of this study revealed that MSCs migrated to lung tissue and ameliorated bronchial asthma in murine model. Further studies are needed to evaluate the efficacy of MSCs for the treatment of asthma. Copyright © 2011 Elsevier B.V. All rights reserved.

ABT-089, but not ABT-107, ameliorates nicotine withdrawal-induced cognitive deficits in C57BL6/J mice

PubMed Central

Yildirim, Emre; Connor, David A.; Gould, Thomas J.

2015-01-01

Nicotine withdrawal produces cognitive deficits that can predict relapse. Amelioration of these cognitive deficits emerges as a target in current smoking cessation therapies. In rodents, withdrawal from chronic nicotine disrupts contextual fear conditioning (CFC), whereas acute nicotine enhances this hippocampus-specific learning and memory. These modifications are mediated by β2-subunit-containing (β2*) nicotinic acetylcholine receptors in the hippocampus. We aimed to test ABT-089, a partial agonist of α4β2*, and ABT-107, an α7 nicotinic acetylcholine receptor agonist, for amelioration of cognitive deficits induced by withdrawal from chronic nicotine in mice. Mice underwent chronic nicotine administration (12.6 mg/kg/day or saline for 12 days), followed by 24 h of withdrawal. At the end of withdrawal, mice received 0.3 or 0.6 mg/kg ABT-089 or 0.3 mg/kg ABT-107 (doses were determined through initial dose–response experiments and prior studies) and were trained and tested for CFC. Nicotine withdrawal produced deficits in CFC that were reversed by acute ABT-089, but not ABT-107. Cued conditioning was not affected. Taken together, our results suggest that modulation of hippocampal learning and memory using ABT-089 may be an effective component of novel therapeutic strategies for nicotine addiction. PMID:25426579

Resistant starch alters gut microbiome and metabolomics profiles concurrent with amelioration of chronic kidney disease in rats

USDA-ARS?s Scientific Manuscript database

Patients and animals with chronic kidney disease (CKD) exhibit profound alterations in the gut environment including shifts in microbial composition, increased fecal pH, and increased blood levels of gut microbe-derived metabolites (xeno-metabolites). The fermentable dietary fiber—high amylose maize...

DHEA supplementation to dexamethasone-treated rabbits alleviates oxidative stress in kidney-cortex and attenuates albuminuria.

PubMed

Kiersztan, Anna; Trojan, Nina; Tempes, Aleksandra; Nalepa, Paweł; Sitek, Joanna; Winiarska, Katarzyna; Usarek, Michał

2017-11-01

Our recent study has shown that dehydroepiandrosterone (DHEA) administered to rabbits partially ameliorated several dexamethasone (dexP) effects on hepatic and renal gluconeogenesis, insulin resistance and plasma lipid disorders. In the current investigation, we present the data on DHEA protective action against dexP-induced oxidative stress and albuminuria in rabbits. Four groups of adult male rabbits were used in the in vivo experiment: (1) control, (2) dexP-treated, (3) DHEA-treated and (4) both dexP- and DHEA-treated. Administration of dexP resulted in accelerated generation of renal hydroxyl free radicals (HFR) and malondialdehyde (MDA), accompanied by diminished superoxide dismutase (SOD) and catalase activities and a dramatic rise in urinary albumin/creatinine ratio. Treatment with DHEA markedly reduced dexP-induced oxidative stress in kidney-cortex due to a decline in NADPH oxidase activity and enhancement of catalase activity. Moreover, DHEA effectively attenuated dexP-evoked albuminuria. Surprisingly, dexP-treated rabbits exhibited elevation of GSH/GSSG ratio, accompanied by a decrease in glutathione peroxidase (GPx) and glutathione-S-transferase (GST) activities as well as an increase in glucose-6-phosphate dehydrogenase (G6PDH) activity. Treatment with DHEA resulted in a decline in GSH/GSSG ratio and glutathione reductase (GR) activity, accompanied by an elevation of GPx activity. Interestingly, rabbits treated with both dexP and DHEA remained the control values of GSH/GSSG ratio. As the co-administration of DHEA with dexP resulted in (i) reduction of oxidative stress in kidney-cortex, (ii) attenuation of albuminuria and (iii) normalization of glutathione redox state, DHEA might limit several undesirable renal side effects during chronic GC treatment of patients suffering from allergies, asthma, rheumatoid arthritis and lupus. Moreover, its supplementation might be particularly beneficial for the therapy of patients with glucocorticoid-induced diabetes. Copyright © 2017 Elsevier Ltd. All rights reserved.

Differential effects of chronic lorazepam and alprazolam on benzodiazepine binding and GABAA-receptor function.

PubMed Central

Galpern, W. R.; Miller, L. G.; Greenblatt, D. J.; Shader, R. I.

1990-01-01

1. Chronic benzodiazepine administration has been associated with tolerance and with downregulation of gamma-aminobutyric acidA (GABAA)-receptor binding and function. However, effects of individual benzodiazepines on brain regions have varied. 2. To compare the effects of chronic lorazepam and alprazolam, we have administered these drugs to mice for 1 and 7 days (2 mg kg-1 day-1) and determined benzodiazepine receptor binding in vivo with and without administration of CL 218,872, 25 mg kg-1 i.p., and GABA-dependent chloride uptake in 3 brain regions at these time points. 3. Benzodiazepine binding was decreased in the cortex and hippocampus at day 7 compared to day 1 of lorazepam, with an increase in CL 218,872-resistant (Type 2) sites in both regions. Maximal GABA-dependent chloride uptake was also decreased in the cortex and hippocampus at day 7. 4. Binding was decreased only in the cortex after 7 days of alprazolam, with no significant change in Type 2 binding. Maximal GABA-dependent chloride uptake was also decreased only in the cortex. 5. These data suggest that the effects of chronic benzodiazepine administration on the GABAA-receptor may be both region-specific and receptor subtype-specific. PMID:1964820

Role of insular cortex in visceral hypersensitivity model in rats subjected to chronic stress.

PubMed

Yi, LiSha; Sun, HuiHui; Ge, Chao; Chen, Ying; Peng, HaiXia; Jiang, YuanXi; Wu, Ping; Tang, YinHan; Meng, QingWei; Xu, ShuChang

2014-12-30

Abnormal processing of visceral sensation at the level of the central nervous system has been proven to be important in the pathophysiologic mechanisms of stress related functional gastrointestinal disorders. However, the specific mechanism is still not clear. The insular cortex (IC) was considered as one important visceral sensory area. Moreover, the IC has been shown to be involved in various neuropsychiatric diseases such as panic disorders and post-traumatic stress disorder. However, whether the IC is important in psychological stress related visceral hypersensitivity has not been studied yet. In our study, through destruction of the bilateral IC, we explored whether the IC played a critical role in the formation of visceral hypersensitivity induced by chronic stress on rats. Chronic partial restraint stress was used to establish viscerally hypersensitive rat model. Bilateral IC lesions were generated by N-methyl-D-day (door) aspartate. After a recovery period of 7 days, 14-day consecutive restraint stress was performed. The visceromotor response to colorectal distension was monitored by recording electromyogram to measure rats׳ visceral sensitivity. We found that bilateral insular cortex lesion could markedly inhibit the formation of visceral hypersensitivity induced by chronic stress. The insular cortex plays a critical role in the pathophysiology of stress-related visceral hypersensitivity.

Ventromedial prefrontal cortex stimulation enhances memory and hippocampal neurogenesis in the middle-aged rats

PubMed Central

Liu, Albert; Jain, Neeraj; Vyas, Ajai; Lim, Lee Wei

2015-01-01

Memory dysfunction is a key symptom of age-related dementia. Although recent studies have suggested positive effects of electrical stimulation for memory enhancement, its potential targets remain largely unknown. In this study, we hypothesized that spatially targeted deep brain stimulation of ventromedial prefrontal cortex enhanced memory functions in a middle-aged rat model. Our results show that acute stimulation enhanced the short-, but not the long-term memory in the novel-object recognition task. Interestingly, after chronic high-frequency stimulation, both the short- and long-term memories were robustly improved in the novel-object recognition test and Morris water-maze spatial task compared to sham. Our results also demonstrated that chronic ventromedial prefrontal cortex high-frequency stimulation upregulated neurogenesis-associated genes along with enhanced hippocampal cell proliferation. Importantly, these memory behaviors were strongly correlated with the hippocampal neurogenesis. Overall, these findings suggest that chronic ventromedial prefrontal cortex high-frequency stimulation may serve as a novel effective therapeutic target for dementia-related disorders. DOI: http://dx.doi.org/10.7554/eLife.04803.001 PMID:25768425

Benefits of agomelatine in behavioral, neurochemical and blood brain barrier alterations in prenatal valproic acid induced autism spectrum disorder.

PubMed

Kumar, Hariom; Sharma, B M; Sharma, Bhupesh

2015-12-01

Valproic acid administration during gestational period causes behavior and biochemical deficits similar to those observed in humans with autism spectrum disorder. Although worldwide prevalence of autism spectrum disorder has been increased continuously, therapeutic agents to ameliorate the social impairment are very limited. The present study has been structured to investigate the therapeutic potential of melatonin receptor agonist, agomelatine in prenatal valproic acid (Pre-VPA) induced autism spectrum disorder in animals. Pre-VPA has produced reduction in social interaction (three chamber social behavior apparatus), spontaneous alteration (Y-Maze), exploratory activity (Hole board test), intestinal motility, serotonin levels (prefrontal cortex and ileum) and prefrontal cortex mitochondrial complex activity (complex I, II, IV). Furthermore, Pre-VPA has increased locomotor activity (actophotometer), anxiety, brain oxidative stress (thiobarbituric acid reactive species, glutathione, and catalase), nitrosative stress (nitrite/nitrate), inflammation (brain and ileum myeloperoxidase activity), calcium levels and blood brain barrier leakage in animals. Treatment with agomelatine has significantly attenuated Pre-VPA induced reduction in social interaction, spontaneous alteration, exploratory activity intestinal motility, serotonin levels and prefrontal cortex mitochondrial complex activity. Furthermore, agomelatine also attenuated Pre-VPA induced increase in locomotion, anxiety, brain oxidative stress, nitrosative stress, inflammation, calcium levels and blood brain barrier leakage. It is concluded that, Pre-VPA has induced autism spectrum disorder, which was attenuated by agomelatine. Agomelatine has shown ameliorative effect on behavioral, neurochemical and blood brain barrier alteration in Pre-VPA exposed animals. Thus melatonin receptor agonists may provide beneficial therapeutic strategy for managing autism spectrum disorder. Copyright © 2015 Elsevier Ltd. All rights reserved.

Sodium Phenylbutyrate and Edaravone Abrogate Chronic Restraint Stress-Induced Behavioral Deficits: Implication of Oxido-Nitrosative, Endoplasmic Reticulum Stress Cascade, and Neuroinflammation.

PubMed

Jangra, Ashok; Sriram, Chandra Shaker; Dwivedi, Shubham; Gurjar, Satendra Singh; Hussain, Md Iftikar; Borah, Probodh; Lahkar, Mangala

2017-01-01

Chronic stress exposure can produce deleterious effects on the hippocampus (HC) which eventually leads to cognitive impairment and depression. Endoplasmic reticulum (ER) stress has been reported as one of the major culprits in the development of stress-induced cognitive impairment and depression. We investigated the neuroprotective efficacy of sodium phenylbutyrate (SPB), an ER stress inhibitor, and edaravone, a free radical scavenger, against chronic restraint stress (CRS)-induced cognitive deficits and anxiety- and depressive-like behavior in mice. Adult male Swiss albino mice were restrained for 6 h/day for 28 days and injected (i.p.) with SPB (40 and 120 mg/kg) or edaravone (3 and 10 mg/kg) for the last seven days. After stress cessation, the anxiety- and depressive-like behavior along with spatial learning and memory were examined. Furthermore, oxido-nitrosative stress, proinflammatory cytokines, and gene expression level of ER stress-related genes were assessed in HC and prefrontal cortex (PFC). CRS-exposed mice showed anxiety- and depressive-like behavior, which was significantly improved by SPB and edaravone treatment. In addition, SPB and edaravone treatment significantly alleviated CRS-induced spatial learning and memory impairment. Furthermore, CRS-evoked oxido-nitrosative stress, neuroinflammation, and depletion of Brain-derived neurotrophic factor were significantly ameliorated by SPB and edaravone treatment. We found significant up-regulation of ER stress-related genes in both HC and PFC regions, which were suppressed by SPB and edaravone treatment in CRS mice. Our study provides evidence that SPB and edaravone exerted neuroprotective effects on CRS-induced cognitive deficits and anxiety- and depressive-like behavior, which is possibly coupled with inhibition of oxido-nitrosative stress, neuroinflammation, and ER stress cascade.

Antipsychotic activity of standardized Bacopa extract against ketamine-induced experimental psychosis in mice: Evidence for the involvement of dopaminergic, serotonergic, and cholinergic systems.

PubMed

Chatterjee, Manavi; Verma, Rajkumar; Kumari, Reena; Singh, Seema; Verma, Anil Kumar; Dwivedi, Anil Kumar; Palit, Gautam

2015-01-01

Schizophrenia is a chronic disabling psychiatric disorder affecting 1% of the population worldwide. Due to the adverse effects of available antipsychotic medications, recent investigations have focused on the search for well-tolerated, safe molecules from natural resources to control the severity and progression of schizophrenia. To screen the standardized extract of Bacopa monniera Linn. (Scrophulariaceae) (BM) for its antipsychotic potential in the ketamine-induced psychosis model with mice. Graded dose of BM (40, 80, and 120 mg/kg, p.o.) were given to the mice 1 h prior to ketamine administration and tested for positive symptoms and cognitive deficits. A chronic ketamine treatment regimen was used to study the effect of BM on negative symptoms such as immobility enhancement. Each mouse was used once for the behavioral studies. BM reduced ketamine-induced hyperactivity with an EC50 value of 76.60 mg/kg. The 80 mg/kg dose was used for all other behavior analysis. Pretreatment with BM at 80 mg/kg showed two-fold increases in transfer latency time (TLT) in passive avoidance task. Chronic BM pretreatment (80 mg/kg p.o. daily × 10 d) ameliorated the ketamine-induced enhanced immobility effect by 21% in the forced swim test. BM treatment reversed ketamine-induced increase in monoamine oxidase activity in both cortex and striatum and normalized the acetylcholinesterase activity and the glutamate levels in the hippocampus. Overall our findings suggest that BM possesses antipsychotic properties which might be due to its modulatory action on dopamine, serotonin, and glutamate neurotransmission.

Less contribution of mast cells to the progression of renal fibrosis in Rat kidneys with chronic renal failure.

PubMed

Baba, Asuka; Tachi, Masahiro; Ejima, Yutaka; Endo, Yasuhiro; Toyama, Hiroaki; Saito, Kazutomo; Abe, Nozomu; Yamauchi, Masanori; Miura, Chieko; Kazama, Itsuro

2017-02-01

Chronic renal failure (CRF) is histopathologically characterized by tubulointerstitial fibrosis in addition to glomerulosclerosis. Although mast cells are known to infiltrate into the kidneys with chronic inflammation, we know little about their contribution to the pathogenesis of renal fibrosis associated with CRF. The aim of this study was to reveal the involvement of mast cells in the progression of renal fibrosis in CRF. Using a rat model with CRF resulting from 5/6 nephrectomy, we examined the histopathological features of the kidneys and the infiltration of mast cells into the renal interstitium. By treating the rats with a potent mast cell stabilizer, tranilast, we also examined the involvement of mast cells in the progression of renal fibrosis associated with CRF. The CRF rat kidneys were characterized by the wide staining of collagen III and increased number of myofibroblasts, indicating the progression of renal fibrosis. Compared to T-lymphocytes or macrophages, the number of tryptase-positive mast cells was much smaller within the fibrotic kidneys and they did not proliferate in situ. The mRNA expression of mast cell-derived fibroblast-activating factors was not increased in the renal cortex isolated from CRF rat kidneys. Treatment with tranilast did not suppress the progression of renal fibrosis, nor did it ameliorate the progression of glomerulosclerosis and the interstitial proliferation of inflammatory leukocytes. This study demonstrated for the first time that mast cells are neither increased nor activated in the fibrotic kidneys of CRF rats. Compared to T-lymphocytes or macrophages that proliferate in situ within the fibrotic kidneys, mast cells were less likely to contribute to the progression of renal fibrosis associated with CRF. © 2016 Asian Pacific Society of Nephrology.

Transglutaminase 2 overexpression induces depressive-like behavior and impaired TrkB signaling in mice

PubMed Central

Pandya, Chirayu D; Hoda, Nasrul; Crider, Amanda; Peter, Diya; Kutiyanawalla, Ammar; Kumar, Sanjiv; Ahmed, Anthony O; Turecki, Gustavo; Hernandez, Caterina M; Terry, Alvin V

2016-01-01

Serotonin (5-HT) and brain derived neurotrophic factor (BDNF) are two signaling molecules that play important regulatory roles in the development and plasticity of neural circuits that are known to be altered in depression. However, the mechanism by which 5-HT regulates BDNF signaling is unknown. In the present study, we found that 5-HT treatment increases BDNF receptor, TrkB (tropomyosin related kinase B) levels in mouse primary cortical neurons via a Rac1 (RAS-related C3 botulinum toxin substrate 1)-dependent mechanism. Significant increases in the levels of transglutaminase 2 (TG2, which is implicated in transamidation of 5-HT to Rac1) are observed in the mouse prefrontal cortex (PFC) following chronic exposure to stress. We also found that TG2 levels are increased in the postmortem PFC of depressed suicide subjects relative to matched controls. Moreover, in mice, neuronal overexpression of TG2 resulted in the atrophy of neurons and reduced levels of TrkB in the PFC as well as a depressive-like phenotype. Overexpression of TG2 in mouse cortical neurons reduced TrkB levels as a result of impaired endocytosis of TrkB. TG2 inhibition by either a viral particle or pharmacological approach attenuated behavioral deficits caused by chronic unpredictable stress. Moreover, the overexpression of TrkB in the mouse PFC ameliorated the depressive-like phenotype of TG2 overexpressed mice. Taken together, these postmortem and preclinical findings identify TG2 as a critical mediator of the altered TrkB expression and depressive-like behaviors associated with chronic exposure to stress and suggest that TG2 may represent a novel therapeutic target in depression. PMID:27620841

38 CFR 4.43 - Osteomyelitis.

Code of Federal Regulations, 2013 CFR

2013-07-01

... DISABILITIES Disability Ratings The Musculoskeletal System § 4.43 Osteomyelitis. Chronic, or recurring, suppurative osteomyelitis, once clinically identified, including chronic inflammation of bone marrow, cortex...

38 CFR 4.43 - Osteomyelitis.

Code of Federal Regulations, 2012 CFR

2012-07-01

... DISABILITIES Disability Ratings The Musculoskeletal System § 4.43 Osteomyelitis. Chronic, or recurring, suppurative osteomyelitis, once clinically identified, including chronic inflammation of bone marrow, cortex...

38 CFR 4.43 - Osteomyelitis.

Code of Federal Regulations, 2011 CFR

2011-07-01

... DISABILITIES Disability Ratings The Musculoskeletal System § 4.43 Osteomyelitis. Chronic, or recurring, suppurative osteomyelitis, once clinically identified, including chronic inflammation of bone marrow, cortex...

38 CFR 4.43 - Osteomyelitis.

Code of Federal Regulations, 2010 CFR

2010-07-01

... DISABILITIES Disability Ratings The Musculoskeletal System § 4.43 Osteomyelitis. Chronic, or recurring, suppurative osteomyelitis, once clinically identified, including chronic inflammation of bone marrow, cortex...

38 CFR 4.43 - Osteomyelitis.

Code of Federal Regulations, 2014 CFR

2014-07-01

... DISABILITIES Disability Ratings The Musculoskeletal System § 4.43 Osteomyelitis. Chronic, or recurring, suppurative osteomyelitis, once clinically identified, including chronic inflammation of bone marrow, cortex...

Disrupted prediction errors index social deficits in autism spectrum disorder

PubMed Central

Balsters, Joshua H; Apps, Matthew A J; Bolis, Dimitris; Lehner, Rea; Gallagher, Louise; Wenderoth, Nicole

2017-01-01

Abstract Social deficits are a core symptom of autism spectrum disorder; however, the perturbed neural mechanisms underpinning these deficits remain unclear. It has been suggested that social prediction errors—coding discrepancies between the predicted and actual outcome of another’s decisions—might play a crucial role in processing social information. While the gyral surface of the anterior cingulate cortex signalled social prediction errors in typically developing individuals, this crucial social signal was altered in individuals with autism spectrum disorder. Importantly, the degree to which social prediction error signalling was aberrant correlated with diagnostic measures of social deficits. Effective connectivity analyses further revealed that, in typically developing individuals but not in autism spectrum disorder, the magnitude of social prediction errors was driven by input from the ventromedial prefrontal cortex. These data provide a novel insight into the neural substrates underlying autism spectrum disorder social symptom severity, and further research into the gyral surface of the anterior cingulate cortex and ventromedial prefrontal cortex could provide more targeted therapies to help ameliorate social deficits in autism spectrum disorder. PMID:28031223

The Hepatoprotective Effect of Selenium-Enriched Yeast and Gum Arabic Combination on Carbon Tetrachloride-Induced Chronic Liver Injury in Rats.

PubMed

Hamid, Mohammed; Abdulrahim, Yassin; Liu, Dandan; Qian, Gang; Khan, Alamzeb; Huang, Kehe

2018-02-01

The antioxidant and anti-inflammatory effects of selenium-enriched yeast (SY) and Gum Arabic (GA) have been reported. This study aimed to determine the hepatoprotective effect of SY and GA combination on carbon tetrachloride (CCl 4 )-induced chronic liver injury in rats and to explore their synergistic mechanisms of action. Forty adult male Wistar rats randomly allotted to 5 groups: (A) worked as control, (B) was administered CCl 4 , (C-E) were fed daily by GA, SY, and GA+SY respectively after mixing with basal diet, following CCl 4 -intoxication. GA and SY combination significantly ameliorated CCl 4 -induced reduction in serum total protein with elevation in aspartate transaminase (AST) and alanine transaminase (ALT) in addition to restoring the histopathological changes and hepatic content of hydroxyproline. GA and SY combination was also effective in reducing lipid peroxidation (MDA), consistent with an increase in total antioxidant capacity (T-AOC), glutathione (GSH), superoxide dismutase (SOD) activities, indicating the suppression of liver oxidative stress. Furthermore, liver inflammation was ameliorated by GA and SY combination through inhibition of nuclear factor-kappa (NF-κB), tumor necrosis factor-alpha (TNF-α), cyclooxygenase-2(COX-2), monocyte chemotactic protein-1 (MCP-1), and toll-like receptor 4(TLR-4) over expression in the liver. Moreover, the up-regulation of proliferating cell nuclear antigen (PCNA) expression by GA and SY combination enhanced the regeneration of liver tissue after CCl 4 -administration. The expression of Collagen1, alpha-smooth muscle actin (α-SMA), and transforming growth factor-beta1 (TGFβ1), was obviously ameliorated by GA and SY combination, suggesting the amelioration of profibrotic response of the liver. Taken together, our current study suggests that GA and SY combination exhibit a significant hepatoprotective activity, which more efficient than GA or SY alone. Chronic liver diseases are the serious health problems, which increase the morbidity and mortality in the world today. Selenium-enriched yeast (SY) and Gum Arabic (GA) combination might be potential dietary agents could obviously ameliorate chronic liver damage, higher than GA and SY alone. They act to suppress the inflammation and inhibit the profibrotic response as well as support the liver regeneration. © 2018 Institute of Food Technologists®.

Altered structural connectivity of pain-related brain network in burning mouth syndrome-investigation by graph analysis of probabilistic tractography.

PubMed

Wada, Akihiko; Shizukuishi, Takashi; Kikuta, Junko; Yamada, Haruyasu; Watanabe, Yusuke; Imamura, Yoshiki; Shinozaki, Takahiro; Dezawa, Ko; Haradome, Hiroki; Abe, Osamu

2017-05-01

Burning mouth syndrome (BMS) is a chronic intraoral pain syndrome featuring idiopathic oral pain and burning discomfort despite clinically normal oral mucosa. The etiology of chronic pain syndrome is unclear, but preliminary neuroimaging research has suggested the alteration of volume, metabolism, blood flow, and diffusion at multiple brain regions. According to the neuromatrix theory of Melzack, pain sense is generated in the brain by the network of multiple pain-related brain regions. Therefore, the alteration of pain-related network is also assumed as an etiology of chronic pain. In this study, we investigated the brain network of BMS brain by using probabilistic tractography and graph analysis. Fourteen BMS patients and 14 age-matched healthy controls underwent 1.5T MRI. Structural connectivity was calculated in 83 anatomically defined regions with probabilistic tractography of 60-axis diffusion tensor imaging and 3D T1-weighted imaging. Graph theory network analysis was used to evaluate the brain network at local and global connectivity. In BMS brain, a significant difference of local brain connectivity was recognized at the bilateral rostral anterior cingulate cortex, right medial orbitofrontal cortex, and left pars orbitalis which belong to the medial pain system; however, no significant difference was recognized at the lateral system including the somatic sensory cortex. A strengthened connection of the anterior cingulate cortex and medial prefrontal cortex with the basal ganglia, thalamus, and brain stem was revealed. Structural brain network analysis revealed the alteration of the medial system of the pain-related brain network in chronic pain syndrome.

Dopamine D3 receptor antagonism contributes to blonanserin-induced cortical dopamine and acetylcholine efflux and cognitive improvement.

PubMed

Huang, Mei; Kwon, Sunoh; Oyamada, Yoshihiro; Rajagopal, Lakshmi; Miyauchi, Masanori; Meltzer, Herbert Y

2015-11-01

Blonanserin is a novel atypical antipsychotic drug (APD), which, unlike most atypical APDs, has a slightly higher affinity for dopamine (DA) D2 than serotonin (5-HT)2A receptors, and is an antagonist at both, as well as at D3 receptors. The effects of atypical APDs to enhance rodent cortical, hippocampal, limbic, and dorsal striatal (dSTR) DA and acetylcholine (ACh) release, contribute to their ability to improve novel object recognition (NOR) in rodents treated with sub-chronic (sc) phencyclidine (PCP) and cognitive impairment associated with schizophrenia (CIAS). Here we determined the ability of blonanserin, the D3 antagonist NGB 2904, and the typical APD, haloperidol, a D2 antagonist, to enhance neurotransmitter efflux in the medial prefrontal cortex (mPFC) and dSTR of mice, and to ameliorate the scPCP-induced deficit in NOR in rats. Blonanserin, 10mg/kg, i.p., increased DA, norepinephrine (NE), and ACh efflux in mPFC and dSTR. NGB 2904, 3mg/kg, increased DA and ACh, but not NE, efflux in mPFC, and DA, but not ACh, efflux in dSTR. Haloperidol increased DA and NE efflux in dSTR only. The selective D3 agonist PD 128907 partially blocked the blonanserin-induced cortical ACh, DA, NE and striatal DA efflux. NGB 2904, 3mg/kg, like blonanserin, 1mg/kg, and the combination of sub-effective doses of NGB 2904 and blonanserin (both 0.3mg/kg), ameliorated the scPCP-induced NOR deficit in rats. These results suggest that D3 receptor blockade may contribute to the ability of blonanserin to increase cortical DA and ACh efflux, as well as to restore NOR and improve CIAS. Copyright © 2015 Elsevier Inc. All rights reserved.

Low-protein diet supplemented with ketoacids ameliorates proteinuria in 3/4 nephrectomised rats by directly inhibiting the intrarenal renin-angiotensin system.

PubMed

Zhang, Jia-Ying; Yin, Ying; Ni, Li; Long, Quan; You, Li; Zhang, Qian; Lin, Shan-Yan; Chen, Jing

2016-11-01

Low-protein diet plus ketoacids (LPD+KA) has been reported to decrease proteinuria in patients with chronic kidney diseases (CKD). However, the mechanisms have not been clarified. As over-activation of intrarenal renin-angiotensin system (RAS) has been shown to play a key role in the progression of CKD, the current study was performed to investigate the direct effects of LPD+KA on intrarenal RAS, independently of renal haemodynamics. In this study, 3/4 subtotal renal ablated rats were fed 18 % normal-protein diet (Nx-NPD), 6 % low-protein diet (Nx-LPD) or 5 % low-protein diet plus 1 % ketoacids (Nx-LPD+KA) for 12 weeks. Sham-operated rats fed NPD served as controls. The level of proteinuria and expression of renin, angiotensin II (AngII) and its type 1 receptors (AT1R) in the renal cortex were markedly higher in Nx-NPD group than in the sham group. LPD+KA significantly decreased the proteinuria and inhibited intrarenal RAS activation. To exclude renal haemodynamic impact on intrarenal RAS, the serum samples derived from the different groups were added to the culture medium of mesangial cells. It showed that the serum from Nx-NPD directly induced higher expression of AngII, AT1R, fibronectin and transforming growth factor-β1 in the mesangial cells than in the control group. Nx-LPD+KA serum significantly inhibited these abnormalities. Then, proteomics and biochemical detection suggested that the mechanisms underlying these beneficial effects of LPD+KA might be amelioration of the nutritional metabolic disorders and oxidative stress. In conclusion, LPD+KA could directly inhibit the intrarenal RAS activation, independently of renal haemodynamics, thus attenuating the proteinuria in CKD rats.

Huperzine A alleviates synaptic deficits and modulates amyloidogenic and nonamyloidogenic pathways in APPswe/PS1dE9 transgenic mice.

PubMed

Wang, Ying; Tang, Xi Can; Zhang, Hai Yan

2012-02-01

Huperzine A (HupA) is a potent acetylcholinesterase inhibitor (AChEI) used in the treatment of Alzheimer's disease (AD). Recently, HupA was shown to be active in modulating the nonamyloidogenic metabolism of β-amyloid precursor protein (APP) in APP-transfected human embryonic kidney cell line (HEK293swe). However, in vivo research concerning the mechanism of HupA in APP transgenic mice has not yet been fully elucidated. The present study indicates that the loss of dendritic spine density and synaptotagmin levels in the brain of APPswe/presenilin-1 (PS1) transgenic mice was significantly ameliorated by chronic HupA treatment and provides evidence that this neuroprotection was associated with reduced amyloid plaque burden and oligomeric β-amyloid (Aβ) levels in the cortex and hippocampus of APPswe/PS1dE9 transgenic mice. Our findings further demonstrate that the amelioration effect of HupA on Aβ deposits may be mediated, at least in part, by regulation of the compromised expression of a disintegrin and metalloprotease 10 (ADAM10) and excessive membrane trafficking of β-site APP cleavage enzyme 1 (BACE1) in these transgenic mice. In addition, extracellular signal-regulated kinases 1/2 (Erk1/2) phosphorylation may also be partially involved in the effect of HupA on APP processing. In conclusion, our work for the first time demonstrates the neuroprotective effect of HupA on synaptic deficits in APPswe/PS1dE9 transgenic mice and further clarifies the potential pharmacological targets for this protective effect, in which modulation of nonamyloidogenic and amyloidogenic APP processing pathways may be both involved. These findings may provide adequate evidence for the clinical and experimental benefits gained from HupA treatment. Copyright © 2011 Wiley Periodicals, Inc.

Up-regulation of glyoxalase 1 by mangiferin prevents diabetic nephropathy progression in streptozotocin-induced diabetic rats.

PubMed

Liu, Yao-Wu; Zhu, Xia; Zhang, Liang; Lu, Qian; Wang, Jian-Yun; Zhang, Fan; Guo, Hao; Yin, Jia-Le; Yin, Xiao-Xing

2013-12-05

Advanced glycation endproducts (AGEs) and its precursor methylglyoxal are associated with diabetic nephropathy (DN). Mangiferin has many beneficial biological activities, including anti-inflammatory, anti-oxidative and anti-diabetic effects. We investigated the effect of mangiferin on DN and its potential mechanism associated with glyoxalase 1 (Glo-1), a detoxifying enzyme of methylglyoxal, in streptozotocin-induced rat model of DN. Diabetic rats were treated orally with mangiferin (15, 30, and 60 mg/kg) or distilled water for 9 weeks. Kidney tissues were collected for morphologic observation and the determination of associated biochemical parameters. The cultured mesangial cells were used to measure the activity of Glo-1 in vitro. Chronic treatment with mangiferin significantly ameliorated renal dysfunction in diabetic rats, as evidenced by decreases in albuminuria, blood urea nitrogen, kidney weight index, periodic acid-schiff stain positive mesangial matrix area, glomerular extracellular matrix expansion and accumulation, and glomerular basement membrane thickness. Meanwhile, mangiferin treatment caused substantial increases in the enzymatic activity of Glo-1 in vivo and in vitro, and protein and mRNA expression of Glo-1, reduced levels of AGEs and the protein and mRNA expression of their receptor (RAGE) in the renal cortex of diabetic rats. Moreover, mangiferin significantly attenuated oxidative stress damage as reflected by the lowered malondialdehyde and the increased glutathione levels in the kidney of diabetic rats. However, mangiferin did not affect the blood glucose and body weight of diabetic rats. Therefore, mangiferin can remarkably ameliorate DN in rats through inhibiting the AGEs/RAGE aix and oxidative stress damage, and Glo-1 may be a target for mangiferin action. Copyright © 2013 Elsevier B.V. All rights reserved.

[Influence of environmental enrichment on parameters of behavior in open field test in the rats born from females with chronic alcoholization].

PubMed

Vakhnin, V A; Briukhin, G V

2014-04-01

The aim of this work was studying of morphology of a brain and the analysis of behavior at posterity of females of rats with a chronic alcoholic intoxication. As object of research were taken 60-day animals received from mothers with chronic alcoholic injury of hepatobiliary systems. During certain time (1.5 months) the part of animals grew in standard conditions, and another--in the "enriched" environment. The behavior analysis was spent in the open field test. Also was carried out research of a thickness of a cortex and a molecular layer of a forebrain. Work included three series of experiments. It is established, that the posterity of mothers with chronic injury of the hepatobiliary systems is characterized by the lowered motorial and research activity, increased by emotional reactivity that is accompanied by changes of structure of a cortex. The long finding of "alcoholic" animals in the "enriched" environment within 1.5 months promoted increasing of motorial and research activity, emotional reactance, change of structure of a cortex.

Chronic moderate alcohol consumption relieves high-fat high-cholesterol diet-induced liver fibrosis in a rat model.

PubMed

Sun, Furong; Zhuang, Zhenjie; Zhang, Dai; Chen, Yushuai; Liu, Shu; Gao, Nan; Shi, Junping; Wang, Bingyuan

2018-05-30

Nonalcoholic fatty liver disease is a worldwide health issue and chronic alcohol consumption may have different effects on this disease. This study explored the role of chronic moderate alcohol consumption on high-fat high-cholesterol (HFHC) diet-induced liver fibrosis in a rodent model. Male Sprague-Dawley rats were divided into five groups: standard chow group, standard chow plus Er Guo Tou (EGT, a Chinese spirits made from fermented cereals) group, HFHC group, HFHC plus EGT group, and HFHC plus pure ethanol group. Rats were fed standard chow or HFHC chow for 12 weeks. EGT or pure ethanol was administrated at a daily dose of 4 g/kg body weight via intra-gastric gavage from the week four. At the end of week 12, hematoxylin and eosin staining, Sirius red and immunohistochemistry of liver sections were examined. The hepatic expression of F4/80, TNF-α, IL-1β, IL-6, CXCL1, CXCL2, α-SMA, Collagen, TGF-β, MMP2, MMP9, and TIMP1 was calculated. Both moderate EGT and pure ethanol did not increase plasma endotoxin in the portal vein comparing with the FHFC group. EGT and pure ethanol did not improve hepatic inflammation, but ameliorated liver fibrosis in histology. Moderate EGT and pure ethanol ameliorated HFHC diet-induced activation of Kupffer cells and hepatic stellate cells. In conclusion, chronic moderate EGT and pure ethanol could ameliorate HFHC diet-induced liver fibrosis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Prunella vulgaris attenuates prepulse inhibition deficit and attention disruption induced by MK-801 in mice.

PubMed

Park, Se Jin; Jeon, Se Jin; Dela Peña, Ike C; Lee, Hyung Eun; Kim, Dong Hyun; Kim, Jong Min; Lee, Young Woo; Jung, Jun Man; Shin, Bum Young; Lee, Seungheon; Cheong, Jae Hoon; Shin, Chan Young; Jang, Dae Sik; Ryu, Jong Hoon

2013-12-01

Prunella vulgaris var. lilacina is widely distributed in Korea, Japan, China, and Europe, and it has been traditionally used to treat inflammation or hypertension. In the present study, we investigated the effects of the ethanolic extract of the spikes of Prunella vulgaris var. lilacina (EEPV) on dizocilpine (MK-801)-induced schizophrenia-like phenotype behaviors such as the disruption of prepulse inhibition and attention deficits in mice. We also determined the effect of EEPV on MK-801-induced alterations in phosphorylated extracellular signal-regulated kinase, phosphorylated protein kinase B, phospho-glycogen synthase kinase 3-β, and phosphorylated cAMP response element-binding protein levels in the cortex and hippocampus of mice. MK-801-induced prepulse inhibition deficits were ameliorated by the administration of EEPV, as shown in the acoustic startle response test. Furthermore, EEPV attenuated the MK-801-induced attention deficits in the water finding test. We also found that EEPV attenuated the increased phosphorylated extracellular signal-regulated kinase, phosphorylated protein kinase B, or phospho-glycogen synthase kinase 3-β levels induced by MK-801 in the cortex but not in the hippocampus. These results suggest that EEPV could be useful for treating schizophrenia because EEPV ameliorates prepulse inhibition disruption and attention deficits induced by MK-801. Copyright © 2013 John Wiley & Sons, Ltd.

Oxytocin attenuates deficits in social interaction but not recognition memory in a prenatal valproic acid-induced mouse model of autism.

PubMed

Hara, Yuta; Ago, Yukio; Higuchi, Momoko; Hasebe, Shigeru; Nakazawa, Takanobu; Hashimoto, Hitoshi; Matsuda, Toshio; Takuma, Kazuhiro

2017-11-01

Recent studies have reported that oxytocin ameliorates behavioral abnormalities in both animal models and individuals with autism spectrum disorders (ASD). However, the mechanisms underlying the ameliorating effects of oxytocin remain unclear. In this study, we examined the effects of intranasal oxytocin on impairments in social interaction and recognition memory in an ASD mouse model in which animals are prenatally exposed to valproic acid (VPA). We found that a single intranasal administration of oxytocin restored social interaction deficits for up to 2h in mice prenatally exposed to VPA, but there was no effect on recognition memory impairments. Additionally, administration of oxytocin across 2weeks improved prenatal VPA-induced social interaction deficits for at least 24h. In contrast, there were no effects on the time spent sniffing in control mice. Immunohistochemical analysis revealed that intranasal administration of oxytocin increased c-Fos expression in the paraventricular nuclei (PVN), prefrontal cortex, and somatosensory cortex, but not the hippocampal CA1 and CA3 regions of VPA-exposed mice, suggesting the former regions may underlie the effects of oxytocin. These findings suggest that oxytocin attenuates social interaction deficits through the activation of higher cortical areas and the PVN in an ASD mouse model. Copyright © 2017 Elsevier Inc. All rights reserved.

Recovered neuronal viability revealed by Iodine-123-iomazenil SPECT following traumatic brain injury.

PubMed

Koizumi, Hiroyasu; Fujisawa, Hirosuke; Kurokawa, Tetsu; Suehiro, Eiichi; Iwanaga, Hideyuki; Nakagawara, Jyoji; Suzuki, Michiyasu

2010-10-01

We evaluated cortical damages following traumatic brain injury (TBI) in the acute phase with [(123)I] iomazenil (IMZ) single photon emission computed tomography (SPECT). In all, 12 patients with cerebral contusion following TBI were recruited. All patients underwent IMZ SPECT within 1 week after TBI. To investigate the changes in distribution of IMZ in the cortex in the chronic phase, after conventional treatment, patients underwent IMZ SPECT again. A decrease in the accumulation of radioligand for the central benzodiazepine receptor in the cortex corresponding to the contusion revealed with computed tomography (CT) scans and magnetic resonance imaging (MRI) were shown on IMZ SPECT in the acute phase in all patients. In 9 of 12 patients (75%), images of IMZ SPECT obtained in the chronic phase of TBI showed that areas with a decreased distribution of IMZ were remarkably reduced in comparison with those obtained in the acute phase. Both CT scans and MRI showed a normal appearance of the cortex morphologically, where the binding potential of IMZ recovered in the chronic phase. Reduced binding potential of radioligand for the central benzodiazepine receptor is considered to be an irreversible reaction; however, in this study, IMZ accumulation in the cortex following TBI was recovered in the chronic phase in several patients. [(123)I] iomazenil SPECT may have a potential to disclose a reversible vulnerability of neurons following TBI.

Recovered neuronal viability revealed by Iodine-123-iomazenil SPECT following traumatic brain injury

PubMed Central

Koizumi, Hiroyasu; Fujisawa, Hirosuke; Kurokawa, Tetsu; Suehiro, Eiichi; Iwanaga, Hideyuki; Nakagawara, Jyoji; Suzuki, Michiyasu

2010-01-01

We evaluated cortical damages following traumatic brain injury (TBI) in the acute phase with [123I] iomazenil (IMZ) single photon emission computed tomography (SPECT). In all, 12 patients with cerebral contusion following TBI were recruited. All patients underwent IMZ SPECT within 1 week after TBI. To investigate the changes in distribution of IMZ in the cortex in the chronic phase, after conventional treatment, patients underwent IMZ SPECT again. A decrease in the accumulation of radioligand for the central benzodiazepine receptor in the cortex corresponding to the contusion revealed with computed tomography (CT) scans and magnetic resonance imaging (MRI) were shown on IMZ SPECT in the acute phase in all patients. In 9 of 12 patients (75%), images of IMZ SPECT obtained in the chronic phase of TBI showed that areas with a decreased distribution of IMZ were remarkably reduced in comparison with those obtained in the acute phase. Both CT scans and MRI showed a normal appearance of the cortex morphologically, where the binding potential of IMZ recovered in the chronic phase. Reduced binding potential of radioligand for the central benzodiazepine receptor is considered to be an irreversible reaction; however, in this study, IMZ accumulation in the cortex following TBI was recovered in the chronic phase in several patients. [123I] iomazenil SPECT may have a potential to disclose a reversible vulnerability of neurons following TBI. PMID:20683454

Baicalin Ameliorates Liver Injury Induced by Chronic plus Binge Ethanol Feeding by Modulating Oxidative Stress and Inflammation via CYP2E1 and NRF2 in Mice

PubMed Central

He, Ping; Wu, Yafeng; Shun, Jianchao; Liang, Yaodong; Cheng, Mingliang

2017-01-01

Alcoholic liver injury leads to serious complication including death. The potential role of baicalin at the transcription level in mice model of alcohol injury is not known yet. In this study, we examined the effect of baicalin against chronic plus binge ethanol model in mice and understanding the mechanism of protection. Liver function, histology, steatosis, inflammation, NF-κB activity, oxidative stress sources, nuclear translocation of NRF2 transcription factor, and cell death were assessed. Treatment with baicalin ameliorated ethanol-induced oxidative stress, inflammation, and cell death. Baicalin attenuated ethanol-induced proinflammatory molecules such as TNF-α, IL-1β, MIP-2, and MCP-1 and reversed redox-sensitive transcription factor NF-κB activation. Baicalin also modulated Kupffer cell activation in vitro. Baicalin inhibited ethanol-induced expression of reactive oxygen species (ROS) generating enzymes NOX2, p67phox, xanthine oxidase, and iNOS in addition to CYP2E1 activities. Baicalin also enhanced ethanol-induced NRF2 nuclear translocation and increased downstream target gene HO-1 as antioxidant defense. Finally, baicalin reduced significant apoptotic and necrotic cell death. Our study suggests that baicalin ameliorates chronic plus binge ethanol-induced liver injury involving molecular crosstalk of multiple pathways at the transcriptional level and through upregulation of antioxidant defense mechanism. PMID:28951767

Root bark of Morus alba ameliorates the depressive-like behaviors in diabetic rats.

PubMed

Ye, Mei; Ke, Yuting; Liu, Bingyang; Yuan, Yanyan; Wang, Fuyan; Bu, Shizhong; Zhang, Yisheng

2017-01-10

Diabetes-induced depression is one of the severe chronic complications of diabetes mellitus. Up to now, there are only a few effective medicines to prevent or manage the co-morbidity of diabetes and depression. The present study was to investigate the effect of root bark of Morus alba (RBM) on depressive-like behaviors in the diabetic rats established by a high fat diet and a low dose of streptozotocin. Depressive-like behaviors were measured by the open field test, locomotor activity test and forced swimming test. Plasma glucose and lipid parameters were also measured. Expression of Brain-derived neurotrophic factor (BDNF) and phosphorylation of extracellular signal-regulated kinase (ERK) and Akt in the prefrontal cortex (PFC) were assessed. The results showed that a 4-week administration of RBM (10g/kg, ig) significantly reversed the depressive-like behaviors. BDNF expression and phosphorylation of ERK and Akt were increased in the PFC following RBM treatment in the diabetic rats. The data demonstrated that RBM could improve the depressive-like behaviors induced by diabetes, suggesting a therapeutic potential of RBM for the diabetes-associated depression. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Disrupted resting-state functional connectivity in minimally treated chronic schizophrenia.

PubMed

Wang, Xijin; Xia, Mingrui; Lai, Yunyao; Dai, Zhengjia; Cao, Qingjiu; Cheng, Zhang; Han, Xue; Yang, Lei; Yuan, Yanbo; Zhang, Yong; Li, Keqing; Ma, Hong; Shi, Chuan; Hong, Nan; Szeszko, Philip; Yu, Xin; He, Yong

2014-07-01

The pathophysiology of chronic schizophrenia may reflect long term brain changes related to the disorder. The effect of chronicity on intrinsic functional connectivity patterns in schizophrenia without the potentially confounding effect of antipsychotic medications, however, remains largely unknown. We collected resting-state fMRI data in 21 minimally treated chronic schizophrenia patients and 20 healthy controls. We computed regional functional connectivity strength for each voxel in the brain, and further divided regional functional connectivity strength into short-range regional functional connectivity strength and long-range regional functional connectivity strength. General linear models were used to detect between-group differences in these regional functional connectivity strength metrics and to further systematically investigate the relationship between these differences and clinical/behavioral variables in the patients. Compared to healthy controls, the minimally treated chronic schizophrenia patients showed an overall reduced regional functional connectivity strength especially in bilateral sensorimotor cortex, right lateral prefrontal cortex, left insula and right lingual gyrus, and these regional functional connectivity strength decreases mainly resulted from disruption of short-range regional functional connectivity strength. The minimally treated chronic schizophrenia patients also showed reduced long-range regional functional connectivity strength in the bilateral posterior cingulate cortex/precuneus, and increased long-range regional functional connectivity strength in the right lateral prefrontal cortex and lingual gyrus. Notably, disrupted short-range regional functional connectivity strength mainly correlated with duration of illness and negative symptoms, whereas disrupted long-range regional functional connectivity strength correlated with neurocognitive performance. All of the results were corrected using Monte-Carlo simulation. This exploratory study demonstrates a disruption of intrinsic functional connectivity without long-term exposure to antipsychotic medications in chronic schizophrenia. Furthermore, this disruption was connection-distance dependent, thus raising the possibility for differential neural pathways in neurocognitive impairment and psychiatric symptoms in schizophrenia. Copyright © 2014 Elsevier B.V. All rights reserved.

The Posterior Medial Cortex in Urologic Chronic Pelvic Pain Syndrome: Detachment from Default Mode Network. A Resting-State Study from the MAPP Research Network

PubMed Central

Martucci, Katherine T.; Shirer, William R.; Bagarinao, Epifanio; Johnson, Kevin A.; Farmer, Melissa A.; Labus, Jennifer S.; Apkarian, A. Vania; Deutsch, Georg; Harris, Richard E.; Mayer, Emeran A.; Clauw, Daniel J.; Greicius, Michael D.; Mackey, Sean C.

2015-01-01

Altered resting-state brain activity, as a measure of functional connectivity, is commonly observed in chronic pain. Identifying a reliable signature pattern of altered resting-state activity for chronic pain could provide strong mechanistic insights and serve as a highly beneficial neuroimaging-based diagnostic tool. We collected and analyzed resting-state fMRI data from female patients with urologic chronic pelvic pain syndrome (UCPPS, N = 45) and matched healthy participants (N = 45) as part of a NIDDK funded multicenter project (www.mappnetwork.org). Using dual regression and seed-based analyses, we observed significantly decreased functional connectivity of the default mode network (DMN) to two regions in the posterior medial cortex (PMC): the posterior cingulate cortex (PCC) and left precuneus (TFCE, FWE corrected p<0.05). Further investigation revealed that patients demonstrated increased functional connectivity between the PCC and several brain regions implicated in pain, sensory, motor, and emotion regulation processes (e.g., insular cortex, dorsolateral prefrontal cortex, thalamus, globus pallidus, putamen, amygdala, hippocampus). The left precuneus demonstrated decreased functional connectivity to several regions of pain processing, reward, and higher executive functioning within the prefrontal (orbitofrontal, anterior cingulate, ventromedial prefrontal) and parietal cortices (angular gyrus, superior and inferior parietal lobules). The altered PMC connectivity was associated with several phenotype measures, including pain and urologic symptom intensity, depression, anxiety, quality of relationships and self-esteem levels in patients. Collectively, these findings indicate that in UCPPS patients, regions of the PMC are detached from the DMN, while neurological processes of self-referential thought and introspection may be joined to pain and emotion regulatory processes. PMID:26010458

Region-specific disruption of the blood-brain barrier following repeated inflammatory dural stimulation in a rat model of chronic trigeminal allodynia

PubMed Central

Fried, Nathan T; Maxwell, Christina R; Elliott, Melanie B; Oshinsky, Michael L

2017-01-01

Background The blood-brain barrier (BBB) has been hypothesized to play a role in migraine since the late 1970s. Despite this, limited investigation of the BBB in migraine has been conducted. We used the inflammatory soup rat model of trigeminal allodynia, which closely mimics chronic migraine, to determine the impact of repeated dural inflammatory stimulation on BBB permeability. Methods The sodium fluorescein BBB permeability assay was used in multiple brain regions (trigeminal nucleus caudalis (TNC), periaqueductal grey, frontal cortex, sub-cortex, and cortex directly below the area of dural activation) during the episodic and chronic stages of repeated inflammatory dural stimulation. Glial activation was assessed in the TNC via GFAP and OX42 immunoreactivity. Minocycline was tested for its ability to prevent BBB disruption and trigeminal sensitivity. Results No astrocyte or microglial activation was found during the episodic stage, but BBB permeability and trigeminal sensitivity were increased. Astrocyte and microglial activation, BBB permeability, and trigeminal sensitivity were increased during the chronic stage. These changes were only found in the TNC. Minocycline treatment prevented BBB permeability modulation and trigeminal sensitivity during the episodic and chronic stages. Discussion Modulation of BBB permeability occurs centrally within the TNC following repeated dural inflammatory stimulation and may play a role in migraine. PMID:28457145

Effects of rolipram, a phosphodiesterase 4 inhibitor, in combination with imipramine on depressive behavior, CRE-binding activity and BDNF level in learned helplessness rats.

PubMed

Itoh, Tetsuji; Tokumura, Miwa; Abe, Kohji

2004-09-13

The brain cAMP regulating system and its downstream elements play a pivotal role in the therapeutic effects of antidepressants. We previously reported the increase in activities of phosphodiesterase 4, a major phosphodiesterase isozyme hydrolyzing cAMP, in the frontal cortex and hippocampus of learned helplessness rats, an animal model for depression. The present study was undertaken to examine the combination of effects of rolipram, a phosphodiesterase 4 inhibitor, with imipramine, a typical tricyclic antidepressant, on depressive behavior in learned helplessness rats. Concurrently, cAMP-response element (CRE)-binding activity and brain-derived neurotrophic factor (BDNF) levels related to the therapeutic effects of antidepressants were determined. Repeated administration of imipramine (1.25-10 mg/kg, i.p.) or rolipram (1.25 mg/kg, i.p.) reduced the number of escape failures in learned helplessness rats. Imipramine could not completely ameliorate the escape behavior to a level similar to that of non-stressed rats even at 10 mg/kg. However, repeated coadministration of rolipram with imipramine (1.25 and 2.5 mg/kg, respectively) almost completely eliminated the escape failures in learned helplessness rats. The reduction of CRE-binding activities and BDNF levels in the frontal cortex or hippocampus in learned helplessness rats were ameliorated by treatment with imipramine or rolipram alone. CRE-binding activities and/or BDNF levels of the frontal cortex and hippocampus were significantly increased by treatment with a combination of rolipram and imipramine compared to those in imipramine-treated rats. These results indicated that coadministration of phosphodiesterase type 4 inhibitors with antidepressants may be more effective for depression therapy and suggest that elevation of the cAMP signal transduction pathway is involved in the antidepressive effects.

Cannabinoid receptor-2 (CB2) agonist ameliorates colitis in IL-10{sup −/−} mice by attenuating the activation of T cells and promoting their apoptosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Singh, Udai P.; Singh, Narendra P.; Singh, Balwan

2012-01-15

Inflammatory bowel disease (IBD) is a chronic intestinal inflammation caused by hyperactivated effector immune cells that produce pro-inflammatory cytokines. Recent studies have shown that the cannabinoid system may play a critical role in mediating protection against intestinal inflammation. However, the effect of cannabinoid receptor induction after chronic colitis progression has not been investigated. Here, we investigate the effect of cannabinoid receptor-2 (CB2) agonist, JWH-133, after chronic colitis in IL-10{sup −/−} mice. JWH-133 effectively attenuated the overall clinical score, and reversed colitis-associated pathogenesis and decrease in body weight in IL-10{sup −/−} mice. After JWH-133 treatment, the percentage of CD4{sup +} Tmore » cells, neutrophils, mast cells, natural killer (NK1.1) cells, and activated T cells declined in the intestinal lamina propria (LP) and mesenteric lymph nodes (MLN) of mice with chronic colitis. JWH-133 was also effective in ameliorating dextran sodium sulfate (DSS)-induced colitis. In this model, JWH-133 reduced the number and percentage of macrophages and IFN-γ expressing cells that were induced during colitis progression. Treatment with aminoalkylindole 6-iodo-pravadoline (AM630), a CB2 receptor antagonist, reversed the colitis protection provided by JWH-133 treatment. Also, activated T cells were found to undergo apoptosis following JWH-133 treatment both in-vivo and in-vitro. These findings suggest that JWH-133 mediates its effect through CB2 receptors, and ameliorates chronic colitis by inducing apoptosis in activated T cells, reducing the numbers of activated T cells, and suppressing induction of mast cells, NK cells, and neutrophils at sites of inflammation in the LP. These results support the idea that the CB2 receptor agonists may serve as a therapeutic modality against IBD. -- Highlights: ► JWH-133, a cannnabinoid receptor-2 agonist ameliorates experimental colitis. ► JWH-133 suppressed inflammation and toxicity to colon by inducing T cell apoptosis. ► JWH-133 decreased mast cells, macrophages, NK cells, IFN-γ{sup +} cells in the LPL. ► AM630, a cannnabinoid receptor-2 antagonist inverted the colitis defense of JWH-133. ► Cannnabinoid receptor-2 may serve as a novel therapeutic target for IBD.« less

Impaired Functional Connectivity in the Prefrontal Cortex: A Mechanism for Chronic Stress-Induced Neuropsychiatric Disorders

PubMed Central

Negrón-Oyarzo, Ignacio; Aboitiz, Francisco; Fuentealba, Pablo

2016-01-01

Chronic stress-related psychiatric diseases, such as major depression, posttraumatic stress disorder, and schizophrenia, are characterized by a maladaptive organization of behavioral responses that strongly affect the well-being of patients. Current evidence suggests that a functional impairment of the prefrontal cortex (PFC) is implicated in the pathophysiology of these diseases. Therefore, chronic stress may impair PFC functions required for the adaptive orchestration of behavioral responses. In the present review, we integrate evidence obtained from cognitive neuroscience with neurophysiological research with animal models, to put forward a hypothesis that addresses stress-induced behavioral dysfunctions observed in stress-related neuropsychiatric disorders. We propose that chronic stress impairs mechanisms involved in neuronal functional connectivity in the PFC that are required for the formation of adaptive representations for the execution of adaptive behavioral responses. These considerations could be particularly relevant for understanding the pathophysiology of chronic stress-related neuropsychiatric disorders. PMID:26904302

Six Month Oral Toxicity Study of WR238605 Succinate in Rats. Volume 2

DTIC Science & Technology

1996-02-02

chronic, per {vascular Accumulation, foamy macrophage KIDNEY Mineralization Inf laomat ion, chronic Nephropathy Hydronephrosis Pyelonephritis...KIDNEY # EX Mineralization Inflammation, chronic Nephropathy Hydronephrosis Py»lonaphrItIs Hyperplasia, pelvic epithelium Pigmentation, cortex...Mineralization Inf Lajaaat ion, chronic Nephropathy Hydronephrosis Pigmentation, cor ten (1) - - - ɚ> (1) - ə> - (1) - ə> - 2L

Ginseng ameliorates chronic histopathologic changes in a murine model of asthma.

PubMed

Babayigit, Arzu; Olmez, Duygu; Karaman, Ozkan; Bagriyanik, H Alper; Yilmaz, Osman; Kivcak, Bijen; Erbil, Guven; Uzuner, Nevin

2008-01-01

Currently, asthma therapies are effective in reducing inflammation but airway remodeling is poorly responsive to these agents. New therapeutic options that have fewer side effects and reverse chronic changes in the lungs are essential. This study aimed to determine the efficacy of oral administration of ginseng on lung histopathology in a murine model of chronic asthma. BALB/c mice were divided into four groups: control, placebo, ginseng, and dexamethasone. All mice except those in the control group were sensitized and challenged with ovalbumin. Then, mice in the ginseng group were given 2 gr/kg per day of ginseng and mice in the dexamethasone group received 1 mg/kg per day of dexamethasone via orogastic gavage once daily for 1 week. Lung histopathology was evaluated by using light and electron microscopy in all groups. All of the chronic changes of airways in the ginseng group were significantly ameliorated when compared with the placebo group. When compared with the dexamethasone group, the ginseng group had significantly lower numbers of mast cell count. Thicknesses of basement membrane, epithelium, and subepithelial smooth muscle were not statistically different between the ginseng and dexamethasone groups. Goblet cell numbers were much more reduced in the dexamethasone group. Ginseng is effective in resolving the established chronic histopathological changes of the lungs in the murine model of asthma.

Regional inactivations of primate ventral prefrontal cortex reveal two distinct mechanisms underlying negative bias in decision making.

PubMed

Clarke, Hannah F; Horst, Nicole K; Roberts, Angela C

2015-03-31

Dysregulation of the orbitofrontal and ventrolateral prefrontal cortices is implicated in anxiety and mood disorders, but the specific contributions of each region are unknown, including how they gate the impact of threat on decision making. To address this, the effects of GABAergic inactivation of these regions were studied in marmoset monkeys performing an instrumental approach-avoidance decision-making task that is sensitive to changes in anxiety. Inactivation of either region induced a negative bias away from punishment that could be ameliorated with anxiolytic treatment. However, whereas the effects of ventrolateral prefrontal cortex inactivation on punishment avoidance were seen immediately, those of orbitofrontal cortex inactivation were delayed and their expression was dependent upon an amygdala-anterior hippocampal circuit. We propose that these negative biases result from deficits in attentional control and punishment prediction, respectively, and that they provide the basis for understanding how distinct regional prefrontal dysregulation contributes to the heterogeneity of anxiety disorders with implications for cognitive-behavioral treatment strategies.

Opposing Effects of Acute versus Chronic Blockade of Frontal Cortex Somatostatin-Positive Inhibitory Neurons on Behavioral Emotionality in Mice

PubMed Central

Soumier, Amelie; Sibille, Etienne

2014-01-01

Reduced expression of somatostatin (SST) is reported across chronic brain conditions including major depression and normal aging. SST is a signaling neuropeptide and marker of gamma-amino butyric acid (GABA) neurons, which specifically inhibit pyramidal neuron dendrites. Studies in auditory cortex suggest that chronic reduction in dendritic inhibition induces compensatory homeostatic adaptations that oppose the effects of acute inhibition. Whether such mechanisms occur in frontal cortex (FC) and affect behavioral outcome is not known. Here, we used two complementary viral vector strategies to examine the effects of acute vs chronic inhibition of SST-positive neurons on behavioral emotionality in adult mice. SST-IRES-Cre mice were injected in FC (prelimbic/precingulate) with CRE-dependent adeno-associated viral (AAV) vector encoding the engineered Gi/o-coupled human muscarinic M4 designer receptor exclusively activated by a designer drug (DREADD-hM4Di) or a control reporter (AAV-DIO-mCherry) for acute or chronic cellular inhibition. A separate cohort was injected with CRE-dependent AAV vectors expressing diphtheria toxin (DTA) to selectively ablate FC SST neurons. Mice were assessed for anxiety- and depressive-like behaviors (defined as emotionality). Results indicate that acute inhibition of FC SST neurons increased behavioral emotionality, whereas chronic inhibition decreased behavioral emotionality. Furthermore, ablation of FC SST neurons also decreased behavioral emotionality under baseline condition and after chronic stress. Together, our results reveal opposite effects of acute and chronic inhibition of FC SST neurons on behavioral emotionality and suggest the recruitment of homeostatic plasticity mechanisms that have implications for understanding the neurobiology of chronic brain conditions affecting dendritic-targeting inhibitory neurons. PMID:24690741

Opposing effects of acute versus chronic blockade of frontal cortex somatostatin-positive inhibitory neurons on behavioral emotionality in mice.

PubMed

Soumier, Amelie; Sibille, Etienne

2014-08-01

Reduced expression of somatostatin (SST) is reported across chronic brain conditions including major depression and normal aging. SST is a signaling neuropeptide and marker of gamma-amino butyric acid (GABA) neurons, which specifically inhibit pyramidal neuron dendrites. Studies in auditory cortex suggest that chronic reduction in dendritic inhibition induces compensatory homeostatic adaptations that oppose the effects of acute inhibition. Whether such mechanisms occur in frontal cortex (FC) and affect behavioral outcome is not known. Here, we used two complementary viral vector strategies to examine the effects of acute vs chronic inhibition of SST-positive neurons on behavioral emotionality in adult mice. SST-IRES-Cre mice were injected in FC (prelimbic/precingulate) with CRE-dependent adeno-associated viral (AAV) vector encoding the engineered Gi/o-coupled human muscarinic M4 designer receptor exclusively activated by a designer drug (DREADD-hM4Di) or a control reporter (AAV-DIO-mCherry) for acute or chronic cellular inhibition. A separate cohort was injected with CRE-dependent AAV vectors expressing diphtheria toxin (DTA) to selectively ablate FC SST neurons. Mice were assessed for anxiety- and depressive-like behaviors (defined as emotionality). Results indicate that acute inhibition of FC SST neurons increased behavioral emotionality, whereas chronic inhibition decreased behavioral emotionality. Furthermore, ablation of FC SST neurons also decreased behavioral emotionality under baseline condition and after chronic stress. Together, our results reveal opposite effects of acute and chronic inhibition of FC SST neurons on behavioral emotionality and suggest the recruitment of homeostatic plasticity mechanisms that have implications for understanding the neurobiology of chronic brain conditions affecting dendritic-targeting inhibitory neurons.

Antidepressant-like effect of oleanolic acid in mice exposed to the repeated forced swimming test.

PubMed

Yi, Li-Tao; Li, Jing; Liu, Qing; Geng, Di; Zhou, Ya-Fei; Ke, Xiao-Qing; Chen, Huan; Weng, Lian-Jin

2013-05-01

The study aimed to explore the antidepressant-like effect of oleanolic acid and its possible mechanism related to the monoaminergic system and neurotrophin in mice exposed to the repeated forced swimming test (FST). Both the duration and the latency of immobility affected by oleanolic acid (10, 20 and 40 mg/kg) were evaluated in the FST repeated at intervals on days 1, 7 and 14, followed by neurochemical and brain-derived neurotrophic factor (BDNF) analyses in the mouse brain regions of frontal cortex and whole hippocampus. A repeated analysis of variance (ANOVA) indicated that over retesting the immobility time increased, whereas latency to immobility tended to decrease. Minute-by-minute analysis showed that immobility time also increased during the 4-min course of the test. In addition, post-hoc Dunnett's test demonstrated that sub-chronic and chronic, but not acute, oleanolic acid treatment reduced the immobility time (sub-chronic: 20 mg/kg, 43.5%; chronic: 10 mg/kg, 19.3%; 20 mg/kg, 31.8%) and increased the latency to immobility (sub-chronic: 10 mg/kg, 60.6%; 20 mg/kg, 80.1%; chronic: 10 mg/kg, 121.8%; 20 mg/kg, 140.8%; 40 mg/kg, 80.0%). Furthermore, chronic administration of oleanolic acid significantly increased serotonin (5-HT) levels (frontal cortex: 44.5%, 41.9%, 27.5% for 10, 20, 40 mg/kg; hippocampus: 57.2%, 80.9% for 10, 20 mg/kg), decreased 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratio (frontal cortex: 31.6%, 30.1%, 23.5%; hippocampus: 40.6%, 47.7%, 29.2% for 10, 20, 40 mg/kg) and elevated norepinephrine (NE) levels (hippocampus: 20 mg/kg, 45.4%) but did not alter dopamine (DA) levels. Moreover, BDNF levels in the two brain regions were also elevated by chronic oleanolic acid treatment (frontal cortex: 20 mg/kg, 67.2%; hippocampus: 10 mg/kg, 36.4%; 20 mg/kg, 55.1%). Taken together, these findings imply that functions of 5-HT, NE and BDNF may be involved in the antidepressant-like effect of oleanolic acid.

Amelioration of chronic fluoride toxicity by calcium and fluoride-free water in rats.

PubMed

Shankar, Priyanka; Ghosh, Sudip; Bhaskarachary, K; Venkaiah, K; Khandare, Arjun L

2013-07-14

The study was undertaken to explore the amelioration of chronic fluoride (F) toxicity (with low and normal Ca) in rats. The study was conducted in two phases. In phase I (6 months), seventy-six Wistar, weanling male rats were assigned to four treatment groups: normal-Ca (0·5 %) diet (NCD), Ca+F - ; low-Ca (0·25 %) diet (LCD), Ca - F - ; NCD +100 parts per million (ppm) F water, Ca+F+; LCD +100 ppm F water, Ca - F+. In phase II (reversal experiment, 3 months), LCD was replaced with the NCD. Treatment groups Ca+F+ and Ca - F+ were divided into two subgroups to compare the effect of continuation v. discontinuation along with Ca supplementation on reversal of chronic F toxicity. In phase I, significantly reduced food efficiency ratio (FER), body weight gain (BWG), faecal F excretion, serum Ca and increased bone F deposition were observed in the treatment group Ca - F+. Reduced serum 25-hydroxy-vitamin D3, increased 1,25-dihydroxy-vitamin D3 and up-regulation of Ca-sensing receptor, vitamin D receptor and S100 Ca-binding protein G (S100G) were observed in treatment groups Ca - F - and Ca - F+. In phase II (reversal phase), FER, BWG and serum Ca in treatment groups Ca - F+/Ca+F - and Ca - F+/Ca+F+ were still lower, as compared with other groups. However, other variables were comparable. Down-regulation of S100G was observed in F-fed groups (Ca+F+/Ca+F+ and Ca - F+/Ca+F+) in phase II. It is concluded that low Ca aggravates F toxicity, which can be ameliorated after providing adequate Ca and F-free water. However, chronic F toxicity can interfere with Ca absorption by down-regulating S100G expression irrespective of Ca nutrition.

Exercise training normalizes renal blood flow responses to acute hypoxia in experimental heart failure: role of the α1-adrenergic receptor.

PubMed

Pügge, Carolin; Mediratta, Jai; Marcus, Noah J; Schultz, Harold D; Schiller, Alicia M; Zucker, Irving H

2016-02-01

Recent data suggest that exercise training (ExT) is beneficial in chronic heart failure (CHF) because it improves autonomic and peripheral vascular function. In this study, we hypothesized that ExT in the CHF state ameliorates the renal vasoconstrictor responses to hypoxia and that this beneficial effect is mediated by changes in α1-adrenergic receptor activation. CHF was induced in rabbits. Renal blood flow (RBF) and renal vascular conductance (RVC) responses to 6 min of 5% isocapnic hypoxia were assessed in the conscious state in sedentary (SED) and ExT rabbits with CHF with and without α1-adrenergic blockade. α1-adrenergic receptor expression in the kidney cortex was also evaluated. A significant decline in baseline RBF and RVC and an exaggerated renal vasoconstriction during acute hypoxia occurred in CHF-SED rabbits compared with the prepaced state (P < 0.05). ExT diminished the decline in baseline RBF and RVC and restored changes during hypoxia to those of the prepaced state. α1-adrenergic blockade partially prevented the decline in RBF and RVC in CHF-SED rabbits and eliminated the differences in hypoxia responses between SED and ExT animals. Unilateral renal denervation (DnX) blocked the hypoxia-induced renal vasoconstriction in CHF-SED rabbits. α1-adrenergic protein in the renal cortex of animals with CHF was increased in SED animals and normalized after ExT. These data provide evidence that the acute decline in RBF during hypoxia is caused entirely by the renal nerves but is only partially mediated by α1-adrenergic receptors. Nonetheless, α1-adrenergic receptors play an important role in the beneficial effects of ExT in the kidney. Copyright © 2016 the American Physiological Society.

Gonadectomy prevents the increase in blood pressure and glomerular injury in angiotensin-converting enzyme 2 knockout diabetic male mice. Effects on renin-angiotensin system.

PubMed

Clotet, Sergi; Soler, María José; Rebull, Marta; Gimeno, Javier; Gurley, Susan B; Pascual, Julio; Riera, Marta

2016-09-01

Angiotensin-converting enzyme 2 (ACE2) deletion worsens kidney injury, and its amplification ameliorates diabetic nephropathy. Male sex increases the incidence, prevalence, and progression of chronic kidney disease in our environment. Here, we studied the effect of ACE2 deficiency and gonadectomy (GDX) on diabetic nephropathy and its relationship with fibrosis, protein kinase B (Akt) activation, and the expression of several components of the renin-angiotensin system (RAS).Mice were injected with streptozotocin to induce diabetes and followed for 19 weeks. Physiological and renal parameters were studied in wild-type and ACE2 knockout (ACE2KO) male mice with and without GDX. Diabetic ACE2KO showed increased blood pressure (BP), glomerular injury, and renal fibrosis compared with diabetic wild-type. Gonadectomized diabetic ACE2KO presented a decrease in BP. In the absence of ACE2, GDX attenuated albuminuria and renal lesions, such as mesangial matrix expansion and podocyte loss. Both, α-smooth muscle actin accumulation and collagen deposition were significantly decreased in renal cortex of gonadectomized diabetic ACE2KO but not diabetic wild-type mice. GDX also reduced circulating ACE activity in ACE2KO mice. Loss of ACE2 modified the effect of GDX on cortical gene expression of RAS in diabetic mice. Akt phosphorylation in renal cortex was increased by diabetes and loss of ACE2 and decreased by GDX in control and diabetic ACE2KO but not in wild-type mice. Our results suggest that GDX may exert a protective effect within the kidney under pathological conditions of diabetes and ACE2 deficiency. This renoprotection may be ascribed to different mechanisms such as decrease in BP, modulation of RAS, and downregulation of Akt-related pathways.

Neuro magnetic resonance spectroscopy using wavelet decomposition and statistical testing identifies biochemical changes in people with spinal cord injury and pain.

PubMed

Stanwell, Peter; Siddall, Philip; Keshava, Nirmal; Cocuzzo, Daniel; Ramadan, Saadallah; Lin, Alexander; Herbert, David; Craig, Ashley; Tran, Yvonne; Middleton, James; Gautam, Shiva; Cousins, Michael; Mountford, Carolyn

2010-11-01

Spinal cord injury (SCI) can be accompanied by chronic pain, the mechanisms for which are poorly understood. Here we report that magnetic resonance spectroscopy measurements from the brain, collected at 3T, and processed using wavelet-based feature extraction and classification algorithms, can identify biochemical changes that distinguish control subjects from subjects with SCI as well as subdividing the SCI group into those with and without chronic pain. The results from control subjects (n=10) were compared to those with SCI (n=10). The SCI cohort was made up of subjects with chronic neuropathic pain (n=5) and those without chronic pain (n=5). The wavelet-based decomposition of frequency domain MRS signals employs statistical significance testing to identify features best suited to discriminate different classes. Moreover, the features benefit from careful attention to the post-processing of the spectroscopy data prior to the comparison of the three cohorts. The spectroscopy data, from the thalamus, best distinguished control subjects without SCI from those with SCI with a sensitivity and specificity of 0.9 (Percentage of Correct Classification). The spectroscopy data obtained from the prefrontal cortex and anterior cingulate cortex both distinguished between SCI subjects with chronic neuropathic pain and those without pain with a sensitivity and specificity of 1.0. In this study, where two underlying mechanisms co-exist (i.e. SCI and pain), the thalamic changes appear to be linked more strongly to SCI, while the anterior cingulate cortex and prefrontal cortex changes appear to be specifically linked to the presence of pain. Copyright 2010 Elsevier Inc. All rights reserved.

Long-term Ameliorative Effects of the Antidepressant Fluoxetine Exposure on Cognitive Deficits in 3 × TgAD Mice.

PubMed

Jin, Li; Gao, Li-Feng; Sun, Dong-Sheng; Wu, Hao; Wang, Qun; Ke, Dan; Lei, Hao; Wang, Jian-Zhi; Liu, Gong-Ping

2017-08-01

Fluoxetine, a selective serotonin reuptake inhibitor, is neuroprotective; therefore, it has been applied to treat some neurodegenerative disorders. For instance, chronic fluoxetine exposure has short-term effects on Alzheimer's disease (AD). However, the long-term ameliorative effects of fluoxetine exposure on AD have not been reported. In the present study, 6-month-old 3 × TgAD mice were treated with fluoxetine for 15 days, and then the influence of fluoxetine was detected at 20 days after the drug withdrawal. We found that chronic fluoxetine treatment ameliorated cognitive deficits of 3 × TgAD mice and increased the volume of the hippocampal CA1 and dentate gyrus (DG) with increased neuron number and dendritic spine density. Meanwhile, fluoxetine exposure also stimulated the long-term potentiation (LTP) in hippocampal DG. The synaptic-related protein expression increased via activation of the cyclic AMP response element binding (CREB) protein/brain-derived neurotrophic factor (BDNF) signaling pathway induced by fluoxetine exposure. Lastly, we found that fluoxetine treatment decreased beta-amyloid (Aβ) levels. These results further certified that fluoxetine may be a potent effective drug for AD.

Host regulation of liver fibroproliferative pathology during experimental schistosomiasis via interleukin-4 receptor alpha.

PubMed

Nono, Justin Komguep; Ndlovu, Hlumani; Aziz, Nada Abdel; Mpotje, Thabo; Hlaka, Lerato; Brombacher, Frank

2017-08-01

Interleukin-4 receptor (IL-4Rα) is critical for the initiation of type-2 immune responses and implicated in the pathogenesis of experimental schistosomiasis. IL-4Rα mediated type-2 responses are critical for the control of pathology during acute schistosomiasis. However, type-2 responses tightly associate with fibrogranulomatous inflammation that drives host pathology during chronic schistosomiasis. To address such controversy on the role of IL-4Rα, we generated a novel inducible IL-4Rα-deficient mouse model that allows for temporal knockdown of il-4rα gene after oral administration of Tamoxifen. Interrupting IL-4Rα mediated signaling during the acute phase impaired the development of protective type-2 immune responses, leading to rapid weight loss and premature death, confirming a protective role of IL-4Rα during acute schistosomiasis. Conversely, IL-4Rα removal at the chronic phase of schistosomiasis ameliorated the pathological fibro-granulomatous pathology and reversed liver scarification without affecting the host fitness. This amelioration of the morbidity was accompanied by a reduced Th2 response and increased frequencies of FoxP3+ Tregs and CD1dhiCD5+ Bregs. Collectively, these data demonstrate that IL-4Rα mediated signaling has two opposing functions during experimental schistosomiasis depending on the stage of advancement of the disease and indicate that interrupting IL-4Rα mediated signaling is a viable therapeutic strategy to ameliorate liver fibroproliferative pathology in diseases like chronic schistosomiasis.

Type-2 diabetes mellitus reduces cortical thickness and decreases oxidative metabolism in sensorimotor regions after stroke.

PubMed

Ferris, Jennifer K; Peters, Sue; Brown, Katlyn E; Tourigny, Katherine; Boyd, Lara A

2018-05-01

Individuals with type-2 diabetes mellitus experience poor motor outcomes after ischemic stroke. Recent research suggests that type-2 diabetes adversely impacts neuronal integrity and function, yet little work has considered how these neuronal changes affect sensorimotor outcomes after stroke. Here, we considered how type-2 diabetes impacted the structural and metabolic function of the sensorimotor cortex after stroke using volumetric magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). We hypothesized that the combination of chronic stroke and type-2 diabetes would negatively impact the integrity of sensorimotor cortex as compared to individuals with chronic stroke alone. Compared to stroke alone, individuals with stroke and diabetes had lower cortical thickness bilaterally in the primary somatosensory cortex, and primary and secondary motor cortices. Individuals with stroke and diabetes also showed reduced creatine levels bilaterally in the sensorimotor cortex. Contralesional primary and secondary motor cortex thicknesses were negatively related to sensorimotor outcomes in the paretic upper-limb in the stroke and diabetes group such that those with thinner primary and secondary motor cortices had better motor function. These data suggest that type-2 diabetes alters cerebral energy metabolism, and is associated with thinning of sensorimotor cortex after stroke. These factors may influence motor outcomes after stroke.

Chronic baclofen desensitizes GABA(B)-mediated G-protein activation and stimulates phosphorylation of kinases in mesocorticolimbic rat brain.

PubMed

Keegan, Bradley M T; Beveridge, Thomas J R; Pezor, Jeffrey J; Xiao, Ruoyu; Sexton, Tammy; Childers, Steven R; Howlett, Allyn C

2015-08-01

The GABAB receptor is a therapeutic target for CNS and neuropathic disorders; however, few preclinical studies have explored effects of chronic stimulation. This study evaluated acute and chronic baclofen treatments on GABAB-activated G-proteins and signaling protein phosphorylation as indicators of GABAB signaling capacity. Brain sections from rats acutely administered baclofen (5 mg/kg, i.p.) showed no significant differences from controls in GABAB-stimulated GTPγS binding in any brain region, but displayed significantly greater phosphorylation/activation of focal adhesion kinase (pFAK(Tyr397)) in mesocorticolimbic regions (caudate putamen, cortex, hippocampus, thalamus) and elevated phosphorylated/activated glycogen synthase kinase 3-β (pGSK3β(Tyr216)) in the prefrontal cortex, cerebral cortex, caudate putamen, nucleus accumbens, thalamus, septum, and globus pallidus. In rats administered chronic baclofen (5 mg/kg, t.i.d. for five days), GABAB-stimulated GTPγS binding was significantly diminished in the prefrontal cortex, septum, amygdala, and parabrachial nucleus compared to controls. This effect was specific to GABAB receptors: there was no effect of chronic baclofen treatment on adenosine A1-stimulated GTPγS binding in any region. Chronically-treated rats also exhibited increases in pFAK(Tyr397) and pGSK3β(Tyr216) compared to controls, and displayed wide-spread elevations in phosphorylated dopamine- and cAMP-regulated phosphoprotein-32 (pDARPP-32(Thr34)) compared to acutely-treated or control rats. We postulate that those neuroadaptive effects of GABAB stimulation mediated by G-proteins and their sequelae correlate with tolerance to several of baclofen's effects, whereas sustained signaling via kinase cascades points to cross-talk between GABAB receptors and alternative mechanisms that are resistant to desensitization. Both desensitized and sustained signaling pathways should be considered in the development of pharmacotherapies targeting the GABA system. Copyright © 2015 Elsevier Ltd. All rights reserved.

Plasticity and alterations of trunk motor cortex following spinal cord injury and non-stepping robot and treadmill training.

PubMed

Oza, Chintan S; Giszter, Simon F

2014-06-01

Spinal cord injury (SCI) induces significant reorganization in the sensorimotor cortex. Trunk motor control is crucial for postural stability and propulsion after low thoracic SCI and several rehabilitative strategies are aimed at trunk stability and control. However little is known about the effect of SCI and rehabilitation training on trunk motor representations and their plasticity in the cortex. Here, we used intracortical microstimulation to examine the motor cortex representations of the trunk in relation to other representations in three groups of chronic adult complete low thoracic SCI rats: chronic untrained, treadmill trained (but 'non-stepping') and robot assisted treadmill trained (but 'non-stepping') and compared with a group of normal rats. Our results demonstrate extensive and significant reorganization of the trunk motor cortex after chronic adult SCI which includes (1) expansion and rostral displacement of trunk motor representations in the cortex, with the greatest significant increase observed for rostral (to injury) trunk, and slight but significant increase of motor representation for caudal (to injury) trunk at low thoracic levels in all spinalized rats; (2) significant changes in coactivation and the synergy representation (or map overlap) between different trunk muscles and between trunk and forelimb. No significant differences were observed between the groups of transected rats for the majority of the comparisons. However, (3) the treadmill and robot-treadmill trained groups of rats showed a further small but significant rostral migration of the trunk representations, beyond the shift caused by transection alone. We conclude that SCI induces a significant reorganization of the trunk motor cortex, which is not qualitatively altered by non-stepping treadmill training or non-stepping robot assisted treadmill training, but is shifted further from normal topography by the training. This shift may potentially make subsequent rehabilitation with stepping longer or less successful. Copyright © 2014 Elsevier Inc. All rights reserved.

Prenatal phencyclidine treatment induces behavioral deficits through impairment of GABAergic interneurons in the prefrontal cortex.

PubMed

Toriumi, Kazuya; Oki, Mika; Muto, Eriko; Tanaka, Junko; Mouri, Akihiro; Mamiya, Takayoshi; Kim, Hyoung-Chun; Nabeshima, Toshitaka

2016-06-01

We previously reported that prenatal treatment with phencyclidine (PCP) induces glutamatergic dysfunction in the prefrontal cortex (PFC), leading to schizophrenia-like behavioral deficits in adult mice. However, little is known about the prenatal effect of PCP treatment on other types of neurons. We focused on γ-aminobutyric acid (GABA)-ergic interneurons and evaluated the effect of prenatal PCP exposure on the neurodevelopment of GABAergic interneurons in the PFC. PCP was administered at the dose of 10 mg/kg/day to pregnant dams from embryonic day 6.5 to 18.5. After the pups were reared to adult, we analyzed their GABAergic system in the PFC using immunohistological, biochemical, and behavioral analyses in adulthood. The prenatal PCP treatment decreased the density of parvalbumin-positive cells and reduced the expression level of glutamic acid decarboxylase 67 (GAD67) and GABA content of the PFC in adults. Additionally, prenatal PCP treatment induced behavioral deficits in adult mice, such as hypersensitivity to PCP and prepulse inhibition (PPI) deficits. These behavioral deficits were ameliorated by pretreatment with the GABAB receptor agonist baclofen. Furthermore, the density of c-Fos-positive cells was decreased after the PPI test in the PFC of mice treated with PCP prenatally, and this effect was ameliorated by pretreatment with baclofen. These findings suggest that prenatal treatment with PCP induced GABAergic dysfunction in the PFC, which caused behavioral deficits.

Oral metformin-ascorbic acid co-administration ameliorates alcohol-induced hepatotoxicity in rats.

PubMed

Adeneye, A A; Benebo, A S

2007-01-01

Alcoholic liver disease remains a major cause of liver failure worldwide with no available curative or prophylactic therapy as at present. High dose metformin is reported to ameliorate liver injuries in both human and animal models of acute and chronic alcoholic liver injuries. The aim of the present in vivo animal study was to determine whether metformin-ascorbic acid co-administration also prevents alcoholic hepatotoxicity in chronic alcohol exposure. In the present study, ameliorating effect of 200 mg/ kg/day of ascorbic acid (Asc), 500 mg/kg/day of metformin (Met) and their co-administration (Met-Asc) were investigated in 5 groups of 50% ethanol-treated male Wistar rats for 2 weeks of the experiment. The body weight of each rat was taken on days 1, 7, and 14 of the experiment, respectively. On day 15, fasted blood samples for plasma lipids and liver enzyme markers were collected via cardiac puncture from the rats under diethyl ether anaesthesia. Results showed that administration of graded oral doses of 50% ethanol for 14 days significantly (p<0.001) elevated the plasma liver enzymes--aspartate aminotransferase (AST), alanine aminotansferase (ALT) and alkaline phosphatase (ALP). Two weeks of ethanol treatment also induced alterations in the plasma triglycerides (PTG), total cholesterol (PTC), high density lipoprotein (HDL-c), and low density lipoprotein (LDL-c). However, these elevations were significantly (p<0.05) attenuated by Asc, Met, and Met-Asc after 14 days of oral treatment, with Met-Asc having higher significant (p<0.001) ameliorating effect than Asc alone but with comparative effect to that of Met alone. High dose metformin-ascorbic acid co-administration protected the liver against the deleterious effects of chronic high dose alcohol and the hepatoprotective effect of Met-Asc appeared to be due mainly to the metformin molecule of the drug combination. However, further studies would be required to evaluate the mechanisms underlying the observed effects.

AMD3100 ameliorates cigarette smoke-induced emphysema-like manifestations in mice.

PubMed

Barwinska, Daria; Oueini, Houssam; Poirier, Christophe; Albrecht, Marjorie E; Bogatcheva, Natalia V; Justice, Matthew J; Saliba, Jacob; Schweitzer, Kelly S; Broxmeyer, Hal E; March, Keith L; Petrache, Irina

2018-05-10

We have shown that cigarette smoke (CS)-induced pulmonary emphysema-like manifestations are preceded by marked suppression of the number and function of bone marrow hematopoietic progenitor cells (HPC). To investigate if a limited availability of HPC may contribute to CS-induced lung injury, we used an FDA-approved antagonist of the interactions of SDF-1 with its receptor CXCR4 to promote intermittent HPC mobilization and tested its ability to limit emphysema-like injury following chronic CS. We administered AMD3100 (5mg/kg) to mice during a chronic CS exposure protocol of up to 24 weeks. AMD3100 treatment did not affect either lung SDF-1 levels, which were reduced by CS, or lung inflammatory cell counts. However, AMD3100 markedly improved CS-induced bone marrow HPC suppression and significantly ameliorated emphysema-like endpoints such as alveolar airspace size, lung volumes, and lung static compliance. These results suggest that antagonism of SDF-1 binding to CXCR4 is associated with protection of both bone marrow and lungs during chronic CS exposure, thus encouraging future studies of potential therapeutic benefit of AMD3100 in emphysema.

The Influence of Work-Related Chronic Stress on the Regulation of Emotion and on Functional Connectivity in the Brain

PubMed Central

Golkar, Armita; Johansson, Emilia; Kasahara, Maki; Osika, Walter; Perski, Aleksander; Savic, Ivanka

2014-01-01

Despite mounting reports about the negative effects of chronic occupational stress on cognitive and emotional functions, the underlying mechanisms are unknown. Recent findings from structural MRI raise the question whether this condition could be associated with a functional uncoupling of the limbic networks and an impaired modulation of emotional stress. To address this, 40 subjects suffering from burnout symptoms attributed to chronic occupational stress and 70 controls were investigated using resting state functional MRI. The participants' ability to up- regulate, down-regulate, and maintain emotion was evaluated by recording their acoustic startle response while viewing neutral and negatively loaded images. Functional connectivity was calculated from amygdala seed regions, using explorative linear correlation analysis. Stressed subjects were less capable of down-regulating negative emotion, but had normal acoustic startle responses when asked to up-regulate or maintain emotion and when no regulation was required. The functional connectivity between the amygdala and the anterior cingulate cortex correlated with the ability to down-regulate negative emotion. This connectivity was significantly weaker in the burnout group, as was the amygdala connectivity with the dorsolateral prefrontal cortex and the motor cortex, whereas connectivity from the amygdala to the cerebellum and the insular cortex were stronger. In subjects suffering from chronic occupational stress, the functional couplings within the emotion- and stress-processing limbic networks seem to be altered, and associated with a reduced ability to down-regulate the response to emotional stress, providing a biological substrate for a further facilitation of the stress condition. PMID:25184294

Chronic stress from adolescence to aging in the prefrontal cortex: A neuroimmune perspective.

PubMed

Macht, Victoria A; Reagan, Lawrence P

2018-04-01

The development of the organism is a critical variable which influences the magnitude, duration, and reversibility of the effects of chronic stress. Such factors are relevant to the prefrontal cortex (PFC), as this brain region is the last to mature, the first to decline, and is highly stress-sensitive. Therefore, this review will examine the intersection between the nervous system and immune system at glutamatergic synapses in the PFC across three developmental periods: adolescence, adulthood, and aging. Glutamatergic synapses are tightly juxtaposed with microglia and astrocytes, and each of these cell types exhibits their own developmental trajectory. Not only does chronic stress differentially impact each of these cell types across development, but chronic stress also alters intercellular communication within this quad-partite synapse. These observations suggest that developmental shifts in both neural and immune function across neurons, microglia, and astrocytes mediate shifting effects of chronic stress on glutamatergic transmission. Copyright © 2018 Elsevier Inc. All rights reserved.

Astaxanthin alleviates cerebral edema by modulating NKCC1 and AQP4 expression after traumatic brain injury in mice.

PubMed

Zhang, Mingkun; Cui, Zhenwen; Cui, Hua; Cao, Yang; Zhong, Chunlong; Wang, Yong

2016-08-31

Astaxanthin is a carotenoid pigment that possesses potent antioxidative, anti-inflammatory, antitumor, and immunomodulatory activities. Previous studies have demonstrated that astaxanthin displays potential neuroprotective properties for the treatment of central nervous system diseases, such as ischemic brain injury and subarachnoid hemorrhage. This study explored whether astaxanthin is neuroprotective and ameliorates neurological deficits following traumatic brain injury (TBI). Our results showed that, following CCI, treatment with astaxanthin compared to vehicle ameliorated neurologic dysfunctions after day 3 and alleviated cerebral edema and Evans blue extravasation at 24 h (p < 0.05). Astaxanthin treatment decreased AQP4 and NKCC1 mRNA levels in a dose-dependent manner at 24 h. AQP4 and NKCC1 protein expressions in the peri-contusional cortex were significantly reduced by astaxanthin at 24 h (p < 0.05). Furthermore, we also found that bumetanide (BU), an inhibitor of NKCC1, inhibited trauma-induced AQP4 upregulation (p < 0.05). Our data suggest that astaxanthin reduces TBI-related injury in brain tissue by ameliorating AQP4/NKCC1-mediated cerebral edema and that NKCC1 contributes to the upregulation of AQP4 after TBI.

Altered resting-state functional connectivity in women with chronic fatigue syndrome.

PubMed

Kim, Byung-Hoon; Namkoong, Kee; Kim, Jae-Jin; Lee, Seojung; Yoon, Kang Joon; Choi, Moonjong; Jung, Young-Chul

2015-12-30

The biological underpinnings of the psychological factors characterizing chronic fatigue syndrome (CFS) have not been extensively studied. Our aim was to evaluate alterations of resting-state functional connectivity in CFS patients. Participants comprised 18 women with CFS and 18 age-matched female healthy controls who were recruited from the local community. Structural and functional magnetic resonance images were acquired during a 6-min passive-viewing block scan. Posterior cingulate cortex seeded resting-state functional connectivity was evaluated, and correlation analyses of connectivity strength were performed. Graph theory analysis of 90 nodes of the brain was conducted to compare the global and local efficiency of connectivity networks in CFS patients with that in healthy controls. The posterior cingulate cortex in CFS patients showed increased resting-state functional connectivity with the dorsal and rostral anterior cingulate cortex. Connectivity strength of the posterior cingulate cortex to the dorsal anterior cingulate cortex significantly correlated with the Chalder Fatigue Scale score, while the Beck Depression Inventory (BDI) score was controlled. Connectivity strength to the rostral anterior cingulate cortex significantly correlated with the Chalder Fatigue Scale score. Global efficiency of the posterior cingulate cortex was significantly lower in CFS patients, while local efficiency showed no difference from findings in healthy controls. The findings suggest that CFS patients show inefficient increments in resting-state functional connectivity that are linked to the psychological factors observed in the syndrome. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Toxoplasma gondii Infection in Mice Impairs Long-Term Fear Memory Consolidation through Dysfunction of the Cortex and Amygdala.

PubMed

Ihara, Fumiaki; Nishimura, Maki; Muroi, Yoshikage; Mahmoud, Motamed Elsayed; Yokoyama, Naoaki; Nagamune, Kisaburo; Nishikawa, Yoshifumi

2016-10-01

Chronic infection with Toxoplasma gondii becomes established in tissues of the central nervous system, where parasites may directly or indirectly modulate neuronal function. Epidemiological studies have revealed that chronic infection in humans is a risk factor for developing mental diseases. However, the mechanisms underlying parasite-induced neuronal dysfunction in the brain remain unclear. Here, we examined memory associated with conditioned fear in mice and found that T. gondii infection impairs consolidation of conditioned fear memory. To examine the brain pathology induced by T. gondii infection, we analyzed the parasite load and histopathological changes. T. gondii infects all brain areas, yet the cortex exhibits more severe tissue damage than other regions. We measured neurotransmitter levels in the cortex and amygdala because these regions are involved in fear memory expression. The levels of dopamine metabolites but not those of dopamine were increased in the cortex of infected mice compared with those in the cortex of uninfected mice. In contrast, serotonin levels were decreased in the amygdala and norepinephrine levels were decreased in the cortex and amygdala of infected mice. The levels of cortical dopamine metabolites were associated with the time spent freezing in the fear-conditioning test. These results suggest that T. gondii infection affects fear memory through dysfunction of the cortex and amygdala. Our findings provide insight into the mechanisms underlying the neurological changes seen during T. gondii infection. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Effects of chronic stress in adolescence on learned fear, anxiety, and synaptic transmission in the rat prelimbic cortex.

PubMed

Negrón-Oyarzo, Ignacio; Pérez, Miguel Ángel; Terreros, Gonzalo; Muñoz, Pablo; Dagnino-Subiabre, Alexies

2014-02-01

The prelimbic cortex and amygdala regulate the extinction of conditioned fear and anxiety, respectively. In adult rats, chronic stress affects the dendritic morphology of these brain areas, slowing extinction of learned fear and enhancing anxiety. The aim of this study was to determine whether rats subjected to chronic stress in adolescence show changes in learned fear, anxiety, and synaptic transmission in the prelimbic cortex during adulthood. Male Sprague Dawley rats were subjected to seven days of restraint stress on postnatal day forty-two (PND 42, adolescence). Afterward, the fear-conditioning paradigm was used to study conditioned fear extinction. Anxiety-like behavior was measured one day (PND 50) and twenty-one days (PND 70, adulthood) after stress using the elevated-plus maze and dark-light box tests, respectively. With another set of rats, excitatory synaptic transmission was analyzed with slices of the prelimbic cortex. Rats that had been stressed during adolescence and adulthood had higher anxiety-like behavior levels than did controls, while stress-induced slowing of learned fear extinction in adolescence was reversed during adulthood. As well, the field excitatory postsynaptic potentials of stressed adolescent rats had significantly lower amplitudes than those of controls, although the amplitudes were higher in adulthood. Our results demonstrate that short-term stress in adolescence induces strong effects on excitatory synaptic transmission in the prelimbic cortex and extinction of learned fear, where the effect of stress on anxiety is more persistent than on the extinction of learned fear. These data contribute to the understanding of stress neurobiology. Copyright © 2013 Elsevier B.V. All rights reserved.

Therapy-related longitudinal brain perfusion changes in patients with chronic pelvic pain syndrome.

PubMed

Weisstanner, Christian; Mordasini, Livio; Thalmann, George N; Verma, Rajeev K; Rummel, Christian; Federspiel, Andrea; Kessler, Thomas M; Wiest, Roland

2017-08-03

The imaging method most frequently employed to identify brain areas involved in neuronal processing of nociception and brain pain perception is blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI). Arterial spin labelling (ASL), in contrast, offers advantages when slow varying changes in brain function are investigated. Chronic pelvic pain syndrome (CPPS) is a disorder of, mostly, young males that leads to altered pain perceptions in structures related to the pelvis. We aimed to investigate the potential of ASL to monitor longitudinal cranial blood flow (CBF) changes in patients with CPPS. In a randomised, placebo-controlled, double-blind single centre trial, we investigated treatment effects in CPPS after 12 weeks in patients that underwent sono-electro-magnetic therapy vs placebo. We investigated changes of CBF related to treatment outcome using pseudo-continuous arterial spin labelling (pCASL)-MRI. We observed CBF downregulation in the prefrontal cortex and anterior cingulate cortex and upregulation in the dorsolateral prefrontal cortex in responders. Nonresponders presented with CBF upregulation in the hippocampus. In patients with a history of CPPS of less than 12 months, there were significant correlations between longitudinal CBF changes and the Chronic Prostatitis Symptom Index pain subscore within the joint clusters anterior cingulate cortex and left anterior prefrontal cortex in responders, and the right hippocampus in nonresponders. We demonstrated therapy-related and stimulus-free longitudinal CBF changes in core areas of the pain matrix using ASL. ASL may act as a complementary noninvasive method to functional MRI and single-photon emission computed tomography / positron emission tomography, especially in the longitudinal assessment of pain response in clinical trials.

Depression in chronic ketamine users: Sex differences and neural bases.

PubMed

Li, Chiang-Shan R; Zhang, Sheng; Hung, Chia-Chun; Chen, Chun-Ming; Duann, Jeng-Ren; Lin, Ching-Po; Lee, Tony Szu-Hsien

2017-11-30

Chronic ketamine use leads to cognitive and affective deficits including depression. Here, we examined sex differences and neural bases of depression in chronic ketamine users. Compared to non-drug using healthy controls (HC), ketamine-using females but not males showed increased depression score as assessed by the Center of Epidemiological Studies Depression Scale (CES-D). We evaluated resting state functional connectivity (rsFC) of the subgenual anterior cingulate cortex (sgACC), a prefrontal structure consistently implicated in the pathogenesis of depression. Compared to HC, ketamine users (KU) did not demonstrate significant changes in sgACC connectivities at a corrected threshold. However, in KU, a linear regression against CES-D score showed less sgACC connectivity to the orbitofrontal cortex (OFC) with increasing depression severity. Examined separately, male and female KU showed higher sgACC connectivity to bilateral superior temporal gyrus and dorsomedial prefrontal cortex (dmPFC), respectively, in correlation with depression. The linear correlation of sgACC-OFC and sgACC-dmPFC connectivity with depression was significantly different in slope between KU and HC. These findings highlighted changes in rsFC of the sgACC as associated with depression and sex differences in these changes in chronic ketamine users. Copyright © 2017 Elsevier B.V. All rights reserved.

Taurine restores the exploratory behavior following alcohol withdrawal and decreases BDNF mRNA expression in the frontal cortex of chronic alcohol-treated rats.

PubMed

Hansen, Alana Witt; Almeida, Felipe Borges; Bandiera, Solange; Pulcinelli, Rianne Remus; Fragoso, Ana Luiza Rodrigues; Schneider, Ricardo; Barros, Helena Maria Tannhauser; Gomez, Rosane

2017-10-01

Alcohol use disorder is an alarming health problem, and the withdrawal symptoms increase the risk of relapse. We have hypothesized that taurine, a multitarget substance acting as a gamma-aminobutyric acid A receptor (GABA A R) positive modulator and a partial inhibitor of N-methyl-d-aspartate (NMDA) glutamate receptors, may reduce the withdrawal symptoms or modify behaviors when combined with alcohol. Therefore, we investigated the effects of taurine on behavior in the open field test (OFT), the GABA A R α 2 subunit and BDNF mRNA expression in the frontal cortex of rats after chronic alcohol treatment or upon withdrawal. Rats received alcohol 2g/kg (alcohol and withdrawal groups) or water (control group) twice daily by oral gavage for 28days. On day 29, the withdrawal rats received water instead of alcohol, and all groups were reallocated to receive 100mg/kg taurine or vehicle intraperitoneally, once a day for 5days. On day 33, the rats were exposed to OFT; 18h later, they were euthanized, and the frontal cortex was dissected for GABA A R α 2 subunit detection and BDNF mRNA expression determination by real-time quantitative PCR. Taurine administration restored rearing behavior to the control levels in the withdrawal rats. Taurine also showed anxiolytic-like effects in control rats and did not change the behaviors in the chronic alcohol group. Chronic alcohol treatment or withdrawal did not change the GABA A R α 2 subunit or BDNF mRNA expression in the frontal cortex, but taurine decreased the α 2 subunit level in control rats and to the BDNF levels in the alcohol rat group. We conclude that taurine restored exploratory behavior after alcohol withdrawal but that this effect was not related to the GABA A R α 2 subunit or BDNF mRNA expression in the frontal cortex of the rats. Copyright © 2017 Elsevier Inc. All rights reserved.

Altered prefrontal correlates of monetary anticipation and outcome in chronic pain.

PubMed

Martucci, Katherine T; Borg, Nicholas; MacNiven, Kelly H; Knutson, Brian; Mackey, Sean C

2018-04-04

Chronic pain may alter both affect- and value-related behaviors, which represents a potentially treatable aspect of chronic pain experience. Current understanding of how chronic pain influences the function of brain reward systems, however, is limited. Using a monetary incentive delay task and functional magnetic resonance imaging (fMRI), we measured neural correlates of reward anticipation and outcomes in female participants with the chronic pain condition of fibromyalgia (N = 17) and age-matched, pain-free, female controls (N = 15). We hypothesized that patients would demonstrate lower positive arousal, as well as altered reward anticipation and outcome activity within corticostriatal circuits implicated in reward processing. Patients demonstrated lower arousal ratings as compared with controls, but no group differences were observed for valence, positive arousal, or negative arousal ratings. Group fMRI analyses were conducted to determine predetermined region of interest, nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC), responses to potential gains, potential losses, reward outcomes, and punishment outcomes. Compared with controls, patients demonstrated similar, although slightly reduced, NAcc activity during gain anticipation. Conversely, patients demonstrated dramatically reduced mPFC activity during gain anticipation-possibly related to lower estimated reward probabilities. Further, patients demonstrated normal mPFC activity to reward outcomes, but dramatically heightened mPFC activity to no-loss (nonpunishment) outcomes. In parallel to NAcc and mPFC responses, patients demonstrated slightly reduced activity during reward anticipation in other brain regions, which included the ventral tegmental area, anterior cingulate cortex, and anterior insular cortex. Together, these results implicate altered corticostriatal processing of monetary rewards in chronic pain.

Spinal Cord Injury Causes Brain Inflammation Associated with Cognitive and Affective Changes: Role of Cell Cycle Pathways

PubMed Central

Zhao, Zaorui; Sabirzhanov, Boris; Stoica, Bogdan A.; Kumar, Alok; Luo, Tao; Skovira, Jacob; Faden, Alan I.

2014-01-01

Experimental spinal cord injury (SCI) causes chronic neuropathic pain associated with inflammatory changes in thalamic pain regulatory sites. Our recent studies examining chronic pain mechanisms after rodent SCI showed chronic inflammatory changes not only in thalamus, but also in other regions including hippocampus and cerebral cortex. Because changes appeared similar to those in our rodent TBI models that are associated with neurodegeneration and neurobehavioral dysfunction, we examined effects of mouse SCI on cognition, depressive-like behavior, and brain inflammation. SCI caused spatial and retention memory impairment and depressive-like behavior, as evidenced by poor performance in the Morris water maze, Y-maze, novel objective recognition, step-down passive avoidance, tail suspension, and sucrose preference tests. SCI caused chronic microglial activation in the hippocampus and cerebral cortex, where microglia with hypertrophic morphologies and M1 phenotype predominated. Stereological analyses showed significant neuronal loss in the hippocampus at 12 weeks but not 8 d after injury. Increased cell-cycle-related gene (cyclins A1, A2, D1, E2F1, and PCNA) and protein (cyclin D1 and CDK4) expression were found chronically in hippocampus and cerebral cortex. Systemic administration of the selective cyclin-dependent kinase inhibitor CR8 after SCI significantly reduced cell cycle gene and protein expression, microglial activation and neurodegeneration in the brain, cognitive decline, and depression. These studies indicate that SCI can initiate a chronic brain neurodegenerative response, likely related to delayed, sustained induction of M1-type microglia and related cell cycle activation, which result in cognitive deficits and physiological depression. PMID:25122899

Chronic morbidities after traumatic brain injury: an update for the advanced practice nurse.

PubMed

Bay, Esther H; Chartier, Kattlynn S

2014-06-01

Emerging data suggest that traumatic brain injury (TBI) is a disease process with considerable long-range morbidities requiring lifelong monitoring and treatment. Multiple chronic morbidities develop across the life span after TBI, including mental health disorders, headaches, seizures, and neuroendocrine imbalances as well as chronic diseases. Still, there has been limited focus on effective guides and strategies for helping persons with TBI meet their chronic health needs as they live with the consequences of TBI. The advanced practice nurse is well positioned to participate collaboratively in practices that promote health screening and chronic disease management after TBI to ameliorate distress and enhance quality of life as persons with TBI live with lifelong consequences.

Support vector machine and fuzzy C-mean clustering-based comparative evaluation of changes in motor cortex electroencephalogram under chronic alcoholism.

PubMed

Kumar, Surendra; Ghosh, Subhojit; Tetarway, Suhash; Sinha, Rakesh Kumar

2015-07-01

In this study, the magnitude and spatial distribution of frequency spectrum in the resting electroencephalogram (EEG) were examined to address the problem of detecting alcoholism in the cerebral motor cortex. The EEG signals were recorded from chronic alcoholic conditions (n = 20) and the control group (n = 20). Data were taken from motor cortex region and divided into five sub-bands (delta, theta, alpha, beta-1 and beta-2). Three methodologies were adopted for feature extraction: (1) absolute power, (2) relative power and (3) peak power frequency. The dimension of the extracted features is reduced by linear discrimination analysis and classified by support vector machine (SVM) and fuzzy C-mean clustering. The maximum classification accuracy (88 %) with SVM clustering was achieved with the EEG spectral features with absolute power frequency on F4 channel. Among the bands, relatively higher classification accuracy was found over theta band and beta-2 band in most of the channels when computed with the EEG features of relative power. Electrodes wise CZ, C3 and P4 were having more alteration. Considering the good classification accuracy obtained by SVM with relative band power features in most of the EEG channels of motor cortex, it can be suggested that the noninvasive automated online diagnostic system for the chronic alcoholic condition can be developed with the help of EEG signals.

Elevated gamma-aminobutyric acid levels in chronic schizophrenia.

PubMed

Ongür, Dost; Prescot, Andrew P; McCarthy, Julie; Cohen, Bruce M; Renshaw, Perry F

2010-10-01

Despite widely replicated abnormalities of gamma-aminobutyric acid (GABA) neurons in schizophrenia postmortem, few studies have measured tissue GABA levels in vivo. We used proton magnetic resonance spectroscopy to measure tissue GABA levels in participants with schizophrenia and healthy control subjects in the anterior cingulate cortex and parieto-occipital cortex. Twenty-one schizophrenia participants effectively treated on a stable medication regimen (mean age 39.0, 14 male) and 19 healthy control subjects (mean age 36.3, 12 male) underwent a proton magnetic resonance spectroscopy scan using GABA-selective editing at 4 Tesla after providing informed consent. Data were collected from two 16.7-mL voxels and analyzed using LCModel. We found elevations in GABA/creatine in the schizophrenia group compared with control subjects [F(1,65) = 4.149, p = .046] in both brain areas (15.5% elevation in anterior cingulate cortex, 11.9% in parieto-occipital cortex). We also found a positive correlation between GABA/creatine and glutamate/creatine, which was not accounted for by % GM or brain region. We found elevated GABA/creatinine in participants with chronically treated schizophrenia. Postmortem studies report evidence for dysfunctional GABAergic neurotransmission in schizophrenia. Elevated GABA levels, whether primary to illness or compensatory to another process, may be associated with dysfunctional GABAergic neurotransmission in chronic schizophrenia. Copyright © 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Alteration in 5-HT₂C, NMDA receptor and IP3 in cerebral cortex of epileptic rats: restorative role of Bacopa monnieri.

PubMed

Krishnakumar, Amee; Anju, T R; Abraham, Pretty Mary; Paulose, C S

2015-01-01

Bacopa monnieri is effective in stress management, brain function and a balanced mood. 5-HT2C receptors have been implicated in stress whereas NMDA receptors and mGlu5 play crucial role in memory and cognition. In the present study, we investigated the role of B. monnieri extract in ameliorating pilocarpine induced temporal lobe epilepsy through regulation of 5-HT2C and NMDA receptors in cerebral cortex. Our studies confirmed an increased 5-HT2C receptor function during epilepsy thereby facilitating IP3 release. We also observed an decreased NMDA receptor function with an elevated mGlu5 and GLAST gene expression in epileptic condition indicating the possibility for glutamate mediated excitotoxicity. These alterations lead to impaired behavioural functions as indicated by the Elevated Plus maze test. Carbamazepine and B. monnieri treatments to epileptic rats reversed the alterations in 5-HT2C, NMDA receptor functions and IP3 content thereby effectively managing the neurotransmitter balance in the cerebral cortex.

Ameliorative potential of Vernonia cinerea on chronic constriction injury of sciatic nerve induced neuropathic pain in rats.

PubMed

Thiagarajan, Venkata R K; Shanmugam, Palanichamy; Krishnan, Uma M; Muthuraman, Arunachalam

2014-08-29

The aim of the present study is to investigate the ameliorative potential of ethanolic extract of whole plant of Vernonia cinerea in the chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain in rats. Behavioral parameters such as a hot plate, acetone drop, paw pressure, Von Frey hair and tail immersion tests were performed to assess the degree of thermal, chemical and mechanical hyperalgesia and allodynia. Biochemical changes in sciatic nerve tissue were ruled out by estimating thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and total calcium levels. Ethanolic extract of Vernonia cinerea and pregabalin were administered for 14 consecutive days starting from the day of surgery. CCI of sciatic nerve has been shown to induce significant changes in behavioral, biochemical and histopathological assessments when compared to the sham control group. Vernonia cinerea attenuated in a dose dependent manner the above pathological changes induced by CCI of the sciatic nerve, which is similar to attenuation of the pregabalin pretreated group. The ameliorating effect of ethanolic extract of Vernonia cinerea against CCI of sciatic nerve induced neuropathic pain may be due to the presence of flavonoids and this effect is attributed to anti-oxidative, neuroprotective and calcium channel modulator actions of these compounds.

Ameliorative potential of Vernonia cinerea on chronic constriction injury of sciatic nerve induced neuropathic pain in rats.

PubMed

Thiagarajan, Venkata R K; Shanmugam, Palanichamy; Krishnan, Uma M; Muthuraman, Arunachalam

2014-09-01

The aim of the present study is to investigate the ameliorative potential of ethanolic extract of whole plant of Vernonia cinerea in the chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain in rats. Behavioral parameters such as a hot plate, acetone drop, paw pressure, Von Frey hair and tail immersion tests were performed to assess the degree of thermal, chemical and mechanical hyperalgesia and allodynia. Biochemical changes in sciatic nerve tissue were ruled out by estimating thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and total calcium levels. Ethanolic extract of Vernonia cinerea and pregabalin were administered for 14 consecutive days starting from the day of surgery. CCI of sciatic nerve has been shown to induce significant changes in behavioral, biochemical and histopathological assessments when compared to the sham control group. Vernonia cinerea attenuated in a dose dependent manner the above pathological changes induced by CCI of the sciatic nerve, which is similar to attenuation of the pregabalin pretreated group. The ameliorating effect of ethanolic extract of Vernonia cinerea against CCI of sciatic nerve induced neuropathic pain may be due to the presence of flavonoids and this effect is attributed to anti-oxidative, neuroprotective and calcium channel modulator actions of these compounds.

Inhibition of G0/G1 Switch 2 Ameliorates Renal Inflammation in Chronic Kidney Disease.

PubMed

Matsunaga, Naoya; Ikeda, Eriko; Kakimoto, Keisuke; Watanabe, Miyako; Shindo, Naoya; Tsuruta, Akito; Ikeyama, Hisako; Hamamura, Kengo; Higashi, Kazuhiro; Yamashita, Tomohiro; Kondo, Hideaki; Yoshida, Yuya; Matsuda, Masaki; Ogino, Takashi; Tokushige, Kazutaka; Itcho, Kazufumi; Furuichi, Yoko; Nakao, Takaharu; Yasuda, Kaori; Doi, Atsushi; Amamoto, Toshiaki; Aramaki, Hironori; Tsuda, Makoto; Inoue, Kazuhide; Ojida, Akio; Koyanagi, Satoru; Ohdo, Shigehiro

2016-11-01

Chronic kidney disease (CKD) is a global health problem, and novel therapies to treat CKD are urgently needed. Here, we show that inhibition of G 0 /G 1 switch 2 (G0s2) ameliorates renal inflammation in a mouse model of CKD. Renal expression of chemokine (C-C motif) ligand 2 (Ccl2) was increased in response to p65 activation in the kidneys of wild-type 5/6 nephrectomy (5/6Nx) mice. Moreover, 5/6Nx Clk/Clk mice, which carry homozygous mutations in the gene encoding circadian locomotor output cycles kaput (CLOCK), did not exhibit aggravation of apoptosis or induction of F4/80-positive cells. The renal expression of G0s2 in wild-type 5/6Nx mice was important for the transactivation of Ccl2 by p65. These pathologies were ameliorated by G0s2 knockdown. Furthermore, a novel small-molecule inhibitor of G0s2 expression was identified by high-throughput chemical screening, and the inhibitor suppressed renal inflammation in 5/6Nx mice. These findings indicated that G0s2 inhibitors may have applications in the treatment of CKD. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Surgical Approaches to Chronic Pancreatitis: Indications and Techniques.

PubMed

Dua, Monica M; Visser, Brendan C

2017-07-01

There are a number of surgical strategies for the treatment of chronic pancreatitis. The optimal intervention should provide effective pain relief, improve/maintain quality of life, preserve exocrine and endocrine function, and manage local complications. Pancreaticoduodenectomy was once the standard operation for patients with chronic pancreatitis; however, other procedures such as the duodenum-preserving pancreatic head resections and its variants have been introduced with good long-term results. Pancreatic duct drainage via a lateral pancreaticojejunostomy continues to be effective in ameliorating symptoms and expediting return to normal lifestyle in many patients. This review summarizes operative indications and gives an overview of the different surgical strategies in treating chronic pancreatitis.

Contralesional Cathodal versus Dual Transcranial Direct Current Stimulation for Decreasing Upper Limb Spasticity in Chronic Stroke Individuals: A Clinical and Neurophysiological Study.

PubMed

Del Felice, Alessandra; Daloli, Verena; Masiero, Stefano; Manganotti, Paolo

2016-12-01

Different transcranial direct current stimulation (tDCS) paradigms have been implemented to treat poststroke spasticity, but discordant results have been reported. This study aimed to determine the efficacy and persistence of dual tDCS (anode over affected motor cortex [M1] and cathode over contralateral M1) compared with cathodal tDCS (cathode over contralateral M1) on upper limb (UL) functional, behavioral, and neurophysiological measures in chronic poststroke individuals. Ten subjects with UL spasticity (7 men; mean 62 years; 8 ischemic stroke; years from event: 2.3 years) were enrolled in a cross-over, double-blinded study. Cathodal and dual tDCS, both preceded by 1 week of sham stimulation 1 month before real stimulation, were applied with 3 months interval. Stimulating paradigm was 20 minutes for five consecutive days in each block. Evaluations were performed before (T1), after real or sham treatment (T2), and after 1 (T3), 4 (T4), and 8 weeks (T5). Functional, behavioral, and neurophysiological tests were performed at each time. Both tDCS paradigms decreased spasticity, increased strength, and ameliorated behavioral scales. Cathodal tDCS was superior to dual tDCS in reducing UL distal spasticity immediately after treatment (T2: cathodal > dual: P = .023) and provided a higher and longer lasting reduction at proximal districts (T3: cathodal > dual: P = .042; T4: cathodal > dual: P = .028; T5: cathodal > dual: P = .05). These findings are supported by an H-reflex modulation (overall time effect P > .002). Cathodal tDCS is slightly more effective than dual tDCS in reducing distal UL spasticity in chronic poststroke subjects. A modulation of spinal inhibitory mechanisms, demonstrated by H-reflex modifications, supports this finding. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

1950 MHz Electromagnetic Fields Ameliorate Aβ Pathology in Alzheimer’s Disease Mice

PubMed Central

Jeong, Ye Ji; Kang, Ga-Young; Kwon, Jong Hwa; Choi, Hyung-Do; Pack, Jeong-Ki; Kim, Nam; Lee, Yun-Sil; Lee, Hae-June

2015-01-01

The involvement of radiofrequency electromagnetic fields (RF-EMF) in the neurodegenerative disease, especially Alzheimer’s disease (AD), has received wide consideration, however, outcomes from several researches have not shown consistency. In this study, we determined whether RF-EMF influenced AD pathology in vivo using Tg-5xFAD mice as a model of AD-like amyloid β (Aβ) pathology. The transgenic (Tg)-5xFAD and wild type (WT) mice were chronically exposed to RF-EMF for 8 months (1950 MHz, SAR 5W/kg, 2 hrs/day, 5 days/week). Notably, chronic RF-EMF exposure significantly reduced not only Aβ plaques, APP, and APP carboxyl-terminal fragments (CTFs) in whole brain including hippocampus and entorhinal cortex but also the ratio of Aβ42 and Aβ40 peptide in the hippocampus of Tg-5xFAD mice. We also found that parenchymal expression of β-amyloid precursor protein cleaving enzyme 1(BACE1) and neuroinflammation were inhibited by RF-EMF exposure in Tg-5xFAD. In addition, RF-EMF was shown to rescue memory impairment in Tg-5xFAD. Moreover, gene profiling from microarray data using hippocampus of WT and Tg-5xFAD following RF-EMF exposure revealed that 5 genes (Tshz2, Gm12695, St3gal1, Isx and Tll1), which are involved in Aβ, are significantly altered inTg-5xFAD mice, exhibiting different responses to RF-EMF in WT or Tg-5xFAD mice; RF-EMF exposure in WT mice showed similar patterns to control Tg-5xFAD mice, however, RF-EMF exposure in Tg-5xFAD mice showed opposite expression patterns. These findings indicate that chronic RF-EMF exposure directly affects Aβ pathology in AD but not in normal brain. Therefore, RF-EMF has preventive effects against AD-like pathology in advanced AD mice with a high expression of Aβ, which suggests that RF-EMF can have a beneficial influence on AD. PMID:26017559

Neuromagnetic beta and gamma oscillations in the somatosensory cortex after music training in healthy older adults and a chronic stroke patient.

PubMed

Jamali, Shahab; Fujioka, Takako; Ross, Bernhard

2014-06-01

Extensive rehabilitation training can lead to functional improvement even years after a stroke. Although neuronal plasticity is considered as a main origin of such ameliorations, specific subtending mechanisms need further investigation. Our aim was to obtain objective neuromagnetic measures sensitive to brain reorganizations induced by a music-supported training. We applied 20-Hz vibrotactile stimuli to the index finger and the ring finger, recorded somatosensory steady-state responses with magnetoencephalography, and analyzed the cortical sources displaying oscillations synchronized with the external stimuli in two groups of healthy older adults before and after musical training or without training. In addition, we applied the same analysis for an anecdotic report of a single chronic stroke patient with hemiparetic arm and hand problems, who received music-supported therapy (MST). Healthy older adults showed significant finger separation within the primary somatotopic map. Beta dipole sources were more anterior located compared to gamma sources. An anterior shift of sources and increases in synchrony between the stimuli and beta and gamma oscillations were observed selectively after music training. In the stroke patient a normalization of somatotopic organization was observed after MST, with digit separation recovered after training and stimulus induced gamma synchrony increased. The proposed stimulation paradigm captures the integrity of primary somatosensory hand representation. Source position and synchronization between the stimuli and gamma activity are indices, sensitive to music-supported training. Responsiveness was also observed in a chronic stroke patient, encouraging for the music-supported therapy. Notably, changes in somatosensory responses were observed, even though the therapy did not involve specific sensory discrimination training. The proposed protocol can be used for monitoring changes in neuronal organization during training and will improve the understanding of the brain mechanisms underlying rehabilitation. Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Antidepressant-like Effect of Bacopaside I in Mice Exposed to Chronic Unpredictable Mild Stress by Modulating the Hypothalamic-Pituitary-Adrenal Axis Function and Activating BDNF Signaling Pathway.

PubMed

Zu, Xianpeng; Zhang, Mingjian; Li, Wencai; Xie, Haisheng; Lin, Zhang; Yang, Niao; Liu, Xinru; Zhang, Weidong

2017-11-01

Preliminary studies conducted in our laboratory have confirmed that Bacopaside I (BS-I), a saponin compound isolated from Bacopa monnieri, displayed antidepressant-like activity in the mouse behavioral despair model. The present investigation aimed to verify the antidepressant-like action of BS-I using a mouse model of behavioral deficits induced by chronic unpredictable mild stress (CUMS) and further probe its underlying mechanism of action. Mice were exposed to CUMS for a period of 5 consecutive weeks to induce depression-like behavior. Then, oral gavage administrations with vehicle (model group), fluoxetine (12 mg/kg, positive group) or BS-I (5, 15, 45 mg/kg, treated group) once daily were started during the last two weeks of CUMS procedure. The results showed that BS-I significantly ameliorated CUMS-induced depression-like behaviors in mice, as characterized by an elevated sucrose consumption in the sucrose preference test and reduced immobility time without affecting spontaneous locomotor activity in the forced swimming test, tail suspension test and open field test. It was also found that BS-I treatment reversed the increased level of plasma corticosterone and decreased mRNA and protein expressions of glucocorticoid receptor induced by CUMS exposure, indicating that hypothalamic-pituitary-adrenal (HPA) axis hyperactivity of CUMS-exposed mice was restored by BS-I treatment. Furthermore, chronic administration of BS-I elevated expression levels of brain-derived neurotrophic factor (BDNF) (mRNA and protein) and activated the phosphorylation of extracellular signal-regulated kinase and cAMP response element-binding protein in the hippocampus and prefrontal cortex in mice subjected to CUMS procedure. Taken together, these results indicated that BS-I exhibited an obvious antidepressant-like effect in mouse model of CUMS-induced depression that was mediated, at least in part, by modulating HPA hyperactivity and activating BDNF signaling pathway.

Enhanced Cognitive Effects of Demethoxycurcumin, a Natural Derivative of Curcumin on Scopolamine-Induced Memory Impairment in Mice.

PubMed

Lim, Dong Wook; Son, Hyun Jung; Um, Min Young; Kim, In-Ho; Han, Daeseok; Cho, Suengmok; Lee, Chang-Ho

2016-08-05

In the present study, we examined the ameliorating effects of demethoxycurcumin (DMC) on memory impairment induced by scopolamine using passive avoidance and Morris water maze tests in mice. Moreover, to determine the neurobiological effects underlying the ameliorating effects of the DMC, choline acetyltransferase (ChAT) immunoreactivity was evaluated in mice exposed to scopolamine. Our results demonstrated that chronic oral administration (28 days) of DMC (10 mg/kg) improved scopolamine-induced learning impairment in the passive avoidance task and memory impairment in the Morris water maze. Moreover, Choline acetyltransferase (ChAT) activity in the DMC-treated group was significantly increased to 33.03% compared with the control group. Our present finding suggests that DMC ameliorates memory impairments induced by scopolamine treatment through reversing the reduction of hippocampal ChAT expression in mice.

Brain glucose metabolism in chronic marijuana users at baseline and during marijuana intoxication.

PubMed

Volkow, N D; Gillespie, H; Mullani, N; Tancredi, L; Grant, C; Valentine, A; Hollister, L

1996-05-31

Despite the widespread abuse of marijuana, knowledge about its effects in the human brain is limited. Brain glucose metabolism with and without delta 9 tetrahydrocannabinol (THC) (main psychoactive component of marijuana) was evaluated in eight normal subjects and eight chronic marijuana abusers with positron emission tomography. At baseline, marijuana abusers showed lower relative cerebellar metabolism than normal subjects. THC increased relative cerebellar metabolism in all subjects, but only abusers showed increases in orbitofrontal cortex, prefrontal cortex, and basal ganglia. Cerebellar metabolism during THC intoxication was significantly correlated with the subjective sense of intoxication. The decreased cerebellar metabolism in marijuana abusers at baseline could account for the motor deficits previously reported in these subjects. The activation of orbitofrontal cortex and basal ganglia by THC in the abusers but not in the normal subjects could underlie one of the mechanisms leading to the drive and the compulsion to self-administer the drug observed in addicted individuals.

Localized cortical chronic traumatic encephalopathy pathology after single, severe axonal injury in human brain.

PubMed

Shively, Sharon B; Edgerton, Sarah L; Iacono, Diego; Purohit, Dushyant P; Qu, Bao-Xi; Haroutunian, Vahram; Davis, Kenneth L; Diaz-Arrastia, Ramon; Perl, Daniel P

2017-03-01

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild impact traumatic brain injury from contact sports. Recently, a consensus panel defined the pathognomonic lesion for CTE as accumulations of abnormally hyperphosphorylated tau (p-tau) in neurons (neurofibrillary tangles), astrocytes and cell processes distributed around small blood vessels at sulcal depths in irregular patterns within the cortex. The pathophysiological mechanism for this lesion is unknown. Moreover, a subset of CTE cases harbors cortical β-amyloid plaques. In this study, we analyzed postmortem brain tissues from five institutionalized patients with schizophrenia and history of surgical leucotomy with subsequent survival of at least another 40 years. Because leucotomy involves severing axons bilaterally in prefrontal cortex, this surgical procedure represents a human model of single traumatic brain injury with severe axonal damage and no external impact. We examined cortical tissues at the leucotomy site and at both prefrontal cortex rostral and frontal cortex caudal to the leucotomy site. For comparison, we analyzed brain tissues at equivalent neuroanatomical sites from non-leucotomized patients with schizophrenia, matched in age and gender. All five leucotomy cases revealed severe white matter damage with dense astrogliosis at the axotomy site and also neurofibrillary tangles and p-tau immunoreactive neurites in the overlying gray matter. Four cases displayed p-tau immunoreactivity in neurons, astrocytes and cell processes encompassing blood vessels at cortical sulcal depths in irregular patterns, similar to CTE. The three cases with apolipoprotein E ε4 haplotype showed scattered β-amyloid plaques in the overlying gray matter, but not the two cases with apolipoprotein E ε3/3 genotype. Brain tissue samples from prefrontal cortex rostral and frontal cortex caudal to the leucotomy site, and all cortical samples from the non-leucotomized patients, showed minimal p-tau and β-amyloid pathology. These findings suggest that chronic axonal damage contributes to the unique pathology of CTE over time.

Poor decision-making by chronic marijuana users is associated with decreased functional responsiveness to negative consequences.

PubMed

Wesley, Michael J; Hanlon, Colleen A; Porrino, Linda J

2011-01-30

Chronic marijuana users (MJ Users) perform poorly on the Iowa Gambling Task (IGT), a complex decision-making task in which monetary wins and losses guide strategy development. This functional magnetic resonance imaging (MRI) study sought to determine if the poor performance of MJ Users was related to differences in brain activity while evaluating wins and losses during the strategy development phase of the IGT. MJ Users (16) and Controls (16) performed a modified IGT in an MRI scanner. Performance was tracked and functional activity in response to early wins and losses was examined. While the MJ Users continued to perform poorly at the end of the task, there was no difference in group performance during the initial strategy development phase. During this phase, before the emergence of behavioral differences, Controls exhibited significantly greater activity in response to losses in the anterior cingulate cortex, medial frontal cortex, precuneus, superior parietal lobe, occipital lobe and cerebellum as compared to MJ Users. Furthermore, in Controls, but not MJ Users, the functional response to losses in the anterior cingulate cortex, ventral medial prefrontal cortex and rostral prefrontal cortex positively correlated with performance over time. These data suggest MJ Users are less sensitive to negative feedback during strategy development. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Electrical stimulation of motor cortex in the uninjured hemisphere after chronic unilateral injury promotes recovery of skilled locomotion through ipsilateral control.

PubMed

Carmel, Jason B; Kimura, Hiroki; Martin, John H

2014-01-08

Partial injury to the corticospinal tract (CST) causes sprouting of intact axons at their targets, and this sprouting correlates with functional improvement. Electrical stimulation of motor cortex augments sprouting of intact CST axons and promotes functional recovery when applied soon after injury. We hypothesized that electrical stimulation of motor cortex in the intact hemisphere after chronic lesion of the CST in the other hemisphere would restore function through ipsilateral control. To test motor skill, rats were trained and tested to walk on a horizontal ladder with irregularly spaced rungs. Eight weeks after injury, produced by pyramidal tract transection, half of the rats received forelimb motor cortex stimulation of the intact hemisphere. Rats with injury and stimulation had significantly improved forelimb control compared with rats with injury alone and achieved a level of proficiency similar to uninjured rats. To test whether recovery of forelimb function was attributable to ipsilateral control, we selectively inactivated the stimulated motor cortex using the GABA agonist muscimol. The dose of muscimol we used produces strong contralateral but no ipsilateral impairments in naive rats. In rats with injury and stimulation, but not those with injury alone, inactivation caused worsening of forelimb function; the initial deficit was reinstated. These results demonstrate that electrical stimulation can promote recovery of motor function when applied late after injury and that motor control can be exerted from the ipsilateral motor cortex. These results suggest that the uninjured motor cortex could be targeted for brain stimulation in people with large unilateral CST lesions.

Therapeutic effects of Qian-Yu decoction and its three extracts on carrageenan-induced chronic prostatitis/chronic pelvic pain syndrome in rats.

PubMed

Zhang, Keda; Zeng, Xiaobin; Chen, Yonggang; Zhao, Rong; Wang, Hui; Wu, Jinhu

2017-01-25

Qian-Yu decoction (QYD) is a traditional Chinese medicinal recipe composed of Radix astragali (Astragalus membranaceus (Fisch.) Bunge var. mongholicus (Bunge) P.K. Hsiao, Fabaceae ), Herba epimedii (Epimedium brevicornum Maxim., Berberidaceae), Herba leonuri (Leonurus japonicus Houtt., Lamiaceae), Cortex phellodendri (Phellodendron chinense Schneid., Rutaceae) and Radix achyranthis bidentatae (Achyranthes bidentata Bl., Amaranthaceae). This study aimed to evaluate the therapeutic activity of QYD against carrageenan-induced chronic prostatic/chronic pelvic pain syndrome (CP/CPPS) in rats and further elucidate its effective components. Three types of components, total polysaccharides, total flavonoids and total saponins were separately extracted from QYD. Carrageenan-induced CP/CPPS rats were intragastrically administered with lyophilized product of QYD, individual extracts and all the combined forms of extracts for three weeks. Prostatic index (PI) was determined and histopathological analysis was performed. The levels of tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), cyclooxygenase-2 (COX-2) and prostaglandin E2 (PEG2) in rat prostate tissues were measured using ELISA. The production of inducible nitric oxide synthase (iNOS) was evaluated by an enzymatic activity assay, and the release of nitric oxide (NO) was determined by a nitrate/nitrite assay. Treatment with QYD significantly ameliorated the histological changes of CP/CPPS rats and reduced the PI by 44.3%, with a marked downregulation of TNF-α (42.8% reduction), IL-1β (45.3%), COX-2 (36.6%), PGE2 (44.2%), iNOS (54.1%) and NO (46.0%). Each of three extracts attenuated the symptom of CP/CPPS, but much more weakly than QYD. The combined administration of three extracts showed efficacy comparable to that of QYD while better than that of any combination of two extracts. A principal component analysis of the six inflammatory mediators as variables indicated that the effects of TS on CP/CPPS were rather different from those of TF and TP, which were similar. QYD can be beneficial in prevention and treatment of CP/CPPS. Polysaccharides, flavonoids and saponins, as the major effective components of QYD, exert a cooperative effect on CP/CPPS.

Cannabinoids Receptor-2 (CB2) agonist ameliorates colitis in IL-10−/− mice by attenuating the activation of T cells and promoting their apoptosis

PubMed Central

Singh, Udai P.; Singh, Narendra P.; Singh, Balwan; Price, Robert L.; Nagarkatti, Mitzi; Nagarkatti, Prakash S.

2014-01-01

Inflammatory bowel disease (IBD) is a chronic intestinal inflammation caused by hyperactivated effector immune cells that produce pro-inflammatory cytokines. Recent studies have shown that the cannabinoid system may play a critical role in mediating protection against intestinal inflammation. However, the effect of cannabinoid receptors induction after chronic colitis progression has not been investigated. Here, we investigate the effect of cannabinoid receptor-2 (CB2) agonist, JWH-133, after chronic colitis in IL-10−/− mice. JWH-133 effectively attenuated the overall clinical score, reversed colitis-associated pathogenesis and decrease in body weight in IL-10−/− mice. After JWH-133 treatment, the percentage of CD4+ T cells, neutrophils, mast cells, natural killer (NK1.1) cells, and activated T cells in the LP of colitis mice declined after JWH-133 treatment in the intestinal lamina propria (LP) and mesenteric lymph nodes (MLN). JWH-133 was also effective in ameliorating dextran sodium sulphate (DSS)-induced colitis. In this model, JWH-133 reduced the number and percentage of macrophages and IFN-γ expressing cells that were induced during colitis progression. Treatment with aminoalkylindole 6-iodopravadoline (AM630), a CB2 receptor antagonist, reversed the colitis protection provided by JWH-133 treatment. Also, activated T cells were found to undergo apoptosis following JWH-133 treatment both in-vivo and in-vitro. These findings suggest that JWH-133 mediates its effect through CB2 receptors, and ameliorates chronic colitis by inducing apoptosis in activated T cells, reducing the numbers of activated T cells, suppressing induction of mast cells, NK cells, and neutrophils at sites of inflammation in the LP. These results support the idea that the CB2 receptor agonists may serve as a therapeutic modality against IBD. PMID:22119709

Early intervention in the 3xTg-AD mice with an amyloid β-antibody fragment ameliorates first hallmarks of Alzheimer disease.

PubMed

Giménez-Llort, Lydia; Rivera-Hernández, Geovanny; Marin-Argany, Marta; Sánchez-Quesada, José L; Villegas, Sandra

2013-01-01

The single-chain variable fragment, scFv-h3D6, has been shown to prevent in vitro toxicity induced by the amyloid β (Aβ) peptide in neuroblastoma cell cultures by withdrawing Aβ oligomers from the amyloid pathway. Present study examined the in vivo effects of scFv-h3D6 in the triple-transgenic 3xTg-AD mouse model of Alzheimer disease. Prior to the treatment, five-month-old female animals, corresponding to early stages of the disease, showed the first behavioral and psychological symptoms of dementia -like behaviors. Cognitive deficits included long- and short-term learning and memory deficits and high swimming navigation speed. After a single intraperitoneal dose of scFv-h3D6, the swimming speed was reversed to normal levels and the learning and memory deficits were ameliorated. Brain tissues of these animals revealed a global decrease of Aβ oligomers in the cortex and olfactory bulb after treatment, but this was not seen in the hippocampus and cerebellum. In the untreated 3xTg-AD animals, we observed an increase of both apoJ and apoE concentrations in the cortex, as well as an increase of apoE in the hippocampus. Treatment significantly recovered the non-pathological levels of these apolipoproteins. Our results suggest that the benefit of scFv-h3D6 occurs at both behavioral and molecular levels.

Neural Dynamics of Autistic Repetitive Behaviors and Fragile X Syndrome: Basal Ganglia Movement Gating and mGluR-Modulated Adaptively Timed Learning.

PubMed

Grossberg, Stephen; Kishnan, Devika

2018-01-01

This article develops the iSTART neural model that proposes how specific imbalances in cognitive, emotional, timing, and motor processes that involve brain regions like prefrontal cortex, temporal cortex, amygdala, hypothalamus, hippocampus, and cerebellum may interact together to cause behavioral symptoms of autism. These imbalances include underaroused emotional depression in the amygdala/hypothalamus, learning of hyperspecific recognition categories that help to cause narrowly focused attention in temporal and prefrontal cortices, and breakdowns of adaptively timed motivated attention and motor circuits in the hippocampus and cerebellum. The article expands the model's explanatory range by, first, explaining recent data about Fragile X syndrome (FXS), mGluR, and trace conditioning; and, second, by explaining distinct causes of stereotyped behaviors in individuals with autism. Some of these stereotyped behaviors, such as an insistence on sameness and circumscribed interests, may result from imbalances in the cognitive and emotional circuits that iSTART models. These behaviors may be ameliorated by operant conditioning methods. Other stereotyped behaviors, such as repetitive motor behaviors, may result from imbalances in how the direct and indirect pathways of the basal ganglia open or close movement gates, respectively. These repetitive behaviors may be ameliorated by drugs that augment D2 dopamine receptor responses or reduce D1 dopamine receptor responses. The article also notes the ubiquitous role of gating by basal ganglia loops in regulating all the functions that iSTART models.

Rosuvastatin ameliorates cognitive impairment in rats fed with high-salt and cholesterol diet via inhibiting acetylcholinesterase activity and amyloid beta peptide aggregation.

PubMed

Husain, I; Akhtar, M; Abdin, M Zainul; Islamuddin, M; Shaharyar, M; Najmi, A K

2018-04-01

Amyloid beta (Aβ) peptide aggregation and cholinergic neurodegeneration are involved in the development of cognitive impairment. Therefore, in this article, we examined rosuvastatin (RSV), an oral hypolipidemic drug, to determine its potential as a dual inhibitor of acetylcholinesterase (AChE) and Aβ peptide aggregation for the treatment of cognitive impairment. Molecular docking study was done to examine the affinity of RSV with Aβ 1-42 and AChE in silico. We also employed neurobehavioral activity tests, biochemical estimation, and histopathology to study the anti-Aβ 1-42 aggregation capability of RSV in vivo. Molecular docking study provided evidence that RSV has the best binding conformer at its receptor site or active site of an enzyme. The cognitive impairment in female Wistar rats was induced by high-salt and cholesterol diet (HSCD) ad libitum for 8 weeks. RSV ameliorated serum cholesterol level, AChE activity, and Aβ 1-42 peptide aggregations in HSCD induced cognitive impairment. In addition, RSV-treated rats showed greater scores in the open field (locomotor activity) test. Moreover, the histopathological studies in the hippocampus and cortex of rat brain also supported that RSV markedly reduced the cognitive impairment and preserved the normal histoarchitectural pattern of the hippocampus and cortex. Taken together, these data indicate that RSV may act as a dual inhibitor of AChE and Aβ 1-42 peptide aggregation, therefore suggesting a therapeutic strategy for cognitive impairment treatment.

Neural Dynamics of Autistic Repetitive Behaviors and Fragile X Syndrome: Basal Ganglia Movement Gating and mGluR-Modulated Adaptively Timed Learning

PubMed Central

Grossberg, Stephen; Kishnan, Devika

2018-01-01

This article develops the iSTART neural model that proposes how specific imbalances in cognitive, emotional, timing, and motor processes that involve brain regions like prefrontal cortex, temporal cortex, amygdala, hypothalamus, hippocampus, and cerebellum may interact together to cause behavioral symptoms of autism. These imbalances include underaroused emotional depression in the amygdala/hypothalamus, learning of hyperspecific recognition categories that help to cause narrowly focused attention in temporal and prefrontal cortices, and breakdowns of adaptively timed motivated attention and motor circuits in the hippocampus and cerebellum. The article expands the model’s explanatory range by, first, explaining recent data about Fragile X syndrome (FXS), mGluR, and trace conditioning; and, second, by explaining distinct causes of stereotyped behaviors in individuals with autism. Some of these stereotyped behaviors, such as an insistence on sameness and circumscribed interests, may result from imbalances in the cognitive and emotional circuits that iSTART models. These behaviors may be ameliorated by operant conditioning methods. Other stereotyped behaviors, such as repetitive motor behaviors, may result from imbalances in how the direct and indirect pathways of the basal ganglia open or close movement gates, respectively. These repetitive behaviors may be ameliorated by drugs that augment D2 dopamine receptor responses or reduce D1 dopamine receptor responses. The article also notes the ubiquitous role of gating by basal ganglia loops in regulating all the functions that iSTART models. PMID:29593596

Swimming attenuates inflammation, oxidative stress, and apoptosis in a rat model of dextran sulfate sodium-induced chronic colitis.

PubMed

Qin, Ling; Yao, Zhi-Qiang; Chang, Qi; Zhao, Ya-Li; Liu, Ning-Ning; Zhu, Xiao-Shan; Liu, Qin-Qin; Wang, Li-Feng; Yang, An-Gang; Gao, Chun-Fang; Li, Jun-Tang

2017-01-31

Increasing evidence suggests that regular physical exercise suppresses chronic inflammation. However, the potential inhibitory effects of swimming on dextran sulfate sodium (DSS)-induced chronic colitis, and its underlying mechanisms, remain unclear. In this study, rats were orally administered DSS to induce chronic colitis, and subsequently treated with or without swimming exercise. A 7-week swimming program (1 or 1.5 hours per day, 5 days per week) ameliorated DSS-caused colon shortening, colon barrier disruption, spleen enlargement, serum LDH release, and reduction of body weight gain. Swimming for 1.5 hours per day afforded greater protection than 1 hour per day. Swimming ameliorated DSS-induced decrease in crypt depth, and increases in myeloperoxidase activity, infiltration of Ly6G+ neutrophils and TNF-α- and IFN-γ-expressing CD3+ T cells, as well as fecal calprotectin and lactoferrin. Swimming inhibited pro-inflammatory cytokine and chemokine production and decreased the protein expression of phosphorylated nuclear factor-κB p65 and cyclooxygenase 2, whereas it elevated interleukin-10 levels. Swimming impeded the generation of reactive oxygen species, malondialdehyde, and nitric oxide; however, it boosted glutathione levels, total antioxidant capacity, and superoxide dismutase and glutathione peroxidase activities. Additionally, swimming decreased caspase-3 activity and expression of apoptosis-inducing factor, cytochrome c, Bax, and cleaved-caspase-3, but increased Bcl-2 levels. Overall, these results suggest that swimming exerts beneficial effects on DSS-induced chronic colitis by modulating inflammation, oxidative stress, and apoptosis.

Swimming attenuates inflammation, oxidative stress, and apoptosis in a rat model of dextran sulfate sodium-induced chronic colitis

PubMed Central

Zhu, Xiao-shan; Liu, Qin-qin; Wang, Li-feng; Yang, An-gang; Gao, Chun-fang; Li, Jun-tang

2017-01-01

Increasing evidence suggests that regular physical exercise suppresses chronic inflammation. However, the potential inhibitory effects of swimming on dextran sulfate sodium (DSS)-induced chronic colitis, and its underlying mechanisms, remain unclear. In this study, rats were orally administered DSS to induce chronic colitis, and subsequently treated with or without swimming exercise. A 7-week swimming program (1 or 1.5 hours per day, 5 days per week) ameliorated DSS-caused colon shortening, colon barrier disruption, spleen enlargement, serum LDH release, and reduction of body weight gain. Swimming for 1.5 hours per day afforded greater protection than 1 hour per day. Swimming ameliorated DSS-induced decrease in crypt depth, and increases in myeloperoxidase activity, infiltration of Ly6G+ neutrophils and TNF-a- and IFN-?-expressing CD3+ T cells, as well as fecal calprotectin and lactoferrin. Swimming inhibited pro-inflammatory cytokine and chemokine production and decreased the protein expression of phosphorylated nuclear factor-?B p65 and cyclooxygenase 2, whereas it elevated interleukin-10 levels. Swimming impeded the generation of reactive oxygen species, malondialdehyde, and nitric oxide; however, it boosted glutathione levels, total antioxidant capacity, and superoxide dismutase and glutathione peroxidase activities. Additionally, swimming decreased caspase-3 activity and expression of apoptosis-inducing factor, cytochrome c, Bax, and cleaved-caspase-3, but increased Bcl-2 levels. Overall, these results suggest that swimming exerts beneficial effects on DSS-induced chronic colitis by modulating inflammation, oxidative stress, and apoptosis. PMID:28030847

Dissociation of nNOS from PSD-95 promotes functional recovery after cerebral ischaemia in mice through reducing excessive tonic GABA release from reactive astrocytes.

PubMed

Lin, Yu-Hui; Liang, Hai-Ying; Xu, Ke; Ni, Huan-Yu; Dong, Jian; Xiao, Hui; Chang, Lei; Wu, Hai-Yin; Li, Fei; Zhu, Dong-Ya; Luo, Chun-Xia

2018-02-01

Mechanisms underlying functional recovery after stroke are little known, and effective drug intervention during the delayed stage is desirable. One potential drug target, the protein-protein interaction between neuronal nitric oxide synthase (nNOS) and postsynaptic density protein 95 (PSD-95), is critical to acute ischaemic damage and neurogenesis. We show that nNOS-PSD-95 dissociation induced by microinjection of a recombinant fusion protein, Tat-nNOS-N 1-133 , or systemic administration of a small-molecule, ZL006, from day 4 to day 10 after photothrombotic ischaemia in mice reduced excessive tonic inhibition in the peri-infarct cortex and ameliorated motor functional outcome. We also demonstrated improved neuroplasticity including increased dendrite spine density and synaptogenesis after reducing excessive tonic inhibition by nNOS-PSD-95 dissociation. Levels of gamma-aminobutyric acid (GABA) and GABA transporter-3/4 (GAT-3/4) are increased in the reactive astrocytes in the peri-infarct cortex. The GAT-3/4-selective antagonist SNAP-5114 reduced tonic inhibition and promoted function recovery, suggesting that increased tonic inhibition in the peri-infarct cortex was due to GABA release from reversed GAT-3/4 in reactive astrocytes. Treatments with Tat-nNOS-N 1-133 or ZL006 after ischaemia inhibited astrocyte activation and GABA production, prevented the reversal of GAT-3/4, and consequently decreased excessive tonic inhibition and ameliorated functional outcome. The underlying molecular mechanisms were associated with epigenetic inhibition of glutamic acid decarboxylase 67 and monoamine oxidase B expression through reduced NO production. The nNOS-PSD-95 interaction is thus a potential target for functional restoration after stroke and ZL006, a small molecule inhibitor of this interaction, is a promising pharmacological lead compound. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Impact of Chronic Stress on the Spatial Learning and GR-PKAc-NF-κB Signaling in the Hippocampus and Cortex in Rats Following Cholinergic Depletion.

PubMed

Lee, Sun-Young; Cho, Woo-Hyun; Lee, Yo-Seob; Han, Jung-Soo

2018-05-01

Studies have shown that the removal of the cholinergic innervation to the hippocampus induces dysfunction of the hypothalamic-pituitary-adrenocortical axis and decreases the number of glucocorticoid receptors (GRs). Subsequent studies have revealed that the loss of cholinergic input to the hippocampus reduces the expression of GRs and activates nuclear factor-kappa B (NF-κB) signaling through interactions with the cytoplasmic catalytic subunit of protein kinase A (PKAc). We examined the effects of chronic stress on cognitive status and GR-PKAc-NF-κB signaling in rats with a loss of cholinergic input to the hippocampus and cortex. Male Sprague-Dawley rats received 192 IgG-saporin injections to selectively eliminate cholinergic neurons in their basal forebrain. Two weeks later, rats were subjected to 1 h of restraint stress per day for 14 days. Rats subjected to both chronic stress and cholinergic depletion showed more severe memory impairments compared to those that received either treatment alone. The reduction in nuclear GR levels induced by cholinergic depletion was unaffected by chronic stress. The activation of NF-κB signaling in the hippocampus and the cerebral cortex induced by cholinergic depletion was augmented by chronic stress, resulting in the increased expression of pro-inflammatory markers, such as inducible nitric oxide synthase and cyclooxygenase-2. The activation of NF-κB induced by cholinergic depletion appears to be aggravated by chronic stress, and this might explain the increased susceptibility of patients with Alzheimer's disease to stress since activation of NF-κB is associated with stress.

Chronic Ketamine Reduces the Peak Frequency of Gamma Oscillations in Mouse Prefrontal Cortex Ex vivo.

PubMed

McNally, James M; McCarley, Robert W; Brown, Ritchie E

2013-01-01

Abnormalities in EEG gamma band oscillations (GBO, 30-80 Hz) serve as a prominent biomarker of schizophrenia (Sz), associated with positive, negative, and cognitive symptoms. Chronic, subanesthetic administration of antagonists of N-methyl-D-aspartate receptors (NMDAR), such as ketamine, elicits behavioral effects, and alterations in cortical interneurons similar to those observed in Sz. However, the chronic effects of ketamine on neocortical GBO are unknown. Thus, here we examine the effects of chronic (five daily i.p. injections) application of ketamine (5 and 30 mg/kg) and the more specific NMDAR antagonist, MK-801 (0.02, 0.5, and 2 mg/kg), on neocortical GBO ex vivo. Oscillations were generated by focal application of the glutamate receptor agonist, kainate (KA), in coronal brain slices containing the prelimbic cortex. This region constitutes the rodent analog of the human dorsolateral prefrontal cortex, a brain region strongly implicated in Sz-pathophysiology. Here we report the novel finding that chronic ketamine elicits a reduction in the peak oscillatory frequency of KA-elicited oscillations (from 47 to 40 Hz at 30 mg/kg). Moreover, the power of GBO in the 40-50 Hz band was reduced. These findings are reminiscent of both the reduced resonance frequency and power of cortical oscillations observed in Sz clinical studies. Surprisingly, MK-801 had no significant effect, suggesting care is needed when equating Sz-like behavioral effects elicited by different NMDAR antagonists to alterations in GBO activity. We conclude that chronic ketamine in the mouse mimics GBO abnormalities observed in Sz patients. Use of this ex vivo slice model may be useful in testing therapeutic compounds which rescue these GBO abnormalities.

The Modulatory Properties of Chronic Antidepressant Drugs Treatment on the Brain Chemokine - Chemokine Receptor Network: A Molecular Study in an Animal Model of Depression.

PubMed

Trojan, Ewa; Ślusarczyk, Joanna; Chamera, Katarzyna; Kotarska, Katarzyna; Głombik, Katarzyna; Kubera, Marta; Basta-Kaim, Agnieszka

2017-01-01

An increasing number of studies indicate that the chemokine system may be the third major communication system of the brain. Therefore, the role of the chemokine system in the development of brain disorders, including depression, has been recently proposed. However, little is known about the impact of the administration of various antidepressant drugs on the brain chemokine - chemokine receptor axis. In the present study, we used an animal model of depression based on the prenatal stress procedure. We determined whether chronic treatment with tianeptine, venlafaxine, or fluoxetine influenced the evoked by prenatal stress procedure changes in the mRNA and protein levels of the homeostatic chemokines, CXCL12 (SDF-1α), CX3CL1 (fractalkine) and their receptors, in the hippocampus and frontal cortex. Moreover, the impact of mentioned antidepressants on the TGF-β, a molecular pathway related to fractalkine receptor (CX3CR1), was explored. We found that prenatal stress caused anxiety and depressive-like disturbances in adult offspring rats, which were normalized by chronic antidepressant treatment. Furthermore, we showed the stress-evoked CXCL12 upregulation while CXCR4 downregulation in hippocampus and frontal cortex. CXCR7 expression was enhanced in frontal cortex but not hippocampus. Furthermore, the levels of CX3CL1 and CX3CR1 were diminished by prenatal stress in the both examined brain areas. The mentioned changes were normalized with various potency by chronic administration of tested antidepressants. All drugs in hippocampus, while tianeptine and venlafaxine in frontal cortex normalized the CXCL12 level in prenatally stressed offspring. Moreover, in hippocampus only fluoxetine enhanced CXCR4 level, while fluoxetine and tianeptine diminished CXCR7 level in frontal cortex. Additionally, the diminished by prenatal stress levels of CX3CL1 and CX3CR1 in the both examined brain areas were normalized by chronic tianeptine and partially fluoxetine administration. Tianeptine modulate also brain TGF-β signaling in the prenatal stress-induced animal model of depression. Our results provide new evidence that not only prenatal stress-induced behavioral disturbances but also changes of CXCL12 and their receptor and at less extend in CX3CL1-CX3CR1 expression may be normalized by chronic antidepressant drug treatment. In particular, the effect on the CXCL12 and their CXCR4 and CXCR7 receptors requires additional studies to elucidate the possible biological consequences.

Brain gray matter alterations in Chinese patients with chronic knee osteoarthritis pain based on voxel-based morphometry

PubMed Central

Liao, Xia; Mao, Cuiping; Wang, Yuan; Zhang, Qingfeng; Cao, Dongyuan; Seminowicz, David A.; Zhang, Ming; Yang, Xiaoli

2018-01-01

Abstract Altered cerebral gray matter volume (GMV) is commonly found in patients with chronic pain. Chronic pain is the prominent characteristic of knee osteoarthritis (KOA), yet little is known about its morphological changes in the brain. Here an MRI study was performed to examine the structural brain abnormalities in 30 KOA patients with knee pain and age-matched healthy subjects. We detected that the patients exhibited significant almost 2-fold age-related decreases of GMV compared to healthy controls. Moreover, KOA patients also had significant loss of regional GMV including in the bilateral orbital frontal cortex (OFC), the right lateral prefrontal cortex (lPFC), and precentral and postcentral cortices. In addition, a high proportion of KOA patients exerted abnormal scores of Hamilton Depression Rating Scale (HAMD), Hamilton Anxiety Scale (HAMA), Mini Mental State examination (MMSE), and Montreal Cognitive Assessment (MoCA) compare to controls. Our results imply that chronic pain conditions which preferentially involve PFC might consider as a “cognitive state.” And emotion and cognitive function about chronic pain should be highly regarded. PMID:29561420

Long-term effects of repetitive transcranial magnetic stimulation (rTMS) in patients with chronic tinnitus.

PubMed

Kleinjung, Tobias; Eichhammer, Peter; Langguth, Berthold; Jacob, Peter; Marienhagen, Joerg; Hajak, Goeran; Wolf, Stephan R; Strutz, Juergen

2005-04-01

The pathophysiologic mechanisms of idiopathic tinnitus remain unclear. Recent studies demonstrated focal brain activation in the auditory cortex of patients with chronic tinnitus. Low-frequency repetitive transcranial magnetic stimulation (rTMS) is able to reduce cortical hyperexcitability. Fusing of the individual PET-scan with the structural MRI-scan (T1, MPRAGE) allowed us to identify exactly the area of increased metabolic activity in the auditory cortex of patients with chronic tinnitus. With the use of a neuronavigational system, this target area was exactly stimulated by the figure 8-shaped magnetic coil. In a prospective study, rTMS (110% motor threshold; 1 Hz; 2000 stimuli/day over 5 days) was performed using a placebo controlled cross-over design. Patients were blinded regarding the stimulus condition. For the sham stimulation a specific sham-coil system was used. Fourteen patients were followed for 6 months. Treatment outcome was assessed with a specific tinnitus questionnaire (Goebel and Hiller). Tertiary referral medical center. Increased metabolic activation in the auditory cortex was verified in all patients. After 5 days of verum rTMS, a highly significant improvement of the tinnitus score was found whereas the sham treatment did not show any significant changes. The treatment outcome after 6 months still demonstrated significant reduction of tinnitus score. These preliminary results demonstrate that neuronavigated rTMS offers new possibilities in the understanding and treatment of chronic tinnitus.

Aberrant temporal and spatial brain activity during rest in patients with chronic pain

PubMed Central

Malinen, Sanna; Vartiainen, Nuutti; Hlushchuk, Yevhen; Koskinen, Miika; Ramkumar, Pavan; Forss, Nina; Kalso, Eija; Hari, Riitta

2010-01-01

In the absence of external stimuli, human hemodynamic brain activity displays slow intrinsic variations. To find out whether such fluctuations would be altered by persistent pain, we asked 10 patients with unrelenting chronic pain of different etiologies and 10 sex- and age-matched control subjects to rest with eyes open during 3-T functional MRI. Independent component analysis was used to identify functionally coupled brain networks. Time courses of an independent component comprising the insular cortices of both hemispheres showed stronger spectral power at 0.12 to 0.25 Hz in patients than in control subjects, with the largest difference at 0.16 Hz. A similar but weaker effect was seen in the anterior cingulate cortex, whereas activity of the precuneus and early visual cortex, used as a control site, did not differ between the groups. In the patient group, seed point-based correlation analysis revealed altered spatial connectivity between insulae and anterior cingulate cortex. The results imply both temporally and spatially aberrant activity of the affective pain-processing areas in patients suffering from chronic pain. The accentuated 0.12- to 0.25-Hz fluctuations in the patient group might be related to altered activity of the autonomic nervous system. PMID:20308545

Oral methylphenidate alleviates the fine motor dysfunction caused by chronic postnatal manganese exposure in adult rats.

PubMed

Beaudin, Stéphane A; Strupp, Barbara J; Lasley, Stephen M; Fornal, Casimir A; Mandal, Shyamali; Smith, Donald R

2015-04-01

Developmental manganese (Mn) exposure is associated with motor dysfunction in children and animal models, but little is known about the underlying neurochemical mechanisms or the potential for amelioration by pharmacotherapy. We investigated whether methylphenidate (MPH) alleviates fine motor dysfunction due to chronic postnatal Mn exposure, and whether Mn exposure impairs brain extracellular dopamine (DA) and norepinephrine (NE) in the prefrontal cortex (PFC) and striatum in adult animals. Rats were orally exposed to 0 or 50 mg Mn/kg/day from postnatal day 1 until the end of the study (PND 145). The staircase test was used to assess skilled forelimb function. Oral MPH (2.5 mg/kg/day) was administered daily 1 h before staircase testing for 16 days. DA and NE levels were measured by dual probe microdialysis. Results show that Mn exposure impaired reaching and grasping skills and the evoked release of DA and NE in the PFC and striatum of adult rats. Importantly, oral MPH treatment fully alleviated the fine motor deficits in the Mn-exposed animals, but did not affect forelimb skills of control rats not exposed to Mn. These results suggest that catecholaminergic hypofunctioning in the PFC and striatum may underlie the Mn-induced fine motor dysfunction, and that oral MPH pharmacotherapy is an effective treatment approach for alleviating this dysfunction in adult animals. The therapeutic potential of MPH for the treatment of motor dysfunction in Mn-exposed children and adults appears promising pending further characterization of MPH efficacy in other functional areas (eg, attention) believed to be affected by developmental Mn exposure. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Amitriptyline is efficacious in ameliorating muscle inflammation and depressive symptoms in the mdx mouse model of Duchenne muscular dystrophy.

PubMed

Manning, Jennifer; Kulbida, Rebecca; Rai, Prerana; Jensen, Lindsay; Bouma, Judith; Singh, Sanjay P; O'Malley, Dervla; Yilmazer-Hanke, Deniz

2014-10-01

Mutations in the structural protein dystrophin underlie muscular dystrophies characterized by progressive deterioration of muscle function. Dystrophin-deficient mdx mice are considered a model for Duchenne muscular dystrophy (DMD). Individuals with DMD are also susceptible to mood disorders, such as depression and anxiety. Therefore, the study objectives were to investigate the effects of the tricyclic antidepressant amitriptyline on mood, learning, central cytokine expression and skeletal muscle inflammation in mdx mice. Amitriptyline-induced effects (10 mg kg(-1) daily s.c. injections, 25 days) on the behaviour of mdx mice were investigated using the open field arena and tail suspension tests. The effects of chronic amitriptyline treatment on inflammatory markers were studied in the muscle and plasma of mdx mice, and mood-associated monoamine and cytokine concentrations were measured in the amygdala, hippocampus, prefrontal cortex, striatum, hypothalamus and midbrain. The mdx mice exhibited increased levels of anxiety and depressive-like behaviour compared with wild-type mice. Amitriptyline treatment had anxiolytic and antidepressant effects in mdx mice associated with elevations in serotonin levels in the amygdala and hippocampus. Inflammation in mdx skeletal muscle tissue was also reduced following amitriptyline treatment as indicated by decreased immune cell infiltration of muscle and lower levels of the pro-inflammatory cytokines tumour necrosis factor-α and interleukin-6 in the forelimb flexors. Interleukin-6 mRNA expression was remarkably reduced in the amygdala of mdx mice by chronic amitriptyline treatment. Positive effects of amitriptyline on mood, in addition to its anti-inflammatory effects in skeletal muscle, may make it an attractive therapeutic option for individuals with DMD. © 2014 The Authors. Experimental Physiology © 2014 The Physiological Society.

Psychotropic effects of Lactobacillus plantarum PS128 in early life-stressed and naïve adult mice.

PubMed

Liu, Yen-Wenn; Liu, Wei-Hsien; Wu, Chien-Chen; Juan, Yi-Chen; Wu, Yu-Chen; Tsai, Huei-Ping; Wang, Sabrina; Tsai, Ying-Chieh

2016-01-15

Ingestion of specific probiotics, namely "psychobiotics", produces psychotropic effects on behavior and affects the hypothalamic-pituitary-adrenal axis and neurochemicals in the brain. We examined the psychotropic effects of a potential psychobiotic bacterium, Lactobacillus plantarum strain PS128 (PS128), on mice subjected to early life stress (ELS) and on naïve adult mice. Behavioral tests revealed that chronic ingestion of PS128 increased the locomotor activities in both ELS and naïve adult mice in the open field test. In the elevated plus maze, PS128 significantly reduced the anxiety-like behaviors in naïve adult mice but not in the ELS mice; whereas the depression-like behaviors were reduced in ELS mice but not in naïve mice in forced swimming test and sucrose preference test. PS128 administration also reduced ELS-induced elevation of serum corticosterone under both basal and stressed states but had no effect on naïve mice. In addition, PS128 reduced inflammatory cytokine levels and increased anti-inflammatory cytokine level in the serum of ELS mice. Furthermore, the dopamine level in the prefrontal cortex (PFC) was significantly increased in PS128 treated ELS and naïve adult mice whereas serotonin (5-HT) level was increased only in the naïve adult mice. These results suggest that chronic ingestion of PS128 could ameliorate anxiety- and depression-like behaviors and modulate neurochemicals related to affective disorders. Thus PS128 shows psychotropic properties and has great potential for improving stress-related symptoms. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Neuronal Activation in the Central Nervous System of Rats in the Initial Stage of Chronic Kidney Disease-Modulatory Effects of Losartan and Moxonidine

PubMed Central

Palkovits, Miklós; Šebeková, Katarína; Klenovics, Kristina Simon; Kebis, Anton; Fazeli, Gholamreza; Bahner, Udo; Heidland, August

2013-01-01

The effect of mild chronic renal failure (CRF) induced by 4/6-nephrectomy (4/6NX) on central neuronal activations was investigated by c-Fos immunohistochemistry staining and compared to sham-operated rats. In the 4/6 NX rats also the effect of the angiotensin receptor blocker, losartan, and the central sympatholyticum moxonidine was studied for two months. In serial brain sections Fos-immunoreactive neurons were localized and classified semiquantitatively. In 37 brain areas/nuclei several neurons with different functional properties were strongly affected in 4/6NX. It elicited a moderate to high Fos-activity in areas responsible for the monoaminergic innervation of the cerebral cortex, the limbic system, the thalamus and hypothalamus (e.g. noradrenergic neurons of the locus coeruleus, serotonergic neurons in dorsal raphe, histaminergic neurons in the tuberomamillary nucleus). Other monoaminergic cell groups (A5 noradrenaline, C1 adrenaline, medullary raphe serotonin neurons) and neurons in the hypothalamic paraventricular nucleus (innervating the sympathetic preganglionic neurons and affecting the peripheral sympathetic outflow) did not show Fos-activity. Stress- and pain-sensitive cortical/subcortical areas, neurons in the limbic system, the hypothalamus and the circumventricular organs were also affected by 4/6NX. Administration of losartan and more strongly moxonidine modulated most effects and particularly inhibited Fos-activity in locus coeruleus neurons. In conclusion, 4/6NX elicits high activity in central sympathetic, stress- and pain-related brain areas as well as in the limbic system, which can be ameliorated by losartan and particularly by moxonidine. These changes indicate a high sensitivity of CNS in initial stages of CKD which could be causative in clinical disturbances. PMID:23818940

BDNF and COX-2 participate in anti-depressive mechanisms of catalpol in rats undergoing chronic unpredictable mild stress.

PubMed

Wang, Jun-Ming; Yang, Lian-He; Zhang, Yue-Yue; Niu, Chun-Ling; Cui, Ying; Feng, Wei-Sheng; Wang, Gui-Fang

2015-11-01

Catalpol, a major compound in Rehmannia glutinosa with both medicinal and nutritional values, has been previously confirmed to shorten the duration of immobility in mice exposed to tail suspension and forced swimming tests. This study attempted to examine the anti-depressive mechanisms of catalpol in rats undergoing chronic unpredictable mild stress (CUMS) by involving brain-derived neurotrophic factor (BDNF) and cyclooxygenase-2 (COX-2). CUMS-exposed rats were given catalpol daily (5, 10, and 20mg/kg, ig) or a reference drug, fluoxetine hydrochloride (FH, 10mg/kg, ig), at 5 weeks after starting the CUMS procedure. Sucrose preference test was performed to observe depression-like behavior, and serum and brain tissues were used for neurochemical and fluorescent quantitative reverse transcription PCR analysis. CUMS induced depression-like behavior, whereas catalpol and FH administration attenuated this symptom. Moreover, CUMS caused excessively elevated levels of serum corticosterone, an index of hypothalamic-pituitary-adrenal (HPA) axis hyperactivation, in a manner attenuated by catalpol and FH administration. Catalpol administration also further decreased BDNF activities, downregulated the mRNA expression of BDNF and tropomyosin-related kinase B (TrkB), and reversed the excessive elevation in the activities and mRNA expression levels of COX-2 and prostaglandin E2 (PGE2) in the hippocampus and frontal cortex of rats undergoing CUMS. Results indicate that catalpol can ameliorate CUMS-induced depression-like behavior, and suggest its mechanisms may partially be ascribed to restoring HPA axis dysfunctions, upregulating BDNF expression and its cognate receptor TrkB, and downregulating COX-2 expression, thereby reducing PGE2 levels in the brain. Copyright © 2015 Elsevier Inc. All rights reserved.

The effects of chronic stress on the human brain: From neurotoxicity, to vulnerability, to opportunity.

PubMed

Lupien, Sonia J; Juster, Robert-Paul; Raymond, Catherine; Marin, Marie-France

2018-04-01

For the last five decades, science has managed to delineate the mechanisms by which stress hormones can impact on the human brain. Receptors for glucocorticoids are found in the hippocampus, amygdala and frontal cortex, three brain regions involved in memory processing and emotional regulation. Studies have shown that chronic exposure to stress is associated with reduced volume of the hippocampus and that chronic stress can modulate volumes of both the amygdala and frontal cortex, suggesting neurotoxic effects of stress hormones on the brain. Yet, other studies report that exposure to early adversity and/or familial/social stressors can increase vulnerability to stress in adulthood. Models have been recently developed to describe the roles that neurotoxic and vulnerability effects can have on the developing brain. These models suggest that developing early stress interventions could potentially counteract the effects of chronic stress on the brain and results going along with this hypothesis are summarized. Copyright © 2018 Elsevier Inc. All rights reserved.

Aniracetam enhances glutamatergic transmission in the prefrontal cortex of stroke-prone spontaneously hypertensive rats.

PubMed

Togashi, Hiroko; Nakamura, Kazuo; Matsumoto, Machiko; Ueno, Ken-ichi; Ohashi, Satoshi; Saito, Hideya; Yoshioka, Mitsuhiro

2002-03-08

The effects of aniracetam, a cognition enhancer, on extracellular levels of glutamate (Glu), gamma-aminobutyric acid (GABA) and nitric oxide metabolites (NOx) were examined in the prefrontal cortex (PFC) and the basolateral amygdala (AMG) in stroke-prone spontaneously hypertensive rats (SHRSP) using in vivo microdialysis. Basal release of Glu, was lower in the AMG of SHRSP than in normotensive Wistar Kyoto rats, whereas no difference in GABA and NOx was noted. Aniracetam (100 mg/kg, p.o.) significantly increased the area under the curve of Glu levels in the PFC, but not in the AMG, of SHRSP. Aniracetam failed to exert any remarkable effects on GABA or NOx levels in either brain region. Our findings suggest that aniracetam enhances cortical glutamatergic release, which may be the mechanism involved in the ameliorating effects of aniracetam on various neuronal dysfunctions.

Brain nicotinic acetylcholine receptors are involved in stress-induced potentiation of nicotine reward in rats.

PubMed

Javadi, Parastoo; Rezayof, Ameneh; Sardari, Maryam; Ghasemzadeh, Zahra

2017-07-01

The aim of the present study was to examine the possible role of nicotinic acetylcholine receptors of the dorsal hippocampus (CA1 regions), the medial prefrontal cortex or the basolateral amygdala in the effect of acute or sub-chronic stress on nicotine-induced conditioned place preference. Our results indicated that subcutaneous administration of nicotine (0.2 mg/kg) induced significant conditioned place preference. Exposure to acute or sub-chronic elevated platform stress potentiated the response of an ineffective dose of nicotine. Pre-conditioning intra-CA1 (0.5-4 µg/rat) or intra-medial prefrontal cortex (0.2-0.3 µg/rat) microinjection of mecamylamine (a non-selective nicotinic acetylcholine receptor antagonist) reversed acute stress-induced potentiation of nicotine reward as measured in the conditioned place preference paradigm. By contrast, pre-conditioning intra-basolateral amygdala microinjection of mecamylamine (4 µg/rat) potentiated the effects of acute stress on nicotine reward. Our findings also showed that intra-CA1 or intra-medial prefrontal cortex, but not intra-basolateral amygdala, microinjection of mecamylamine (4 µg/rat) prevented the effect of sub-chronic stress on nicotine reward. These findings suggest that exposure to elevated platform stress potentiates the rewarding effect of nicotine which may be associated with the involvement of nicotinic acetylcholine receptors. It seems that there is a different contribution of the basolateral amygdala, the medial prefrontal cortex or the CA1 nicotinic acetylcholine receptors in stress-induced potentiation of nicotine-induced conditioned place preference.

Patterns of neural activity predict picture-naming performance of a patient with chronic aphasia.

PubMed

Lee, Yune Sang; Zreik, Jihad T; Hamilton, Roy H

2017-01-08

Naming objects represents a substantial challenge for patients with chronic aphasia. This could be in part because the reorganized compensatory language networks of persons with aphasia may be less stable than the intact language systems of healthy individuals. Here, we hypothesized that the degree of stability would be instantiated by spatially differential neural patterns rather than either increased or diminished amplitudes of neural activity within a putative compensatory language system. We recruited a chronic aphasic patient (KL; 66 year-old male) who exhibited a semantic deficit (e.g., often said "milk" for "cow" and "pillow" for "blanket"). Over the course of four behavioral sessions involving a naming task performed in a mock scanner, we identified visual objects that yielded an approximately 50% success rate. We then conducted two fMRI sessions in which the patient performed a naming task for multiple exemplars of those objects. Multivoxel pattern analysis (MVPA) searchlight revealed differential activity patterns associated with correct and incorrect trials throughout intact brain regions. The most robust and largest cluster was found in the right occipito-temporal cortex encompassing fusiform cortex, lateral occipital cortex (LOC), and middle occipital cortex, which may account for the patient's propensity for semantic naming errors. None of these areas were found by a conventional univariate analysis. By using an alternative approach, we extend current evidence for compensatory naming processes that operate through spatially differential patterns within the reorganized language system. Copyright © 2016 Elsevier Ltd. All rights reserved.

Amantadine Ameliorates Dopamine-Releasing Deficits and Behavioral Deficits in Rats after Fluid Percussion Injury

PubMed Central

Huang, Eagle Yi-Kung; Tsui, Pi-Fen; Kuo, Tung-Tai; Tsai, Jing-Jr.; Chou, Yu-Ching; Ma, Hsin-I; Chiang, Yung-Hsiao; Chen, Yuan-Hao

2014-01-01

Aims To investigate the role of dopamine in cognitive and motor learning skill deficits after a traumatic brain injury (TBI), we investigated dopamine release and behavioral changes at a series of time points after fluid percussion injury, and explored the potential of amantadine hydrochloride as a chronic treatment to provide behavioral recovery. Materials and Methods In this study, we sequentially investigated dopamine release at the striatum and behavioral changes at 1, 2, 4, 6, and 8 weeks after fluid percussion injury. Rats subjected to 6-Pa cerebral cortical fluid percussion injury were treated by using subcutaneous infusion pumps filled with either saline (sham group) or amantadine hydrochloride, with a releasing rate of 3.6mg/kg/hour for 8 weeks. The dopamine-releasing conditions and metabolism were analyzed sequentially by fast scan cyclic voltammetry (FSCV) and high-pressure liquid chromatography (HPLC). Novel object recognition (NOR) and fixed-speed rotarod (FSRR) behavioral tests were used to determine treatment effects on cognitive and motor deficits after injury. Results Sequential dopamine-release deficits were revealed in 6-Pa-fluid-percussion cerebral cortical injured animals. The reuptake rate (tau value) of dopamine in injured animals was prolonged, but the tau value became close to the value for the control group after amantadine therapy. Cognitive and motor learning impairments were shown evidenced by the NOR and FSRR behavioral tests after injury. Chronic amantadine therapy reversed dopamine-release deficits, and behavioral impairment after fluid percussion injuries were ameliorated in the rats treated by using amantadine-pumping infusion. Conclusion Chronic treatment with amantadine hydrochloride can ameliorate dopamine-release deficits as well as cognitive and motor deficits caused by cerebral fluid-percussion injury. PMID:24497943

Arctium lappa ameliorates endothelial dysfunction in rats fed with high fat/cholesterol diets.

PubMed

Lee, Yun Jung; Choi, Deok Ho; Cho, Guk Hyun; Kim, Jin Sook; Kang, Dae Gill; Lee, Ho Sub

2012-08-06

Arctium lappa L. (Asteraceae), burdock, is a medicinal plant that is popularly used for treating hypertension, gout, hepatitis, and other inflammatory disorders. This study was performed to test the effect of ethanol extract of Arctium lappa L. (EAL) seeds on vascular reactivity and inflammatory factors in rats fed a high fat/cholesterol diet (HFCD). EAL-I (100 mg·kg-1/day), EAL-II (200 mg·kg-1/day), and fluvastatin (3 mg·kg-1/day) groups initially received HFCD alone for 8 weeks, with EAL supplementation provided during the final 6 weeks. Treatment with low or high doses of EAL markedly attenuated plasma levels of triglycerides and augmented plasma levels of high-density lipoprotein (HDL) in HFCD-fed rats. Chronic treatment with EAL markedly reduced impairments of acetylcholine (ACh)-induced relaxation of aortic rings. Furthermore, chronic treatment with EAL significantly lowered systolic blood pressure (SBP) and maintained smooth and flexible intimal endothelial layers in HFCD-fed rats. Chronic treatment with EAL suppressed upregulation of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin in the aorta. Chronic treatment with EAL also suppressed increases in matrix metalloproteinase (MMP)-2 expression. These results suggested that EAL can inhibit HFCD-induced vascular inflammation in the rat model. The present study provides evidence that EAL ameliorates HFCD-induced vascular dysfunction through protection of vascular relaxation and suppression of vascular inflammation.

Agmatine for combined treatment of epilepsy, depression and cognitive impairment in chronic epileptic animals.

PubMed

Singh, Tanveer; Bagga, Neetu; Kaur, Anureet; Kaur, Navjot; Gawande, Dinesh Yugraj; Goel, Rajesh Kumar

2017-08-01

Epilepsy is fourth most common neurological disorders associated with depression and cognitive deficits. As per present scenario, none of the antiseizure drugs have been reported successful to have ameliorative effect on epilepsy associated depression and cognitive deficits. Thus, the study was envisioned to assess an ameliorative potential of agmatine on epilepsy and its efficacy and safety for management of associated depression and cognitive deficits. The animals were made epileptic employing pentylenetetrazole (35mg/kg i.p. every 48±2h) kindling model of epilepsy and subsequently were treated with vehicle, valproic acid (300mg/kg/day i.p.) and agmatine (2.5, 5, and 10mg/kg)/day/i.p. for 15days. Except naïve, all the groups were challenged with same pentylenetetrazole dose as employed during kindling on days 5, 10, and 15 to evaluate seizure severity. Two hours after seizure severity test, tail suspension test and passive shock avoidance paradigm was employed to evaluate depression and cognitive behavior respectively. Results suggested that epileptic animals were significantly associated with depression and cognitive impairment. Chronic valproate treatment significantly reduced seizure severity, but was found unable to mitigate depression and cognitive deficits. However, agmatine treatment dose dependently ameliorated seizure severity as well as associated depression and cognitive deficits. On 15th day, animals were euthanized and pertinent neurochemical estimations were carried out in cortical and hippocampal areas of the mice brain. Thus, study concluded that agmatine ameliorated seizure severity, depression and cognitive impairment in epileptic animals, possibly via restoring glutamate-GABA neurotransmission and serotonin synthesis with decreased nitrosative stress. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Altered Primary Motor Cortex Structure, Organization, and Function in Chronic Pain: A Systematic Review and Meta-Analysis.

PubMed

Chang, Wei-Ju; O'Connell, Neil E; Beckenkamp, Paula R; Alhassani, Ghufran; Liston, Matthew B; Schabrun, Siobhan M

2018-04-01

Chronic pain can be associated with movement abnormalities. The primary motor cortex (M1) has an essential role in the formulation and execution of movement. A number of changes in M1 function have been reported in studies of people with chronic pain. This review systematically evaluated the evidence for altered M1 structure, organization, and function in people with chronic pain of neuropathic and non-neuropathic origin. Database searches were conducted and a modified STrengthening the Reporting of OBservational studies in Epidemiology checklist was used to assess the methodological quality of included studies. Meta-analyses, including preplanned subgroup analyses on the basis of condition were performed where possible. Sixty-seven studies (2,290 participants) using various neurophysiological measures were included. There is conflicting evidence of altered M1 structure, organization, and function for neuropathic and non-neuropathic pain conditions. Meta-analyses provided evidence of increased M1 long-interval intracortical inhibition in chronic pain populations. For most measures, the evidence of M1 changes in chronic pain populations is inconclusive. This review synthesizes the evidence of altered M1 structure, organization, and function in chronic pain populations. For most measures, M1 changes are inconsistent between studies and more research with larger samples and rigorous methodology is required to elucidate M1 changes in chronic pain populations. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

The Non-Peptide Vasopressin V1b Receptor Antagonist, SSR149415, Ameliorates Spermatogenesis Function in a Mouse Model of Chronic Social Defeat Stress.

PubMed

Wang, Bin; Zhou, Jian; Zhuang, Yan-Yan; Wang, Liang-Liang; Pu, Jin-Xian; Huang, Yu-Hua; Xia, Fei; Lv, Jin-Xing

2017-11-01

To determine the effects of SSR149415 on testis and spermatogenesis in male mice subjected to chronic social defeat stress, C57BL/6 male mice were divided into two groups: Control and Stress. Then Stress group was subdivided into four subgroups administered water, SSR149415 (1 mg/kg/day), SSR149415 (10 mg/kg/day), SSR149415 (30 mg/kg/day), respectively. The behavioral alterations revealed by social interaction test and open field test were measured. The physical indices, including body weight and gonad weight (testis and epididymis) as well as testis/body weight and cauda epididymis/body weight were detected. Serum hormones, including testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were determined. Sperm count and abnormality as well as testicular histology structure were assessed. The germ cells apoptosis were also evaluated. Chronic social defeat stress-induced behavioral abnormality, as well as gonad atrophy (testis and epididymis) was significantly alleviated in stressed male mice exposed to SSR149415. Regressed serum testosterone levels and elevated serum FSH and LH levels exhibited by stressed male mice were observably reversed following SSR149415 administration. Chronic social defeat stress-induced damage in testicular histology structure and semen quality were also improved after SSR149415 administration. In addition, SSR149415 significantly reversed chronic social defeat stress-induced germ cells apoptosis. Overall, we provide clear evidence indicating the amelioration of chronic social defeat stress-induced behavioral abnormality and testicular dysfunction via SSR149415, promoting the development of drug-directed therapy against this disease. J. Cell. Biochem. 118: 3891-3898, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Administration of 2-arachidonoylglycerol ameliorates both acute and chronic experimental autoimmune encephalomyelitis.

PubMed

Lourbopoulos, Athanasios; Grigoriadis, Nikolaos; Lagoudaki, Roza; Touloumi, Olga; Polyzoidou, Eleni; Mavromatis, Ioannis; Tascos, Nikolaos; Breuer, Aviva; Ovadia, Haim; Karussis, Dimitris; Shohami, Ester; Mechoulam, Raphael; Simeonidou, Constantina

2011-05-16

Experimental autoimmune encephalomyelitis (EAE) is a widely used model of multiple sclerosis (MS) and both conditions have been reported to exhibit reduced endocannabinoid activity. The purpose of this study was to address the effect of exogenously administered 2-arachidonoylglycerol (2AG), an endocannabinoid receptor ligand, on acute phase and chronic disability in EAE. Acute and chronic EAE models were induced in susceptible mice and 2AG-treatment was applied for 14 days from day of disease induction. 2AG-treatment ameliorated acute phase of disease with delay of disease onset in both EAE models and reduced disease mortality and long-term (70 days post-induction) clinical disability in chronic EAE. Reduced axonal pathology in the chronic EAE- (p<0.0001) and increased activation and ramification of microglia in the 2AG-treated acute EAE- (p<0.05) model were noticed. The latter was accompanied by a 2- to 4-fold increase of the M2-macrophages in the perivascular infiltrations (p<0.001) of the 2AG-treated animals in the acute (day 22), although not the chronic (day 70), EAE model. Expression of cannabinoid receptors 1 (CB1R) and 2 (CB2R) was increased in 2AG-treated animals of acute EAE vs. controls (p<0.05). In addition, ex vivo viability assays exhibited reduced proliferation of activated lymph node cells when extracted from 2AG-treated EAE animals, whereas a dose-dependent response of activated lymphocytes to 2AG-treatment in vitro was noticed. Our data indicate for the first time that 2AG treatment may provide direct (via CBRs) and immune (via M2 macrophages) mediated neuroprotection in EAE. Copyright © 2011 Elsevier B.V. All rights reserved.

Chronic ethanol exposure during adolescence in rats induces motor impairments and cerebral cortex damage associated with oxidative stress.

PubMed

Teixeira, Francisco Bruno; Santana, Luana Nazaré da Silva; Bezerra, Fernando Romualdo; De Carvalho, Sabrina; Fontes-Júnior, Enéas Andrade; Prediger, Rui Daniel; Crespo-López, Maria Elena; Maia, Cristiane Socorro Ferraz; Lima, Rafael Rodrigues

2014-01-01

Binge drinking is common among adolescents, and this type of ethanol exposure may lead to long-term nervous system damage. In the current study, we evaluated motor performance and tissue alterations in the cerebral cortex of rats subjected to intermittent intoxication with ethanol from adolescence to adulthood. Adolescent male Wistar rats (35 days old) were treated with distilled water or ethanol (6.5 g/kg/day, 22.5% w/v) during 55 days by gavage to complete 90 days of age. The open field, inclined plane and the rotarod tests were used to assess the spontaneous locomotor activity and motor coordination performance in adult animals. Following completion of behavioral tests, half of animals were submitted to immunohistochemical evaluation of NeuN (marker of neuronal bodies), GFAP (a marker of astrocytes) and Iba1 (microglia marker) in the cerebral cortex while the other half of the animals were subjected to analysis of oxidative stress markers by biochemical assays. Chronic ethanol intoxication in rats from adolescence to adulthood induced significant motor deficits including impaired spontaneous locomotion, coordination and muscle strength. These behavioral impairments were accompanied by marked changes in all cellular populations evaluated as well as increased levels of nitrite and lipid peroxidation in the cerebral cortex. These findings indicate that continuous ethanol intoxication from adolescence to adulthood is able to provide neurobehavioral and neurodegenerative damage to cerebral cortex.

Ferulic acid chronic treatment exerts antidepressant-like effect: role of antioxidant defense system.

PubMed

Lenzi, Juliana; Rodrigues, Andre Felipe; Rós, Adriana de Sousa; de Castro, Amanda Blanski; de Castro, Bianca Blanski; de Lima, Daniela Delwing; Magro, Débora Delwing Dal; Zeni, Ana Lúcia Bertarello

2015-12-01

Oxidative stress has been claimed a place in pathophysiology of depression; however, the details of the neurobiology of this condition remains incompletely understood. Recently, treatments employing antioxidants have been thoroughly researched. Ferulic acid (FA) is a phenolic compound with antioxidant and antidepressant-like effects. Herein, we investigated the involvement of the antioxidant activity of chronic oral FA treatment in its antidepressant-like effect using the tail suspension test (TST) and the forced swimming test (FST) in mice. The modulation of antioxidant system in blood, hippocampus and cerebral cortex was assessed after stress induction through TST and FST. Our results show that FA at the dose of 1 mg/kg has antidepressant-like effect without affecting locomotor activity. The stress induced by despair tests was able to decrease significantly the activities of superoxide dismutase (SOD) in the blood, catalase (CAT) in the blood and cerebral cortex and glutathione peroxidase (GSH-Px) in the cerebral cortex. Thiobarbituric acid-reactive substances (TBA-RS) levels were increased significantly in the cerebral cortex. Furthermore, the results show that FA was capable to increase SOD, CAT and GSH-Px activities and decrease TBA-RS levels in the blood, hippocampus and cerebral cortex. These findings demonstrated that FA treatment in low doses is capable to exert antidepressant-like effect with the involvement of the antioxidant defense system modulation.

Concentrations of strontium, barium, cadmium, copper, zinc, manganese, chromium, antimony, selenium, and lead in the liver and kidneys of dogs according to age, gender, and the occurrence of chronic kidney disease

PubMed Central

Mainzer, Barbara; Lahrssen-Wiederholt, Monika; Schafft, Helmut; Palavinskas, Richard; Breithaupt, Angele; Zentek, Jürgen

2015-01-01

This study was conducted to measure the concentrations of strontium (Sr), barium (Ba), cadmium (Cd), copper (Cu), zinc (Zn), manganese (Mn), chromium (Cr), antimony (Sb), selenium (Se), and lead (Pb) in canine liver, renal cortex, and renal medulla, and the association of these concentrations with age, gender, and occurrence of chronic kidney disease (CKD). Tissues from 50 dogs were analyzed using inductively coupled plasma mass spectrometry. Cu, Zn, and Mn levels were highest in the liver followed by the renal cortex and renal medulla. The highest Sr, Cd, and Se concentrations were measured in the renal cortex while lower levels were found in the renal medulla and liver. Female dogs had higher tissue concentrations of Sr (liver and renal medulla), Cd (liver), Zn (liver and renal cortex), Cr (liver, renal cortex, and renal medulla), and Pb (liver) than male animals. Except for Mn and Sb, age-dependent variations were observed for all element concentrations in the canine tissues. Hepatic Cd and Cr concentrations were higher in dogs with CKD. In conclusion, the present results provide new knowledge about the storage of specific elements in canine liver and kidneys, and can be considered important reference data for diagnostic methods and further investigations. PMID:25234328

Robust selectivity to two-object images in human visual cortex

PubMed Central

Agam, Yigal; Liu, Hesheng; Papanastassiou, Alexander; Buia, Calin; Golby, Alexandra J.; Madsen, Joseph R.; Kreiman, Gabriel

2010-01-01

SUMMARY We can recognize objects in a fraction of a second in spite of the presence of other objects [1–3]. The responses in macaque areas V4 and inferior temporal cortex [4–15] to a neuron’s preferred stimuli are typically suppressed by the addition of a second object within the receptive field (see however [16, 17]). How can this suppression be reconciled with rapid visual recognition in complex scenes? One option is that certain “special categories” are unaffected by other objects [18] but this leaves the problem unsolved for other categories. Another possibility is that serial attentional shifts help ameliorate the problem of distractor objects [19–21]. Yet, psychophysical studies [1–3], scalp recordings [1] and neurophysiological recordings [14, 16, 22–24], suggest that the initial sweep of visual processing contains a significant amount of information. We recorded intracranial field potentials in human visual cortex during presentation of flashes of two-object images. Visual selectivity from temporal cortex during the initial ~200 ms was largely robust to the presence of other objects. We could train linear decoders on the responses to isolated objects and decode information in two-object images. These observations are compatible with parallel, hierarchical and feed-forward theories of rapid visual recognition [25] and may provide a neural substrate to begin to unravel rapid recognition in natural scenes. PMID:20417105

Chronic periodontitis, inflammatory cytokines, and interrelationship with other chronic diseases.

PubMed

Cardoso, Elsa Maria; Reis, Cátia; Manzanares-Céspedes, Maria Cristina

2018-01-01

Periodontal diseases, such as chronic periodontitis, share common inflammatory risk factors with other systemic and chronic inflammatory disorders. Mucosal tissues, such as oral epithelia, are exposed to environmental stressors, such as tobacco and oral bacteria, that might be involved in promoting a systemic inflammatory state. Conversely, chronic disorders can also affect oral health. This review will summarize recent evidence for the interrelationship between chronic periodontitis and other prevalent chronic diseases such as cardiovascular diseases, diabetes, cancer and chronic respiratory diseases. The association with pregnancy is also included due to possible obstetric complications. We will focus on inflammatory cytokines such as TNF-alpha, IL-1, and IL-6, because they have been shown to be increased in patients with chronic periodontitis, in patients with chronic systemic diseases, and in patients with both chronic periodontitis and other chronic diseases. Therefore, an imbalance towards a proinflammatory immune response could underline a bidirectional link between chronic periodontitis and other chronic diseases. Finally, we highlight that a close coordination between dental and other health professionals could promote oral health and prevent or ameliorate other chronic diseases.

Association of dopamine transporter loss in the orbitofrontal and dorsolateral prefrontal cortices with methamphetamine-related psychiatric symptoms.

PubMed

Sekine, Yoshimoto; Minabe, Yoshio; Ouchi, Yasuomi; Takei, Nori; Iyo, Masaomi; Nakamura, Kazuhiko; Suzuki, Katsuaki; Tsukada, Hideo; Okada, Hiroyuki; Yoshikawa, Etsuji; Futatsubashi, Masami; Mori, Norio

2003-09-01

The authors examined dopamine transporter density in the orbitofrontal cortex, dorsolateral prefrontal cortex, and amygdala in methamphetamine users and assessed the relationship of these measures to the subjects' clinical characteristics. Positron emission tomography with [(11)C]WIN 35,428 was used to examine the regions of interest in 11 methamphetamine users and nine healthy comparison subjects. Psychiatric symptoms were evaluated with the Brief Psychiatric Rating Scale. Dopamine transporter density in the three regions studied was significantly lower in the methamphetamine users than in the comparison subjects. The lower dopamine transporter density in the orbitofrontal and dorsolateral prefrontal cortex was significantly correlated with the duration of methamphetamine use and the severity of psychiatric symptoms. Chronic methamphetamine use may cause dopamine transporter reduction in the orbitofrontal cortex, dorsolateral prefrontal cortex, and amygdala in the brain. Psychiatric symptoms in methamphetamine users may be attributable to the decrease in dopamine transporter density in the orbitofrontal cortex and the dorsolateral prefrontal cortex.

Effects of Astragalus Polysaccharides on Dysfunction of Mitochondrial Dynamics Induced by Oxidative Stress.

PubMed

Huang, Yan-Feng; Lu, Lu; Zhu, Da-Jian; Wang, Ming; Yin, Yi; Chen, De-Xiu; Wei, Lian-Bo

2016-01-01

This paper studied the chronic fatigue induced by excessive exercise and the restoration effects of Astragalus polysaccharides (APS) on mitochondria. In vivo, we found that excessive exercise could cause oxidative stress statue which led to morphological and functional changes of mitochondria. The changes, including imbalance between mitochondria fusion-fission processes, activation of mitophagy, and decrease of PGC-1α expression, could be restored by APS. We further confirmed in vitro, and what is more, we found that APS may ameliorate mitochondrial dysfunction through Sirt1 pathway. Based on the results, we may figure out part of the molecular mechanism of mitochondrial amelioration by APS.

L-citrulline provides a novel strategy for treating chronic pulmonary hypertension in newborn infants

PubMed Central

Fike, Candice D.; Summar, Marshall; Aschner, Judy L.

2014-01-01

Effective therapies are urgently needed for infants with forms of pulmonary hypertension that develop or persist beyond the first week of life. The L-arginine nitric oxide (NO) precursor, L-citrulline, improves NO signalling and ameliorates pulmonary hypertension in newborn animal models. In vitro studies demonstrate that manipulating L-citrulline transport alters NO production. Conclusion Strategies that increase the supply and transport of L-citrulline merit pursuit as novel approaches to managing infants with chronic, progressive pulmonary hypertension. PMID:24862864

Brain region- and sex-specific modulation of mitochondrial glucocorticoid receptor phosphorylation in fluoxetine treated stressed rats: effects on energy metabolism.

PubMed

Adzic, Miroslav; Lukic, Iva; Mitic, Milos; Djordjevic, Jelena; Elaković, Ivana; Djordjevic, Ana; Krstic-Demonacos, Marija; Matić, Gordana; Radojcic, Marija

2013-12-01

Antidepressants affect glucocorticoid receptor (GR) functioning partly through modulation of its phosphorylation but their effects on mitochondrial GR have remained undefined. We investigated the ability of chronic fluoxetine treatment to affect chronic stress-induced changes of mitochondrial GR and its phosphoisoforms (pGRs) in the prefrontal cortex and hippocampus of female and male rats. Since mitochondrial GR regulates oxidative phosphorylation, expression of mitochondrial-encoded subunits of cytochrome (cyt) c oxidase and its activity were also investigated. Chronic stress caused accumulation of the GR in mitochondria of female prefrontal cortex, while the changes in the hippocampus were sex-specific at the levels of pGRs. Expression of mitochondrial COXs genes corresponded to chronic stress-modulated mitochondrial GR in both tissues of both genders and to cyt c oxidase activity in females. Moreover, the metabolic parameters in stressed animals were affected by fluoxetine therapy only in the hippocampus. Namely, fluoxetine effects on mitochondrial COXs and cyt c oxidase activity in the hippocampus seem to be conveyed through pGR232 in females, while in males this likely occurs through other mechanisms. In summary, sex-specific regulation of cyt c oxidase by the stress and antidepressant treatment and its differential convergence with mitochondrial GR signaling in the prefrontal cortex and hippocampus could contribute to clarification of sex-dependent vulnerability to stress-related disorders and sex-specific clinical impact of antidepressants. Copyright © 2013 Elsevier Ltd. All rights reserved.

Distinct patterns of brain activity evoked by histamine-induced itch reveal an association with itch intensity and disease severity in atopic dermatitis

PubMed Central

Ishiuji, Y.; Coghill, R.C.; Patel, T.S.; Oshiro, Y.; Kraft, R.A.; Yosipovitch, G.

2009-01-01

Summary Background Little is known about brain mechanisms supporting the experience of chronic puritus in disease states. Objectives To examine the difference in brain processing of histamine-induced itch in patients with active atopic dermatitis (AD) vs. healthy controls with the emerging technique of functional magnetic resonance imaging (fMRI) using arterial spin labelling (ASL). Methods Itch was induced with histamine iontophoresis in eight patients with AD and seven healthy subjects. Results We found significant differences in brain processing of histamine-induced itch between patients with AD and healthy subjects. Patients with AD exhibited bilateral activation of the anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), retrosplenial cingulate cortex and dorsolateral prefrontal cortex (DLPFC) as well as contralateral activation of the caudate nucleus and putamen. In contrast, healthy subjects activated the primary motor cortex, primary somatosensory cortex and superior parietal lobe. The PCC and precuneus exhibited significantly greater activity in patients vs. healthy subjects. A significant correlation between percentage changes of brain activation was noted in the activation of the ACC and contralateral insula and histamine-induced itch intensity as well as disease severity in patients with AD. In addition, an association was noted between DLPFC activity and disease severity. Conclusions Our results demonstrate that ASL fMRI is a promising technique to assess brain activity in chronic itch. Brain activity of acute itch in AD seems to differ from that in healthy subjects. Moreover, the activity in cortical areas involved in affect and emotion correlated to measures of disease severity. PMID:19663870

Chronic intermittent hypoxia induces changes on the expression and activity of neprilysin (EC 3.4.24.11) in the brain of rats.

PubMed

de Oliveira, Renato W; Julian, Guilherme S; Perry, Juliana C; Tufik, Sergio; Chagas, Jair R

2018-06-21

Obstructive sleep apnea (OSA) is a frequent sleeping breathing disorder associated with cognitive impairments. Neprilysin (NEP) is responsible for degrading several substrates related to cognition; however, the effect of chronic intermittent hypoxia (CIH) on NEP is still unknown. This study aimed to evaluate the expression and activity of NEP in cognitive-related brain structures of rats submitted to CIH. Western blot, qRT-PCR and enzyme activity assay, demonstrated that a six-week intermittent hypoxia increased NEP expression and activity, selectively in temporal cortex, but not in the hippocampus and frontal cortex. The increase in NEP activity and expression was reverted followed by two weeks recovery in normoxia. These data show that CIH protocol increases the expression and activity of NEP selectively in the temporal cortex. Additional mechanisms must be investigated to elucidate the effects of CIH in cognition. Copyright © 2018 Elsevier B.V. All rights reserved.

Cortical NMDA receptor expression in human chronic alcoholism: influence of the TaqIA allele of ANKK1.

PubMed

Ridge, Justin P; Dodd, Peter R

2009-10-01

Real-time RT-PCR normalized to GAPDH was used to assay N-methyl-D-aspartate (NMDA) receptor NR1, NR2A and NR2B subunit mRNA in human autopsy cortex tissue from chronic alcoholics with and without comorbid cirrhosis of the liver and matched controls. Subunit expression was influenced by the subject's genotype. The TaqIA polymorphism selectively modulated NMDA receptor mean transcript expression in cirrhotic-alcoholic superior frontal cortex, in diametrically opposite ways in male and female subjects. Genetic make-up may differentially influence vulnerability to brain damage by altering the excitation: inhibition balance, particularly in alcoholics with comorbid cirrhosis of the liver. The TaqIA polymorphism occurs within the poorly characterised ankyrin-repeat containing kinase 1 (ANKK1) gene. Using PCR, ANKK1 mRNA transcript was detected in inferior temporal, occipital, superior frontal and primary motor cortex of control human brain. ANKK1 expression may mediate the influence of the TaqIA polymorphism on phenotype.

Wireless simultaneous stimulation-and-recording device to train cortical circuits in somatosensory cortex.

PubMed

Ramshur, John T; de Jongh Curry, Amy L; Waters, Robert S

2014-01-01

We describe for the first time the design, implementation, and testing of a telemetry controlled simultaneous stimulation and recording device (SRD) to deliver chronic intercortical microstimulation (ICMS) to physiologically identified sites in rat somatosensory cortex (SI) and test hypotheses that chronic ICMS strengthens interhemispheric pathways and leads to functional reorganization in the enhanced cortex. The SRD is a custom embedded device that uses the Cypress Semiconductor's programmable system on a chip (PSoC) that is remotely controlled via Bluetooth. The SRC can record single or multiunit responses from any two of 12 available inputs at 1-15 ksps per channel and simultaneously deliver stimulus pulses (0-255 μA; 10 V compliance) to two user selectable electrodes using monophasic, biphasic, or pseudophasic stimulation waveforms (duration: 0-5 ms, inter-phase interval: 0-5 ms, frequency: 0.1-5 s, delay: 0-10 ms). The SRD was bench tested and validated in vivo in a rat animal model.

Effects of enriched environment on alterations in the prefrontal cortex GFAP- and S100B-immunopositive astrocytes and behavioral deficits in MK-801-treated rats.

PubMed

Rahati, M; Nozari, M; Eslami, H; Shabani, M; Basiri, M

2016-06-21

A plethora of studies have indicated that enriched environment (EE) paradigm provokes plastic and morphological changes in astrocytes with accompanying increments of their density and positively affects the behavior of rodents. We also previously documented that EE could be employed to preclude several behavioral abnormalities, mainly cognitive deficits, attributed to postnatal N-methyl-d-aspartate (NMDA) receptor antagonist (MK-801) treatment, as a rodent model of schizophrenia (SCH) aspects. Given this, the current study quantitatively investigated the number of cells, presumed to be astrocytes, expressing two astroglia-associated proteins (S100B and glial fibrillary acidic protein (GFAP)) by immunohistochemistry in the prefrontal cortex (PFC), along with anxiety and passive avoidance (PA) learning behaviors by utilizing elevated plus maze (EPM) and shuttle-box tests, in MK-801-treated male wistar rats submitted to EE and non-EE rats. Following a treatment regime of sub-chronic MK-801 (1.0mg/kg i.p. daily for five consecutive days from postnatal day (P) 6), S-100B-positive cells and anxiety level were markedly increased, while the GFAP-positive cells and PA learning were notably attenuated. The trend of diminished GFAP-immunopositive cells and elevated S100B-immunostained cells in the PFC was reversed in the SCH-like rats by exposure of animals to EE, commencing from birth up to the time of experiments on P28-85. Additionally, EE exhibited an ameliorating effect on the behavioral abnormalities evoked by MK-801. Overall, present findings support that improper astrocyte functioning and behavioral changes, reminiscent of the many facets of SCH, occur consequential to repetitive administration of MK-801 and that raising rat pups in an EE mitigates these alterations. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Mismatch Negativity in Recent-Onset and Chronic Schizophrenia: A Current Source Density Analysis

PubMed Central

Fulham, W. Ross; Michie, Patricia T.; Ward, Philip B.; Rasser, Paul E.; Todd, Juanita; Johnston, Patrick J.; Thompson, Paul M.; Schall, Ulrich

2014-01-01

Mismatch negativity (MMN) is a component of the event-related potential elicited by deviant auditory stimuli. It is presumed to index pre-attentive monitoring of changes in the auditory environment. MMN amplitude is smaller in groups of individuals with schizophrenia compared to healthy controls. We compared duration-deviant MMN in 16 recent-onset and 19 chronic schizophrenia patients versus age- and sex-matched controls. Reduced frontal MMN was found in both patient groups, involved reduced hemispheric asymmetry, and was correlated with Global Assessment of Functioning (GAF) and negative symptom ratings. A cortically-constrained LORETA analysis, incorporating anatomical data from each individual's MRI, was performed to generate a current source density model of the MMN response over time. This model suggested MMN generation within a temporal, parietal and frontal network, which was right hemisphere dominant only in controls. An exploratory analysis revealed reduced CSD in patients in superior and middle temporal cortex, inferior and superior parietal cortex, precuneus, anterior cingulate, and superior and middle frontal cortex. A region of interest (ROI) analysis was performed. For the early phase of the MMN, patients had reduced bilateral temporal and parietal response and no lateralisation in frontal ROIs. For late MMN, patients had reduced bilateral parietal response and no lateralisation in temporal ROIs. In patients, correlations revealed a link between GAF and the MMN response in parietal cortex. In controls, the frontal response onset was 17 ms later than the temporal and parietal response. In patients, onset latency of the MMN response was delayed in secondary, but not primary, auditory cortex. However amplitude reductions were observed in both primary and secondary auditory cortex. These latency delays may indicate relatively intact information processing upstream of the primary auditory cortex, but impaired primary auditory cortex or cortico-cortical or thalamo-cortical communication with higher auditory cortices as a core deficit in schizophrenia. PMID:24949859

Deep brain stimulation of the dorsal anterior cingulate cortex for the treatment of chronic neuropathic pain.

PubMed

Russo, Jennifer F; Sheth, Sameer A

2015-06-01

Chronic neuropathic pain is estimated to affect 3%-4.5% of the worldwide population. It is associated with significant loss of productive time, withdrawal from the workforce, development of mood disorders such as depression and anxiety, and disruption of family and social life. Current medical therapeutics often fail to adequately treat chronic neuropathic pain. Deep brain stimulation (DBS) targeting subcortical structures such as the periaqueductal gray, the ventral posterior lateral and medial thalamic nuclei, and the internal capsule has been investigated for the relief of refractory neuropathic pain over the past 3 decades. Recent work has identified the dorsal anterior cingulate cortex (dACC) as a new potential neuromodulation target given its central role in cognitive and affective processing. In this review, the authors briefly discuss the history of DBS for chronic neuropathic pain in the United States and present evidence supporting dACC DBS for this indication. They review existent literature on dACC DBS and summarize important findings from imaging and neurophysiological studies supporting a central role for the dACC in the processing of chronic neuropathic pain. The available neurophysiological and empirical clinical evidence suggests that dACC DBS is a viable therapeutic option for the treatment of chronic neuropathic pain and warrants further investigation.

Amygdala, Hippocampus, and Ventral Medial Prefrontal Cortex Volumes Differ in Maltreated Youth with and without Chronic Posttraumatic Stress Disorder.

PubMed

Morey, Rajendra A; Haswell, Courtney C; Hooper, Stephen R; De Bellis, Michael D

2016-02-01

Posttraumatic stress disorder (PTSD) is considered a disorder of recovery where individuals fail to learn and retain extinction of the traumatic fear response. In maltreated youth, PTSD is common, chronic, and associated with comorbidity. Studies of extinction-related structural volumes (amygdala, hippocampus, anterior cingulate cortex (ACC), and ventral medial prefrontal cortex (vmPFC)) and this stress diathesis, in maltreated youth were not previously investigated. In this cross-sectional study, neuroanatomical volumes associated with extinction in maltreated youth with PTSD (N=31), without PTSD (N=32), and in non-maltreated healthy volunteers (n=57) were examined using magnetic resonance imaging. Groups were sociodemographically similar. Participants underwent extensive assessments for strict inclusion/exclusion criteria and DSM-IV disorders. Maltreated youth with PTSD demonstrated decreased right vmPFC volumes compared with both maltreated youth without PTSD and non-maltreated controls. Maltreated youth without PTSD demonstrated larger left amygdala and right hippocampal volumes compared with maltreated youth with PTSD and non-maltreated control youth. PTSD symptoms inversely correlated with right and left hippocampal and left amygdala volumes. Confirmatory masked voxel base morphometry analyses demonstrated greater medial orbitofrontal cortex gray matter intensity in controls than maltreated youth with PTSD. Volumetric results were not influenced by psychopathology or maltreatment variables. We identified volumetric differences in extinction-related structures between maltreated youth with PTSD from those without PTSD. Alterations of the vmPFC may be one mechanism that mediates the pathway from PTSD to comorbidity. Further longitudinal work is needed to determine neurobiological factors related to chronic and persistent PTSD, and to PTSD resilience despite maltreatment.

A Combined Metabonomic and Proteomic Approach Identifies Frontal Cortex Changes in a Chronic Phencyclidine Rat Model in Relation to Human Schizophrenia Brain Pathology

PubMed Central

Wesseling, Hendrik; Chan, Man K; Tsang, T M; Ernst, Agnes; Peters, Fabian; Guest, Paul C; Holmes, Elaine; Bahn, Sabine

2013-01-01

Current schizophrenia (SCZ) treatments fail to treat the broad range of manifestations associated with this devastating disorder. Thus, new translational models that reproduce the core pathological features are urgently needed to facilitate novel drug discovery efforts. Here, we report findings from the first comprehensive label-free liquid-mass spectrometry proteomic- and proton nuclear magnetic resonance-based metabonomic profiling of the rat frontal cortex after chronic phencyclidine (PCP) intervention, which induces SCZ-like symptoms. The findings were compared with results from a proteomic profiling of post-mortem prefrontal cortex from SCZ patients and with relevant findings in the literature. Through this approach, we identified proteomic alterations in glutamate-mediated Ca2+ signaling (Ca2+/calmodulin-dependent protein kinase II, PPP3CA, and VISL1), mitochondrial function (GOT2 and PKLR), and cytoskeletal remodeling (ARP3). Metabonomic profiling revealed changes in the levels of glutamate, glutamine, glycine, pyruvate, and the Ca2+ regulator taurine. Effects on similar pathways were also identified in the prefrontal cortex tissue from human SCZ subjects. The discovery of similar but not identical proteomic and metabonomic alterations in the chronic PCP rat model and human brain indicates that this model recapitulates only some of the molecular alterations of the disease. This knowledge may be helpful in understanding mechanisms underlying psychosis, which, in turn, can facilitate improved therapy and drug discovery for SCZ and other psychiatric diseases. Most importantly, these molecular findings suggest that the combined use of multiple models may be required for more effective translation to studies of human SCZ. PMID:23942359

Does a single session of theta-burst transcranial magnetic stimulation of inferior temporal cortex affect tinnitus perception?

PubMed

Poreisz, Csaba; Paulus, Walter; Moser, Tobias; Lang, Nicolas

2009-05-29

Cortical excitability changes as well as imbalances in excitatory and inhibitory circuits play a distinct pathophysiological role in chronic tinnitus. Repetitive transcranial magnetic stimulation (rTMS) over the temporoparietal cortex was recently introduced to modulate tinnitus perception. In the current study, the effect of theta-burst stimulation (TBS), a novel rTMS paradigm was investigated in chronic tinnitus. Twenty patients with chronic tinnitus completed the study. Tinnitus severity and loudness were monitored using a tinnitus questionnaire (TQ) and a visual analogue scale (VAS) before each session. Patients received 600 pulses of continuous TBS (cTBS), intermittent TBS (iTBS) and intermediate TBS (imTBS) over left inferior temporal cortex with an intensity of 80% of the individual active or resting motor threshold. Changes in subjective tinnitus perception were measured with a numerical rating scale (NRS). TBS applied to inferior temporal cortex appeared to be safe. Although half of the patients reported a slight attenuation of tinnitus perception, group analysis resulted in no significant difference when comparing the three specific types of TBS. Converting the NRS into the VAS allowed us to compare the time-course of aftereffects. Only cTBS resulted in a significant short-lasting improvement of the symptoms. In addition there was no significant difference when comparing the responder and non-responder groups regarding their anamnestic and audiological data. The TQ score correlated significantly with the VAS, lower loudness indicating less tinnitus distress. TBS does not offer a promising outcome for patients with tinnitus in the presented study.

Sulforaphane Ameliorates Okadaic Acid-Induced Memory Impairment in Rats by Activating the Nrf2/HO-1 Antioxidant Pathway.

PubMed

Dwivedi, Subhash; Rajasekar, N; Hanif, Kashif; Nath, Chandishwar; Shukla, Rakesh

2016-10-01

Okadaic acid (OKA) causes memory impairment and attenuates nuclear factor erythroid 2-related factor 2 (Nrf2) along with oxidative stress and neuroinflammation in rats. Sulforaphane (dietary isothiocyanate compound), an activator of Nrf2 signaling, exhibits neuroprotective effects. However, the protective effect of sulforaphane in OKA-induced neurotoxicity remains uninvestigated. Therefore, in the present study, the role of sulforaphane in OKA-induced memory impairment in rats was explored. A significant increased Nrf2 expression in the hippocampus and cerebral cortex was observed in trained (Morris water maze) rats, and a significant decreased Nrf2 expression in memory-impaired (OKA, 200 ng icv) rats indicated its involvement in memory function. Sulforaphane administration (5 and 10 mg/kg, ip, days 1 and 2) ameliorates OKA-induced memory impairment in rats. The treatment also restored Nrf2 and its downstream antioxidant protein expression (GCLC, HO-1) and attenuated oxidative stress (ROS, nitrite, GSH), neuroinflammation (NF-κB, TNF-α, IL-10), and neuronal apoptosis in the cerebral cortex and hippocampus of OKA-treated rats. Further, to determine whether modulation of Nrf2 signaling is responsible for the protective effect of sulforaphane, in vitro, Nrf2 siRNA and its downstream HO-1 inhibition studies were carried out in a rat astrocytoma cell line (C6). The protective effects of sulforaphane were abolished with Nrf2 siRNA and HO-1 inhibition in astrocytes. The results suggest that Nrf2-dependent activation of cellular antioxidant machinery results in sulforaphane-mediated protection against OKA-induced memory impairment in rats. Graphical Abstract ᅟ.

Comparative effect of lurasidone and blonanserin on cortical glutamate, dopamine, and acetylcholine efflux: role of relative serotonin (5-HT)2A and DA D2 antagonism and 5-HT1A partial agonism.

PubMed

Huang, Mei; Panos, John J; Kwon, Sunoh; Oyamada, Yoshihiro; Rajagopal, Lakshmi; Meltzer, Herbert Y

2014-03-01

Atypical antipsychotic drugs (AAPDs) have been suggested to be more effective in improving cognitive impairment in schizophrenia than typical APDs, a conclusion supported by differences in receptor affinities and neurotransmitter efflux in the cortex and the hippocampus. More potent serotonin (5-HT)2A than dopamine (DA) D2 receptors antagonism, and direct or indirect 5-HT1A agonism, characterize almost all AAPDs. Blonanserin, an AAPD, has slightly greater affinity for D2 than 5-HT2A receptors. Using microdialysis and ultra performance liquid chromatography-mass spectrometry/mass spectrometry, we compared the abilities of the typical APD, haloperidol, three AAPDs, blonanserin, lurasidone, and olanzapine, and a selective 5-HT1A partial agonist, tandospirone, and all, except haloperidol, were found to ameliorate the cognitive deficits produced by the N-methyl-d-aspartate antagonist, phencyclidine, altering the efflux of neurotransmitters and metabolites in the rat cortex and nucleus accumbens. Blonanserin, lurasidone, olanzapine, and tandospirone, but not haloperidol, increased the efflux of cortical DA and its metabolites, homovanillic acid and 3,4-dihydroxyphenylacetic acid. Olanzapine and lurasidone increased the efflux of acetylcholine; lurasidone increased glutamate as well. None of the compounds significantly altered the efflux of 5-HT or its metabolite, 5-hydroxyindole acetic acid, or GABA, serine, and glycine. The ability to increase cortical DA efflux was the only shared effect of the compounds which ameliorates the deficit in cognition in rodents following phencyclidine. © 2013 International Society for Neurochemistry.

Autologous cell therapy for cisplatin-induced acute kidney injury by using non-expanded adipose tissue-derived cells.

PubMed

Yasuda, Kaoru; Ozaki, Takenori; Saka, Yousuke; Yamamoto, Tokunori; Gotoh, Momokazu; Ito, Yasuhiko; Yuzawa, Yukio; Matsuo, Seiichi; Maruyama, Shoichi

2012-10-01

Recent studies have demonstrated that cultured mesenchymal stromal cells derived from adipose tissue are useful for regenerative cell therapy. The stromal vascular fraction (SVF) can be obtained readily without culturing and may be clinically applicable. We investigated the therapeutic effects of SVF and used it in the treatment of acute kidney injury (AKI). Liposuction aspirates were obtained from healthy donors who had provided written informed consent. We harvested the SVF and determined the growth factor secretion and anti-apoptotic ability with conditioned medium. To investigate the effect of SVF on AKI, cisplatin was injected into rats and SVF was administrated into the subcupsula of the kidney. Both human and rat SVF cells secreted vascular endothelial growth factor-A (VEGF) and hepatocyte growth factor (HGF). Human SVF-conditioned media had an anti-apoptotic effect, which was inhibited by anti-HGF antibody (Ab) but not by anti-VEGF Ab. In vivo, SVF significantly ameliorated renal function, attenuated tubular damage and increased the cortical blood flow speed. In the SVF-treated group, VEGF levels in the cortex and HGF levels in both the cortex and medulla, especially tubules in the medulla, were significantly higher. Immunostaining revealed that SVF cells expressing VEGF and HGF and remained in the subcapsule on day 14. The present study demonstrates that a subcapsular injection of non-expanded SVF cells ameliorates rat AKI, and that the mechanism probably involves secretion of renoprotective molecules. Administration of human SVF may be clinically applicable and useful as a novel autologous cell therapy against kidney diseases.

Oral administration of metal chelator ameliorates motor dysfunction after a small hemorrhage near the internal capsule in rat.

PubMed

Masuda, Tadashi; Hida, Hideki; Kanda, Yoshie; Aihara, Noritaka; Ohta, Kengo; Yamada, Kazuo; Nishino, Hitoo

2007-01-01

Cerebral hemorrhage leads to local production of free iron, radicals, cytokines, etc. To investigate whether a decrease of iron-mediated radical production influences functional recovery after intracerebral hemorrhage (ICH), a modified ICH rat model with a small hemorrhage near the internal capsule (IC) accompanied with relatively severe motor dysfunction was first developed. Then clioquinol (CQ), an iron chelator that reduces hydroxyl radical production, was orally administrated. Injection of different doses of Type IV collagenase (1.4 mul 1-200 U/ml) into the left striatum near the IC in Wistar rats showed that injection of 7.5 U/ml collagenase resulted in a small hemorrhoidal lesion near the IC with relatively severe motor dysfunction (IC model). Retrograde labeling of neurons in the sensory-motor cortex and axons in the corticospinal tract using Fluoro-gold (FG) injection into the spinal cord (C3-C4) showed that few labeled neurons in the sensory-motor cortex were detected in the IC model, FG-labeled axons disappeared, and FG-including ED-1-positive cells appeared within 24 hr in the IC. Assessments of behavior and histologic analysis after oral administration of CQ in the IC model indicated that oral administration of CQ prevented a decrease of FG-labeled neurons, and resulted in better motor-function recovery. CQ inhibited hydrogen peroxide-induced cell toxicity in oligodendrocytes in vitro, but not in neurons. Our data suggests that CQ ameliorated motor dysfunction after a small hemorrhage near the IC by a mechanism that is related to reduction of chain-reactive hydroxyl radical production in oligodendrocytes.

Chlorpyrifos chronic toxicity in broilers and effect of vitamin C.

PubMed

Kammon, A M; Brar, R S; Sodhi, S; Banga, H S; Singh, J; Nagra, N S

2011-01-01

An experiment was conducted to study chlorpyrifos chronic toxicity in broilers and the protective effect of vitamin C. Oral administration of 0.8 mg/kg body weight (bw) (1/50 LD50) chlorpyrifos (Radar(®)), produced mild diarrhea and gross lesions comprised of paleness, flaccid consistency and slightly enlargement of liver. Histopathologically, chlorpyrifos produced degenerative changes in various organs. Oral administration of 100 mg/kg bw vitamin C partially ameliorated the degenerative changes in kidney and heart. There was insignificant alteration in biochemical and haematological profiles. It is concluded that supplementation of vitamin C reduced the severity of lesions induced by chronic chlorpyrifos toxicity in broilers.

Microstructural Abnormalities Were Found in Brain Gray Matter from Patients with Chronic Myofascial Pain

PubMed Central

Xie, Peng; Qin, Bangyong; Song, Ganjun; Zhang, Yi; Cao, Song; Yu, Jin; Wu, Jianjiang; Wang, Jiang; Zhang, Tijiang; Zhang, Xiaoming; Yu, Tian; Zheng, Hong

2016-01-01

Myofascial pain, presented as myofascial trigger points (MTrPs)-related pain, is a common, chronic disease involving skeletal muscle, but its underlying mechanisms have been poorly understood. Previous studies have revealed that chronic pain can induce microstructural abnormalities in the cerebral gray matter. However, it remains unclear whether the brain gray matters of patients with chronic MTrPs-related pain undergo alteration. In this study, we employed the Diffusion Kurtosis Imaging (DKI) technique, which is particularly sensitive to brain microstructural perturbation, to monitor the MTrPs-related microstructural alterations in brain gray matter of patients with chronic pain. Our results revealed that, in comparison with the healthy controls, patients with chronic myofascial pain exhibited microstructural abnormalities in the cerebral gray matter and these lesions were mainly distributed in the limbic system and the brain areas involved in the pain matrix. In addition, we showed that microstructural abnormalities in the right anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC) had a significant negative correlation with the course of disease and pain intensity. The results of this study demonstrated for the first time that there are microstructural abnormalities in the brain gray matter of patients with MTrPs-related chronic pain. Our findings may provide new insights into the future development of appropriate therapeutic strategies to this disease. PMID:28066193

Nutritional attributes of bakery products

USDA-ARS?s Scientific Manuscript database

Wheat bread has been and continues to be an important source of caloric energy and protein for the people of many continents for thousands of years. In recent years bread, mostly white wheat bread, has also contributed to, but in its whole grain forms may also ameliorate the chronic diseases, assoc...

Palliative Care for Extremely Premature Infants and Their Families

ERIC Educational Resources Information Center

Boss, Renee D.

2010-01-01

Extremely premature infants face multiple acute and chronic life-threatening conditions. In addition, the treatments to ameliorate or cure these conditions often entail pain and discomfort. Integrating palliative care from the moment that extremely premature labor is diagnosed offers families and clinicians support through the process of defining…

Chronic Swimming Exercise Ameliorates Low-Soybean-Oil Diet-Induced Spatial Memory Impairment by Enhancing BDNF-Mediated Synaptic Potentiation in Developing Spontaneously Hypertensive Rats.

PubMed

Cheng, Mei; Cong, Jiyan; Wu, Yulong; Xie, Jiacun; Wang, Siyuan; Zhao, Yue; Zang, Xiaoying

2018-05-01

Exercise and low-fat diets are common lifestyle modifications used for the treatment of hypertension besides drug therapy. However, unrestrained low-fat diets may result in deficiencies of low-unsaturated fatty acids and carry contingent risks of delaying neurodevelopment. While aerobic exercise shows positive neuroprotective effects, it is still unclear whether exercise could alleviate the impairment of neurodevelopment that may be induced by certain low-fat diets. In this research, developing spontaneously hypertensive rats (SHR) were treated with chronic swimming exercise and/or a low-soybean-oil diet for 6 weeks. We found that performance in the Morris water maze was reduced and long-term potentiation in the hippocampus was suppressed by the diet, while a combination treatment of exercise and diet alleviated the impairment induced by the specific low-fat diet. Moreover, the combination treatment effectively increased the expression of brain-derived neurotrophic factor (BDNF) and N-methyl-D-aspartic acid receptor (NMDAR), which were both down-regulated by the low-soybean-oil diet in the hippocampus of developing SHR. These findings suggest that chronic swimming exercise can ameliorate the low-soybean-oil diet-induced learning and memory impairment in developing SHR through the up-regulation of BDNF and NMDAR expression.

Cooling Relief of Acute and Chronic Itch Requires TRPM8 Channels and Neurons.

PubMed

Palkar, Radhika; Ongun, Serra; Catich, Edward; Li, Natalie; Borad, Neil; Sarkisian, Angela; McKemy, David D

2018-06-01

Cooling or the application of mentholated liniments to the skin has been used to treat itch for centuries, yet remarkably little is known about how counter-stimuli such as these induce itch relief. Indeed, there is no clear consensus in the scientific literature as to whether or not cooling does in fact block the transduction of itch signals or if it is simply a placebo effect. This gap in our understanding led us to hypothesize that cooling is antipruritic and, like cooling analgesia, requires function of the cold-gated ion channel TRPM8, a receptor for menthol expressed on peripheral afferent nerve endings. Using a combination of pharmacologic, genetic, and mouse behavioral assays, we find that cooling inhibits both histaminergic and non-histaminergic itch pathways, and that inhibition of itch by cooling requires TRPM8 channels or intact and functional TRPM8-expressing afferent neurons. The cold mimetic menthol is also effective in ameliorating itch in a TRPM8-dependent manner. Moreover, we find that chronic itch can be ameliorated by cooling, demonstrating that this counter-stimulus activates a specific neural circuit that leads to broad itch relief and a potential cellular mechanism for treatment of chronic itch. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Cerium oxide nanoparticles promote neurogenesis and abrogate hypoxia-induced memory impairment through AMPK–PKC–CBP signaling cascade

PubMed Central

Arya, Aditya; Gangwar, Anamika; Singh, Sushil Kumar; Roy, Manas; Das, Mainak; Sethy, Niroj Kumar; Bhargava, Kalpana

2016-01-01

Structural and functional integrity of the brain is adversely affected by reduced oxygen saturation, especially during chronic hypoxia exposure and often encountered by altitude travelers or dwellers. Hypoxia-induced generation of reactive nitrogen and oxygen species reportedly affects the cortex and hippocampus regions of the brain, promoting memory impairment and cognitive dysfunction. Cerium oxide nanoparticles (CNPs), also known as nanoceria, switch between +3 and +4 oxidation states and reportedly scavenge superoxide anions, hydrogen peroxide, and peroxynitrite in vivo. In the present study, we evaluated the neuroprotective as well as the cognition-enhancing activities of nanoceria during hypobaric hypoxia. Using polyethylene glycol-coated 3 nm nanoceria (PEG-CNPs), we have demonstrated efficient localization of PEG-CNPs in rodent brain. This resulted in significant reduction of oxidative stress and associated damage during hypoxia exposure. Morris water maze-based memory function tests revealed that PEG-CNPs ameliorated hypoxia-induced memory impairment. Using microscopic, flow cytometric, and histological studies, we also provide evidences that PEG-CNPs augmented hippocampus neuronal survival and promoted neurogenesis. Molecular studies revealed that PEG-CNPs promoted neurogenesis through the 5′-adenine monophosphate-activated protein kinase–protein kinase C–cyclic adenosine monophosphate response element-binding protein binding (AMPK-PKC-CBP) protein pathway. Our present study results suggest that nanoceria can be translated as promising therapeutic molecules for neurodegenerative diseases. PMID:27069362

Citalopram restores short-term memory deficit and non-cognitive behaviors in APP/PS1 mice while halting the advance of Alzheimer's disease-like pathology.

PubMed

Zhang, Qin; Yang, Chen; Liu, Tianyao; Liu, Liang; Li, Fen; Cai, Yulong; Lv, Keyi; Li, Xin; Gao, Junwei; Sun, Dayu; Xu, Haiwei; Yang, Qingwu; Fan, Xiaotang

2018-03-15

Alzheimer's disease (AD) is the most common cause of dementia. In addition to cognitive impairments, deficits in non-cognitive behaviors are also common neurological sequelae in AD. Here, we show that complex behavioral deficits in 7-month-old APPswe/PSEN1dE9 (APP/PS1) mice include impairments in object recognition, deficient social interaction, increased depression and buried marbles. Citalopram, one of the selective serotonin reuptake inhibitors (SSRIs), ameliorated the amyloid deposition in AD patients and transgenic animal models. After treatment for 4 weeks, citalopram rescued the deficits in short-term memory, sociability and depression in these mice. Further immunohistochemical analysis showed chronic citalopram treatment significantly attenuated β-amyloid deposition and microglial activation in the brains of APP/PS1 mice as demonstrated previously. Parvalbumin (PV) interneurons, which are the primary cellular subtype of GABAergic neurons and considered indispensable for short-term memory and social interaction, also contributed to the progress of depression. Additionally, we found the citalopram could significantly increase the PV-positive neurons in the cortex of APP/PS1 mice without alteration in the hippocampus, which might contribute to the improvement of behavioral performance. Our findings suggest that citalopram might be a potential candidate for the early treatment of AD. Copyright © 2017 Elsevier Ltd. All rights reserved.

Evidences for amelioration of reserpine-induced fibromyalgia in rat by low dose of gamma irradiation and duloxetine.

PubMed

Shibrya, Eman E; Radwan, Rasha R; Abd El Fattah, Mai A; Shabaan, Esmat A; Kenawy, Sanaa A

2017-05-01

Fibromyalgia is a prevalent disorder characterized by chronic widespread pain and complex symptoms. This study was conducted to investigate the potential therapeutic effect of low-dose irradiation (LDI) alone or in combination with duloxetine on the reserpine-induced fibromyalgia in rats. Fibromyalgia was induced by administration of reserpine (1 mg/kg/s.c) for 3 consecutive days. Duloxetine (30 mg/kg, p.o) was administered 60 min before a forced swimming test (FST), and rats were exposed to a single dose of γ-radiation (0.5 Gy) 1 day before the FST. Reserpine significantly increased immobility time in the FST, decreased the amount of 5-hydroxytryptamine, dopamine, and norepinephrine in cerebral cortex. It also increased malondialdehyde and nitric oxide and reduced glutathione contents in brain tissue. LDI alone or combined with duloxetine completely antagonized reserpine-induced fibromyalgia as assessed by the measured parameters. One of the most significant findings in this study was that the therapeutic effect of duloxetine was more pronounced by its combination with LDI. A possible mechanism of action of LDI and duloxetine responsible for their therapeutic effect was discussed. On the basis of the presented evidences, it could be concluded that LDI alone or combined with duloxetine could be of value in the management of fibromyalgia.

CHRONIC DIETARY EXPOSURE WITH INTERMITTENT SPIKE DOSES OF CHLORPYRIFOS FALLS TO ALTER SOMATOSENSORY EVOKED POTENTIALS, COMPOUND NERVE ACTION POTENTIALS, OR NERVE CONDUCTION VELOCITY IN RATS.

EPA Science Inventory

Human exposure to pesticides is often characterized by chronic low level exposure with intermittent spiked higher exposures. Cholinergic transmission is involved in sensory modulation in the cortex and cerebellum, and therefore may be altered following chlorpyrifos (CPF) exposure...

Chronic Gestational Stress Leads to Depressive-Like Behavior and Compromises Medial Prefrontal Cortex Structure and Function during the Postpartum Period

PubMed Central

Leuner, Benedetta; Fredericks, Peter J.; Nealer, Connor; Albin-Brooks, Christopher

2014-01-01

Postpartum depression, which affects approximately 15% of new mothers, is associated with impaired mother-infant interactions and deficits in cognitive function. Exposure to stress during pregnancy is a major risk factor for postpartum depression. However, little is known about the neural consequences of gestational stress. The medial prefrontal cortex (mPFC) is a brain region that has been linked to stress, cognition, maternal care, and mood disorders including postpartum depression. Here we examined the effects of chronic gestational stress on mPFC function and whether these effects might be linked to structural modifications in the mPFC. We found that in postpartum rats, chronic gestational stress resulted in maternal care deficits, increased depressive-like behavior, and impaired performance on an attentional set shifting task that relies on the mPFC. Furthermore, exposure to chronic stress during pregnancy reduced dendritic spine density on mPFC pyramidal neurons and altered spine morphology. Taken together, these findings suggest that pregnancy stress may contribute to postpartum mental illness and its associated symptoms by compromising structural plasticity in the mPFC. PMID:24594708

Changes in the sensitivity of GABAA current rundown to drug treatments in a model of temporal lobe epilepsy

PubMed Central

Cifelli, Pierangelo; Palma, Eleonora; Roseti, Cristina; Verlengia, Gianluca; Simonato, Michele

2013-01-01

The pharmacological treatment of mesial temporal lobe epilepsy (mTLE), the most common epileptic syndrome in adults, is still unsatisfactory, as one-third of the patients are or become refractory to antiepileptic agents. Refractoriness may depend upon drug-induced alterations, but the disease per se may also undergo a progressive evolution that affects the sensitivity to drugs. mTLE has been shown to be associated with a dysfunction of the inhibitory signaling mediated by GABAA receptors. In particular, the repetitive activation of GABAA receptors produces a use-dependent decrease (rundown) of the evoked currents (IGABA), which is markedly enhanced in the hippocampus and cortex of drug-resistant mTLE patients. This phenomenon has been also observed in the pilocarpine model, where the increased IGABA rundown is observed in the hippocampus at the time of the first spontaneous seizure, then extends to the cortex and remains constant in the chronic phase of the disease. Here, we examined the sensitivity of IGABA to pharmacological modulation. We focused on the antiepileptic agent levetiracetam (LEV) and on the neurotrophin brain-derived neurotrophic factor (BDNF), which were previously reported to attenuate mTLE-induced increased rundown in the chronic human tissue. In the pilocarpine model, BDNF displayed a paramount effect, decreasing rundown in the hippocampus at the time of the first seizure, as well as in the hippocampus and cortex in the chronic period. In contrast, LEV did not affect rundown in the hippocampus, but attenuated it in the cortex. Interestingly, this effect of LEV was also observed on the still unaltered rundown observed in the cortex at the time of the first spontaneous seizure. These data suggest that the sensitivity of GABAA receptors to pharmacological interventions undergoes changes during the natural history of mTLE, implicating that the site of seizure initiation and the timing of treatment may highly affect the therapeutic outcome. PMID:23874269

Cannabinoid administration attenuates the progression of simian immunodeficiency virus.

PubMed

Molina, Patricia E; Winsauer, Peter; Zhang, Ping; Walker, Edith; Birke, Leslie; Amedee, Angela; Stouwe, Curtis Vande; Troxclair, Dana; McGoey, Robin; Varner, Kurt; Byerley, Lauri; LaMotte, Lynn

2011-06-01

Δ(9)-Tetrahydrocannabinol (Δ(9)-THC), the primary psychoactive component in marijuana, is FDA approved to ameliorate AIDS-associated wasting. Because cannabinoid receptors are expressed on cells of the immune system, chronic Δ(9)-THC use may impact HIV disease progression. We examined the impact of chronic Δ(9)-THC administration (0.32 mg/kg im, 2 × daily), starting 28 days prior to inoculation with simian immunodeficiency virus (SIV(mac251); 100 TCID(50)/ml, iv), on immune and metabolic indicators of disease during the initial 6 month asymptomatic phase of infection in rhesus macaques. SIV(mac251) inoculation resulted in measurable viral load, decreased lymphocyte CD4(+)/CD8(+) ratio, and increased CD8(+) proliferation. Δ(9)-THC treatment of SIV-infected animals produced minor to no effects in these parameters. However, chronic Δ(9)-THC administration decreased early mortality from SIV infection (p = 0.039), and this was associated with attenuation of plasma and CSF viral load and retention of body mass (p = NS). In vitro, Δ(9)-THC (10 μm) decreased SIV (10 TCID(50)) viral replication in MT4-R5 cells. These results indicate that chronic Δ(9)-THC does not increase viral load or aggravate morbidity and may actually ameliorate SIV disease progression. We speculate that reduced levels of SIV, retention of body mass, and attenuation of inflammation are likely mechanisms for Δ(9)-THC-mediated modulation of disease progression that warrant further study.

Arctium lappa ameliorates endothelial dysfunction in rats fed with high fat/cholesterol diets

PubMed Central

2012-01-01

Background Arctium lappa L. (Asteraceae), burdock, is a medicinal plant that is popularly used for treating hypertension, gout, hepatitis, and other inflammatory disorders. This study was performed to test the effect of ethanol extract of Arctium lappa L. (EAL) seeds on vascular reactivity and inflammatory factors in rats fed a high fat/cholesterol diet (HFCD). Method EAL-I (100 mg·kg−1/day), EAL-II (200 mg·kg−1/day), and fluvastatin (3 mg·kg−1/day) groups initially received HFCD alone for 8 weeks, with EAL supplementation provided during the final 6 weeks. Results Treatment with low or high doses of EAL markedly attenuated plasma levels of triglycerides and augmented plasma levels of high-density lipoprotein (HDL) in HFCD-fed rats. Chronic treatment with EAL markedly reduced impairments of acetylcholine (ACh)-induced relaxation of aortic rings. Furthermore, chronic treatment with EAL significantly lowered systolic blood pressure (SBP) and maintained smooth and flexible intimal endothelial layers in HFCD-fed rats. Chronic treatment with EAL suppressed upregulation of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin in the aorta. Chronic treatment with EAL also suppressed increases in matrix metalloproteinase (MMP)-2 expression. These results suggested that EAL can inhibit HFCD-induced vascular inflammation in the rat model. Conclusion The present study provides evidence that EAL ameliorates HFCD-induced vascular dysfunction through protection of vascular relaxation and suppression of vascular inflammation. PMID:22866890

Mechanism and novel therapeutic approaches to wasting in chronic disease.

PubMed

Ebner, Nicole; Springer, Jochen; Kalantar-Zadeh, Kamyar; Lainscak, Mitja; Doehner, Wolfram; Anker, Stefan D; von Haehling, Stephan

2013-07-01

Cachexia is a multifactorial syndrome defined by continuous loss of skeletal muscle mass - with or without loss of fat mass - which cannot be fully reversed by conventional nutritional support and which may lead to progressive functional impairment and increased death risk. Its pathophysiology is characterized by negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism. Muscle wasting is encountered in virtually all chronic disease states in particular during advanced stages of the respective illness. Several pre-clinical and clinical studies are ongoing to ameliorate this clinical problem. The mechanisms of muscle wasting and cachexia in chronic diseases such as cancer, chronic heart failure, chronic obstructive pulmonary disease and chronic kidney disease are described. We discuss therapeutic targets and such potential modulators as appetite stimulants, selective androgen receptor modulators, amino acids and naturally occurring peptide hormones. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Chronic Electrical Stimulation with a Suprachoroidal Retinal Prosthesis: A Preclinical Safety and Efficacy Study

PubMed Central

Nayagam, David A. X.; Williams, Richard A.; Allen, Penelope J.; Shivdasani, Mohit N.; Luu, Chi D.; Salinas-LaRosa, Cesar M.; Finch, Sue; Ayton, Lauren N.; Saunders, Alexia L.; McPhedran, Michelle; McGowan, Ceara; Villalobos, Joel; Fallon, James B.; Wise, Andrew K.; Yeoh, Jonathan; Xu, Jin; Feng, Helen; Millard, Rodney; McWade, Melanie; Thien, Patrick C.; Williams, Chris E.; Shepherd, Robert K.

2014-01-01

Purpose To assess the safety and efficacy of chronic electrical stimulation of the retina with a suprachoroidal visual prosthesis. Methods Seven normally-sighted feline subjects were implanted for 96–143 days with a suprachoroidal electrode array and six were chronically stimulated for 70–105 days at levels that activated the visual cortex. Charge balanced, biphasic, current pulses were delivered to platinum electrodes in a monopolar stimulation mode. Retinal integrity/function and the mechanical stability of the implant were assessed monthly using electroretinography (ERG), optical coherence tomography (OCT) and fundus photography. Electrode impedances were measured weekly and electrically-evoked visual cortex potentials (eEVCPs) were measured monthly to verify that chronic stimuli were suprathreshold. At the end of the chronic stimulation period, thresholds were confirmed with multi-unit recordings from the visual cortex. Randomized, blinded histological assessments were performed by two pathologists to compare the stimulated and non-stimulated retina and adjacent tissue. Results All subjects tolerated the surgical and stimulation procedure with no evidence of discomfort or unexpected adverse outcomes. After an initial post-operative settling period, electrode arrays were mechanically stable. Mean electrode impedances were stable between 11–15 kΩ during the implantation period. Visually-evoked ERGs & OCT were normal, and mean eEVCP thresholds did not substantially differ over time. In 81 of 84 electrode-adjacent tissue samples examined, there were no discernible histopathological differences between stimulated and unstimulated tissue. In the remaining three tissue samples there were minor focal fibroblastic and acute inflammatory responses. Conclusions Chronic suprathreshold electrical stimulation of the retina using a suprachoroidal electrode array evoked a minimal tissue response and no adverse clinical or histological findings. Moreover, thresholds and electrode impedance remained stable for stimulation durations of up to 15 weeks. This study has demonstrated the safety and efficacy of suprachoroidal stimulation with charge balanced stimulus currents. PMID:24853376

Berberine ameliorates chronic relapsing dextran sulfate sodium-induced colitis in C57BL/6 mice by suppressing Th17 responses.

PubMed

Li, Yan-Hong; Xiao, Hai-Tao; Hu, Dong-Dong; Fatima, Sarwat; Lin, Cheng-Yuan; Mu, Huai-Xue; Lee, Nikki P; Bian, Zhao-Xiang

2016-08-01

Ulcerative colitis (UC) is an increasingly common condition particularly in developed countries. The lack of satisfactory treatment has fueled the search for alternative therapeutic strategies. In recent studies, berberine, a plant alkaloid with a long history of medicinal use in Chinese medicine, has shown beneficial effects against animal models of acute UC. However, UC usually presents as a chronic condition with frequent relapse in patients. How berberine will act on chronic UC remains unclear. In the present study, we adopted dextran sulfate sodium (DSS)-induced chronic relapsing colitis model to assess the ameliorating activity of berberine. Colitis was induced by two cycles of 2.0% DSS for five days followed by 14days of drinking water plus a third cycle consisting of DSS only for five days. The colitis mice were orally administered 20mg/kg berberine from day 13 onward for 30days and monitored daily. The body weight, stool consistency, and stool bleeding were recorded for determination of the disease activity index (DAI). At the end of treatment, animals were sacrificed and samples were collected and subjected to histological, RT-qPCR, Western blot, and LC-MS analyses. Lymphocytes were isolated from spleens and mesenteric lymph nodes (MLN) and cultured for flow cytometry analysis of IL-17 secretion from CD4(+) cells and the Th17 cell differentiation. Results showed that berberine significantly ameliorated the DAI, colon shortening, colon tissue injury, and reduction of colonic expression of tight junction (TJ) protein ZO-1 and occludin of colitis mice. Notably, berberine treatment pronouncedly reduced DSS-upregulated Th17-related cytokine (IL-17 and ROR-γt) mRNAs in the colon. Furthermore, the mRNA expression of IL-6 and IL-23, and the phosphorylation of STAT3 in colon tissues from DSS-treated mice were pronouncedly inhibited by berberine. Moreover, the up-regulation of IL-17 secretion from CD4(+) cells of spleens and MLNs caused by DSS were significantly reversed by berberine treatment. Furthermore, Th17 cell differentiation from naive CD4(+) cells isolated from above DSS colitis mice were suppressed by berberine in a concentration-dependent manner. In summary, we demonstrated for the first time that berberine reduced the severity of chronic relapsing DSS-induced colitis by suppressing Th17 responses. The demonstration of activity in this mouse model supports the possibility of clinical efficacy of berberine in treating chronic UC. Copyright © 2016 Elsevier Ltd. All rights reserved.

Development of closed-loop neural interface technology in a rat model: combining motor cortex operant conditioning with visual cortex microstimulation.

PubMed

Marzullo, Timothy Charles; Lehmkuhle, Mark J; Gage, Gregory J; Kipke, Daryl R

2010-04-01

Closed-loop neural interface technology that combines neural ensemble decoding with simultaneous electrical microstimulation feedback is hypothesized to improve deep brain stimulation techniques, neuromotor prosthetic applications, and epilepsy treatment. Here we describe our iterative results in a rat model of a sensory and motor neurophysiological feedback control system. Three rats were chronically implanted with microelectrode arrays in both the motor and visual cortices. The rats were subsequently trained over a period of weeks to modulate their motor cortex ensemble unit activity upon delivery of intra-cortical microstimulation (ICMS) of the visual cortex in order to receive a food reward. Rats were given continuous feedback via visual cortex ICMS during the response periods that was representative of the motor cortex ensemble dynamics. Analysis revealed that the feedback provided the animals with indicators of the behavioral trials. At the hardware level, this preparation provides a tractable test model for improving the technology of closed-loop neural devices.

Effects of N-acetyl-L-cysteine on redox status and markers of renal function in mice inoculated with Bothrops jararaca and Crotalus durissus terrificus venoms.

PubMed

Barone, Juliana Marton; Frezzatti, Rodrigo; Silveira, Paulo Flavio

2014-03-01

Renal dysfunction is an important aggravating factor in accidents caused by Crotalus durissus terrificus (Cdt) and Bothrops jararaca (Bj) bites. N-acetyl-l-cysteine (NAC) is well known as a nephroprotective antioxidant with low toxicity. The present study investigated the effects of NAC on redox status and markers of renal function in mice that received vehicle (controls) or venoms (v) of Cdt and Bj. In controls NAC promoted hypercreatinemia, hypouremia, hyperosmolality with decreased urea in urine, hyperproteinuria, decreased protein and increased dipeptidyl peptidase IV (DPPIV) in membrane-bound fraction (MF) from renal cortex (RC) and medulla (RM). NAC ameliorated or normalized altered creatinuria, proteinemia and aminopeptidase (AP) acid in MF, AP basic (APB) in soluble fraction (SF), and neutral AP in SF and MF from RC and RM in vBj envenomation. NAC ameliorated or normalized altered neutral AP in SF from RC and RM, and DPPIV and protein in MF from RC in vCdt envenomation. NAC ameliorated or restored renal redox status respectively in vCdt and vBj, and normalized uricemia in both envenomations. These data are promising perspectives that recommend the clinical evaluation of NAC as potential coadjuvant in the anti venom serotherapy for accidents with these snake's genera. Copyright © 2014 Elsevier Ltd. All rights reserved.

Increase in serotonin 5-HT sub 1A receptors in prefrontal and temporal cortices of brains from patients with chronic schizophrenia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hashimoto, Takeshi; Nishino, Naoki; Nakai, Hisao

1991-01-01

Binding studies with ({sup 3}H)8-hydroxy-2-(di-n-propylamino)tetralin (({sup 3}H)8-OH-DPAT), a specific serotonin{sub 1A} (5-HT{sub 1A}) receptor agonist, were done on the autopsied brains from control subjects and from patients with chronic schizophrenia. In the controls, representative Scatchard plots for the specific ({sup 3}H)8-OH-DPAT bindings in the prefrontal cortex and hippocampus revealed a single component of high affinity binding site. The ({sup 3}H)8-OH-DPAT bindings to the prefrontal cortex and hippocampus were potently inhibited by serotonin and 5-HT{sub 1A} agonists, while other neurotransmitters, 5-HT{sub 2} and 5-HT{sub 3} related compounds did not inhibit the binding. The bindings were decreased in the presence of 0.1mMmore » GTP and 0.1mM GppNHp but not in the presence of 0.1mM GMP. In the prefrontal and temporal cortices of schizophrenics, there was a significant increase in the specific ({sup 3}H)8-OH-DPAT binding, by 40% and 60%, respectively, with no change in the hippocampus, amygdala, cingulum, motor cortex, parietal or occipital cortex, as compared to findings in the controls.« less

Motor cortex stimulation does not lead to functional recovery after experimental cortical injury in rats.

PubMed

Schönfeld, Lisa-Maria; Jahanshahi, Ali; Lemmens, Evi; Bauwens, Matthias; Hescham, Sarah-Anna; Schipper, Sandra; Lagiere, Melanie; Hendrix, Sven; Temel, Yasin

2017-01-01

Motor impairments are among the major complications that develop after cortical damage caused by either stroke or traumatic brain injury. Motor cortex stimulation (MCS) can improve motor functions in animal models of stroke by inducing neuroplasticity. In the current study, the therapeutic effect of chronic MCS was assessed in a rat model of severe cortical damage. A controlled cortical impact (CCI) was applied to the forelimb area of the motor cortex followed by implantation of a flat electrode covering the lesioned area. Forelimb function was assessed using the Montoya staircase test and the cylinder test before and after a period of chronic MCS. Furthermore, the effect of MCS on tissue metabolism and lesion size was measured using [18F]-fluorodesoxyglucose (FDG) μPET scanning. CCI caused a considerable lesion at the level of the motor cortex and dorsal striatum together with a long-lasting behavioral phenotype of forelimb impairment. However, MCS applied to the CCI lesion did not lead to any improvement in limb functioning when compared to non-stimulated control rats. Also, MCS neither changed lesion size nor distribution of FDG. The use of MCS as a standalone treatment did not improve motor impairments in a rat model of severe cortical damage using our specific treatment modalities.

Chronic Stress Impairs Prefrontal Cortex-Dependent Response Inhibition and Spatial Working Memory

PubMed Central

Mika, Agnieszka; Mazur, Gabriel J.; Hoffman, Ann N.; Talboom, Joshua S.; Bimonte-Nelson, Heather A.; Sanabria, Federico; Conrad, Cheryl D.

2012-01-01

Chronic stress leads to neurochemical and structural alterations in the prefrontal cortex (PFC) that correspond to deficits in PFC-mediated behaviors. The present study examined the effects of chronic restraint stress on response inhibition (using a response-withholding task, fixed-minimum interval schedule of reinforcement, or FMI), and working memory (using a radial arm water maze, RAWM). Adult male Sprague Dawley rats were first trained on the RAWM and subsequently trained on FMI. Following acquisition of FMI, rats were assigned to a restraint stress (6h/d/28d in wire mesh restrainers) or control condition. Immediately after chronic stress, rats were tested on FMI and subsequently on RAWM. FMI results suggest that chronic stress reduces response inhibition capacity and motivation to initiate the task on selective conditions when food reward was not obtained on the preceding trial. RAWM results suggest that chronic stress produces transient deficits in working memory without altering previously consolidated reference memory. Behavioral measures from FMI failed to correlate with metrics from RAWM except for one in which changes in FMI timing precision negatively correlated with changes in RAWM working memory errors for the controls, a finding that was not observed following chronic stress. Fisher’s r to z transformation revealed no significant differences between control and stress with correlation coefficients. These findings are the first to show that chronic stress impairs both response inhibition and working memory, two behaviors that have never been direct compared within the same animals following chronic stress, using FMI, an appetitive task, and RAWM, a non-appetitive task. PMID:22905921

Spontaneous high-gamma band activity reflects functional organization of auditory cortex in the awake macaque.

PubMed

Fukushima, Makoto; Saunders, Richard C; Leopold, David A; Mishkin, Mortimer; Averbeck, Bruno B

2012-06-07

In the absence of sensory stimuli, spontaneous activity in the brain has been shown to exhibit organization at multiple spatiotemporal scales. In the macaque auditory cortex, responses to acoustic stimuli are tonotopically organized within multiple, adjacent frequency maps aligned in a caudorostral direction on the supratemporal plane (STP) of the lateral sulcus. Here, we used chronic microelectrocorticography to investigate the correspondence between sensory maps and spontaneous neural fluctuations in the auditory cortex. We first mapped tonotopic organization across 96 electrodes spanning approximately two centimeters along the primary and higher auditory cortex. In separate sessions, we then observed that spontaneous activity at the same sites exhibited spatial covariation that reflected the tonotopic map of the STP. This observation demonstrates a close relationship between functional organization and spontaneous neural activity in the sensory cortex of the awake monkey. Copyright © 2012 Elsevier Inc. All rights reserved.

Spontaneous high-gamma band activity reflects functional organization of auditory cortex in the awake macaque

PubMed Central

Fukushima, Makoto; Saunders, Richard C.; Leopold, David A.; Mishkin, Mortimer; Averbeck, Bruno B.

2012-01-01

Summary In the absence of sensory stimuli, spontaneous activity in the brain has been shown to exhibit organization at multiple spatiotemporal scales. In the macaque auditory cortex, responses to acoustic stimuli are tonotopically organized within multiple, adjacent frequency maps aligned in a caudorostral direction on the supratemporal plane (STP) of the lateral sulcus. Here we used chronic micro-electrocorticography to investigate the correspondence between sensory maps and spontaneous neural fluctuations in the auditory cortex. We first mapped tonotopic organization across 96 electrodes spanning approximately two centimeters along the primary and higher auditory cortex. In separate sessions we then observed that spontaneous activity at the same sites exhibited spatial covariation that reflected the tonotopic map of the STP. This observation demonstrates a close relationship between functional organization and spontaneous neural activity in the sensory cortex of the awake monkey. PMID:22681693

Transcriptome comparison in the pituitary-adrenal axis between Beagle and Chinese Field dogs after chronic stress exposure.

PubMed

Luo, Wei; Fang, Meixia; Xu, Haiping; Xing, Huijie; Nie, Qinghua

2015-10-01

Chronic stress can induce a series of maladjustments, and the response to stress is partly regulated by the hypothalamus-pituitary-adrenal axis. The aim of this study was to investigate the genetic mechanisms of this axis regulating stress responsiveness. The pituitary and adrenal cortex of Beagle and Chinese Field Dog (CFD) from a stress exposure group [including Beagle pituitary 1 (BP1), CFD pituitary 1 (CFDP1), Beagle adrenal cortex 1 (BAC1), CFD adrenal cortex 1 (CFDAC1)] and a control group [including Beagle pituitary 2 (BP2), CFD pituitary 2 (CFDP2), Beagle adrenal cortex 2 (BAC2), CFD adrenal cortex 2 (CFDAC2)], selected to perform RNA-seq transcriptome comparisons, showed that 40, 346, 376, 69, 70, 38, 57 and 71 differentially expressed genes were detected in BP1 vs. BP2, CFDP1 vs. CFDP2, BP1 vs. CFDP1, BP2 vs. CFDP2, BAC1 vs. BAC2, CFDAC1 vs. CFDAC2, BAC1 vs. CFDAC1 and BAC2 vs. CFDAC2 respectively. NPB was a gene common to BAC1 vs. BAC2 and CFDAC1 vs. CFDAC2, indicating it was a potential gene affecting response to chronic stress, regardless of the extent of chronic stress induced. PLP1 was a gene common to BP1 vs. CFDP1 and BP2 vs. CFDP2, suggesting its important roles in affecting the stress-tolerance difference between the two breeds, regardless of whether there was stress exposure or not. Pathway analysis found 12, 4, 11 and 1 enriched pathway in the comparisons of BP1 vs. CFDP1, BP2 vs. CFDP2, CFDP1 vs. CFDP2 and BAC1 vs. BAC2 respectively. Glutamatergic synapse, neuroactive ligand-receptor interaction, retrograde endocannabinoid signaling, GABAergic synapse, calcium signaling pathway and dopaminergic synapse were the most significantly enriched pathways in both CFDP1 vs. CFDP2 and BP1 vs. CFDP1. GO, KEGG pathway and gene network analysis demonstrated that GRIA3, GRIN2A, GRIN2B and NPY were important in regulating the stress response in CFD. Nevertheless, ADORA1, CAMK2A, GRM1, GRM7 and NR4A1 might be critical genes contributing to the stress-tolerance difference between CFD and Beagle when subjected to stress exposure. In addition, RGS4 and SYN1 might play important roles both in regulating the stress response in CFD and in affecting the stress-tolerance difference in different breeds. These observations clearly showed that some genes in the adrenal cortex and pituitary could regulate the stress response in Beagle and CFDs, whereas some others could affect the stress-tolerance difference between these two breeds. Our results can contribute to a more comprehensive understanding of the genetic mechanisms of response to chronic stress. © 2015 Stichting International Foundation for Animal Genetics.

Exposure to Inorganic Mercury Causes Oxidative Stress, Cell Death, and Functional Deficits in the Motor Cortex.

PubMed

Teixeira, Francisco B; de Oliveira, Ana C A; Leão, Luana K R; Fagundes, Nathália C F; Fernandes, Rafael M; Fernandes, Luanna M P; da Silva, Márcia C F; Amado, Lilian L; Sagica, Fernanda E S; de Oliveira, Edivaldo H C; Crespo-Lopez, Maria E; Maia, Cristiane S F; Lima, Rafael R

2018-01-01

Mercury is a toxic metal that can be found in the environment in three different forms - elemental, organic and inorganic. Inorganic mercury has a lower liposolubility, which results in a lower organism absorption and reduced passage through the blood-brain barrier. For this reason, exposure models that use inorganic mercury in rats in order to evaluate its effects on the central nervous system are rare, especially in adult subjects. This study investigated if a chronic exposure to low doses of mercury chloride (HgCl2), an inorganic form of mercury, is capable of promoting motor alterations and neurodegenerative in the motor cortex of adult rats. Forty animals were exposed to a dose of 0.375 mg/kg/day, for 45 days. They were then submitted to motor evaluation and euthanized to collect the motor cortex. Measurement of mercury deposited in the brain parenchyma, evaluation of oxidative balance, quantification of cellular cytotoxicity and apoptosis and density of mature neurons and astrocytes of the motor cortex were performed. It was observed that chronic exposure to inorganic mercury caused a decrease in balance and fine motor coordination, formation of mercury deposits and oxidative stress verified by the increase of lipoperoxidation and nitrite concentration and a decrease of the total antioxidant capacity. In addition, we found that this model of exposure to inorganic mercury caused cell death by cytotoxicity and induction of apoptosis with a decreased number of neurons and astrocytes in the motor cortex. Our results provide evidence that exposure to inorganic mercury in low doses, even in spite of its poor ability to cross biological barriers, is still capable of inducing motor deficits, cell death by cytotoxicity and apoptosis, and oxidative stress in the motor cortex of adult rats.

Exposure to Inorganic Mercury Causes Oxidative Stress, Cell Death, and Functional Deficits in the Motor Cortex

PubMed Central

Teixeira, Francisco B.; de Oliveira, Ana C. A.; Leão, Luana K. R.; Fagundes, Nathália C. F.; Fernandes, Rafael M.; Fernandes, Luanna M. P.; da Silva, Márcia C. F.; Amado, Lilian L.; Sagica, Fernanda E. S.; de Oliveira, Edivaldo H. C.; Crespo-Lopez, Maria E.; Maia, Cristiane S. F.; Lima, Rafael R.

2018-01-01

Mercury is a toxic metal that can be found in the environment in three different forms – elemental, organic and inorganic. Inorganic mercury has a lower liposolubility, which results in a lower organism absorption and reduced passage through the blood–brain barrier. For this reason, exposure models that use inorganic mercury in rats in order to evaluate its effects on the central nervous system are rare, especially in adult subjects. This study investigated if a chronic exposure to low doses of mercury chloride (HgCl2), an inorganic form of mercury, is capable of promoting motor alterations and neurodegenerative in the motor cortex of adult rats. Forty animals were exposed to a dose of 0.375 mg/kg/day, for 45 days. They were then submitted to motor evaluation and euthanized to collect the motor cortex. Measurement of mercury deposited in the brain parenchyma, evaluation of oxidative balance, quantification of cellular cytotoxicity and apoptosis and density of mature neurons and astrocytes of the motor cortex were performed. It was observed that chronic exposure to inorganic mercury caused a decrease in balance and fine motor coordination, formation of mercury deposits and oxidative stress verified by the increase of lipoperoxidation and nitrite concentration and a decrease of the total antioxidant capacity. In addition, we found that this model of exposure to inorganic mercury caused cell death by cytotoxicity and induction of apoptosis with a decreased number of neurons and astrocytes in the motor cortex. Our results provide evidence that exposure to inorganic mercury in low doses, even in spite of its poor ability to cross biological barriers, is still capable of inducing motor deficits, cell death by cytotoxicity and apoptosis, and oxidative stress in the motor cortex of adult rats. PMID:29867340

Blonanserin ameliorates phencyclidine-induced visual-recognition memory deficits: the complex mechanism of blonanserin action involving D₃-5-HT₂A and D₁-NMDA receptors in the mPFC.

PubMed

Hida, Hirotake; Mouri, Akihiro; Mori, Kentaro; Matsumoto, Yurie; Seki, Takeshi; Taniguchi, Masayuki; Yamada, Kiyofumi; Iwamoto, Kunihiro; Ozaki, Norio; Nabeshima, Toshitaka; Noda, Yukihiro

2015-02-01

Blonanserin differs from currently used serotonin 5-HT₂A/dopamine-D₂ receptor antagonists in that it exhibits higher affinity for dopamine-D₂/₃ receptors than for serotonin 5-HT₂A receptors. We investigated the involvement of dopamine-D₃ receptors in the effects of blonanserin on cognitive impairment in an animal model of schizophrenia. We also sought to elucidate the molecular mechanism underlying this involvement. Blonanserin, as well as olanzapine, significantly ameliorated phencyclidine (PCP)-induced impairment of visual-recognition memory, as demonstrated by the novel-object recognition test (NORT) and increased extracellular dopamine levels in the medial prefrontal cortex (mPFC). With blonanserin, both of these effects were antagonized by DOI (a serotonin 5-HT₂A receptor agonist) and 7-OH-DPAT (a dopamine-D₃ receptor agonist), whereas the effects of olanzapine were antagonized by DOI but not by 7-OH-DPAT. The ameliorating effect was also antagonized by SCH23390 (a dopamine-D₁ receptor antagonist) and H-89 (a protein kinase A (PKA) inhibitor). Blonanserin significantly remediated the decrease in phosphorylation levels of PKA at Thr(197) and of NR1 (an essential subunit of N-methyl-D-aspartate (NMDA) receptors) at Ser(897) by PKA in the mPFC after a NORT training session in the PCP-administered mice. There were no differences in the levels of NR1 phosphorylated at Ser(896) by PKC in any group. These results suggest that the ameliorating effect of blonanserin on PCP-induced cognitive impairment is associated with indirect functional stimulation of the dopamine-D₁-PKA-NMDA receptor pathway following augmentation of dopaminergic neurotransmission due to inhibition of both dopamine-D₃ and serotonin 5-HT₂A receptors in the mPFC.

Regional Neuroplastic Brain Changes in Patients with Chronic Inflammatory and Non-Inflammatory Visceral Pain

PubMed Central

Hong, Jui-Yang; Labus, Jennifer S.; Jiang, Zhiguo; Ashe-Mcnalley, Cody; Dinov, Ivo; Gupta, Arpana; Shi, Yonggang; Stains, Jean; Heendeniya, Nuwanthi; Smith, Suzanne R.; Tillisch, Kirsten; Mayer, Emeran A.

2014-01-01

Regional cortical thickness alterations have been reported in many chronic inflammatory and painful conditions, including inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS), even though the mechanisms underlying such neuroplastic changes remain poorly understood. In order to better understand the mechanisms contributing to grey matter changes, the current study sought to identify the differences in regional alterations in cortical thickness between healthy controls and two chronic visceral pain syndromes, with and without chronic gut inflammation. 41 healthy controls, 11 IBS subjects with diarrhea, and 16 subjects with ulcerative colitis (UC) underwent high-resolution T1-weighted magnetization-prepared rapid acquisition gradient echo scans. Structural image preprocessing and cortical thickness analysis within the region of interests were performed by using the Laboratory of Neuroimaging Pipeline. Group differences were determined using the general linear model and linear contrast analysis. The two disease groups differed significantly in several cortical regions. UC subjects showed greater cortical thickness in anterior cingulate cortical subregions, and in primary somatosensory cortex compared with both IBS and healthy subjects. Compared with healthy subjects, UC subjects showed lower cortical thickness in orbitofrontal cortex and in mid and posterior insula, while IBS subjects showed lower cortical thickness in the anterior insula. Large effects of correlations between symptom duration and thickness in the orbitofrontal cortex and postcentral gyrus were only observed in UC subjects. The findings suggest that the mechanisms underlying the observed gray matter changes in UC subjects represent a consequence of peripheral inflammation, while in IBS subjects central mechanisms may play a primary role. PMID:24416245

The Impact of Development and Sensory Deprivation on Dendritic Protrusions in the Mouse Barrel Cortex

PubMed Central

Chen, Chia-Chien; Bajnath, Adesh; Brumberg, Joshua C.

2015-01-01

Dendritic protrusions (spines and filopodia) are structural indicators of synapses that have been linked to neuronal learning and memory through their morphological alterations induced by development and experienced-dependent activities. Although previous studies have demonstrated that depriving sensory experience leads to structural changes in neocortical organization, the more subtle effects on dendritic protrusions remain unclear, mostly due to focus on only one specific cell type and/or age of manipulation. Here, we show that sensory deprivation induced by whisker trimming influences the dendritic protrusions of basilar dendrites located in thalamocortical recipient lamina (IV and VI) of the mouse barrel cortex in a layer-specific manner. Following 1 month of whisker trimming after birth, the density of dendritic protrusions increased in layer IV, but decreased in layer VI. Whisker regrowth for 1 month returned protrusion densities to comparable level of age-matched controls in layer VI, but not in layer IV. In adults, chronic sensory deprivation led to an increase in protrusion densities in layer IV, but not in layer VI. In addition, chronic pharmacological blockade of N-methyl-d-aspartate receptors (NMDARs) increased protrusion density in both layers IV and VI, which returned to the control level after 1 month of drug withdrawal. Our data reveal that different cortical layers respond to chronic sensory deprivation in different ways, with more pronounced effects during developmental critical periods than adulthood. We also show that chronically blocking NMDARs activity during developmental critical period also influences the protrusion density and morphology in the cerebral cortex. PMID:24408954

High Sucrose Intake Ameliorates the Accumulation of Hepatic Triacylglycerol Promoted by Restraint Stress in Young Rats.

PubMed

Corona-Pérez, Adriana; Díaz-Muñoz, Mauricio; Rodríguez, Ida Soto; Cuevas, Estela; Martínez-Gómez, Margarita; Castelán, Francisco; Rodríguez-Antolín, Jorge; Nicolás-Toledo, Leticia

2015-11-01

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder. Stress promotes the onset of the NAFLD with a concomitant increment in the activity of the hepatic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1). However, the interaction between the stress and a carbohydrate-enriched diet for the development of NAFLD in young animals is unknown. In the present study, we evaluated the impact of chronic stress on the hepatic triacylglycerol level of young rats fed or not with a high sucrose-diet. For doing this, 21-day old male Wistar rats were allocated into 4 groups: control (C), chronic restraint stress (St), high-sucrose diet (S30), and chronic restraint stress plus a 30 % sucrose diet (St + S30). Chronic restraint stress consisted of 1-hour daily session, 5 days per week and for 4 weeks. Rats were fed with a standard chow and tap water (C group) or 30 % sucrose diluted in water (S30 group). The St + S30 groups consumed less solid food but had an elevated visceral fat accumulation in comparison with the St group. The St group showed a high level of serum corticosterone and a high activity of the hepatic 11β-HSD-1 concomitantly to the augmentation of hepatic steatosis signs, a high hepatic triacylglycerol content, and hepatic oxidative stress. Conversely, the high-sucrose intake in stressed rats (St + S30 group) reduced the hepatic 11β-HSD-1 activity, the level of serum corticosterone, and the hepatic triacylglycerol content. Present findings show that a high-sucrose diet ameliorates the triacylglycerol accumulation in liver promoted by the restraint stress in young male rats.

Dopamine and μ-opioid receptor dysregulation in the brains of binge-eating female rats - possible relevance in the psychopathology and treatment of binge-eating disorder.

PubMed

Heal, David J; Hallam, Michelle; Prow, Michael; Gosden, Jane; Cheetham, Sharon; Choi, Yong K; Tarazi, Frank; Hutson, Peter

2017-06-01

Adult, female rats given irregular, limited access to chocolate develop binge-eating behaviour with normal bodyweight and compulsive/perseverative and impulsive behaviours similar to those in binge-eating disorder. We investigated whether (a) dysregulated central nervous system dopaminergic and opioidergic systems are part of the psychopathology of binge-eating and (b) these neurotransmitter systems may mediate the actions of drugs ameliorating binge-eating disorder psychopathology. Binge-eating produced a 39% reduction of striatal D 1 receptors with 22% and 23% reductions in medial and lateral caudate putamen and a 22% increase of striatal μ-opioid receptors. There was no change in D 1 receptor density in nucleus accumbens, medial prefrontal cortex or dorsolateral frontal cortex, striatal D 2 receptors and dopamine reuptake transporter sites, or μ-opioid receptors in frontal cortex. There were no changes in ligand affinities. The concentrations of monoamines, metabolites and estimates of dopamine (dopamine/dihydroxyphenylacetic acid ratio) and serotonin/5-hydroxyindolacetic acid ratio turnover rates were unchanged in striatum and frontal cortex. However, turnover of dopamine and serotonin in the hypothalamus was increased ~20% and ~15%, respectively. Striatal transmission via D 1 receptors is decreased in binge-eating rats while μ-opioid receptor signalling may be increased. These changes are consistent with the attenuation of binge-eating by lisdexamfetamine, which increases catecholaminergic neurotransmission, and nalmefene, a μ-opioid antagonist.

Enhanced Solubility and Permeability of Salicis cortex Extract by Formulating as a Microemulsion.

PubMed

Piazzini, Vieri; Bigagli, Elisabetta; Luceri, Cristina; Bilia, Anna Rita; Bergonzi, Maria Camilla

2018-04-24

A microemulsion system was developed and investigated as a novel oral formulation to increase the solubility and absorption of Salicis cortex extract. This extract possesses many pharmacological activities, in particular, it is beneficial for back pain and osteoarthritic and rheumatic complaints. In this work, after qualitative and quantitative characterization of the extract and the validation of an HPLC/diode array detector analytical method, solubility studies were performed to choose the best components for microemulsion formulation. The optimized microemulsion consisted of 2.5 g of triacetin, as the oil phase, 2.5 g of Tween 20 as the surfactant, 2.5 g of labrasol as the cosurfactant, and 5 g of water. The microemulsion was visually checked, characterized by light scattering techniques and morphological observations. The developed formulation appeared transparent, the droplet size was around 40 nm, and the ζ -potential result was negative. The maximum loading content of Salicis cortex extract resulted in 40 mg/mL. Furthermore, storage stability studies and an in vitro digestion assay were performed. The advantages offered by microemulsion were evaluated in vitro using artificial membranes and cells, i.e., parallel artificial membrane permeability assay and a Caco-2 model. Both studies proved that the microemulsion was successful in enhancing the permeation of extract compounds, so it could be useful to ameliorate the bioefficacy of Salicis cortex. Georg Thieme Verlag KG Stuttgart · New York.

Chronic intracortical microstimulation (ICMS) of cat sensory cortex using the Utah Intracortical Electrode Array.

PubMed

Rousche, P J; Normann, R A

1999-03-01

In an effort to assess the safety and efficacy of focal intracortical microstimulation (ICMS) of cerebral cortex with an array of penetrating electrodes as might be applied to a neuroprosthetic device to aid the deaf or blind, we have chronically implanted three trained cats in primary auditory cortex with the 100-electrode Utah Intracortical Electrode Array (UIEA). Eleven of the 100 electrodes were hard-wired to a percutaneous connector for chronic access. Prior to implant, cats were trained to "lever-press" in response to pure tone auditory stimulation. After implant, this behavior was transferred to "lever-presses" in response to current injections via single electrodes of the implanted arrays. Psychometric function curves relating injected charge level to the probability of response were obtained for stimulation of 22 separate electrodes in the three implanted cats. The average threshold charge/phase required for electrical stimulus detection in each cat was, 8.5, 8.6, and 11.6 nC/phase respectively, with a maximum charge/phase of 26 nC/phase and a minimum of 1.5 nC/phase thresholds were tracked for varying time intervals, and seven electrodes from two cats were tracked for up to 100 days. Electrodes were stimulated for no more than a few minutes each day. Neural recordings taken from the same electrodes before and after multiple electrical stimulation sessions were very similar in signal/noise ratio and in the number of recordable units, suggesting that the range of electrical stimulation levels used did not damage neurons in the vicinity of the electrodes. Although a few early implants failed, we conclude that ICMS of cerebral cortex to evoke a behavioral response can be achieved with the penetrating UIEA. Further experiments in support of a sensory cortical prosthesis based on ICMS are warranted.

Blockade of α2-adrenergic receptors in prelimbic cortex: impact on cocaine self-administration in adult spontaneously hypertensive rats following adolescent atomoxetine treatment.

PubMed

Baskin, Britahny M; Nic Dhonnchadha, Bríd Á; Dwoskin, Linda P; Kantak, Kathleen M

2017-10-01

Research with the spontaneously hypertensive rat (SHR) model of attention deficit/hyperactivity disorder demonstrated that chronic methylphenidate treatment during adolescence increased cocaine self-administration established during adulthood under a progressive ratio (PR) schedule. Compared to vehicle, chronic atomoxetine treatment during adolescence failed to increase cocaine self-administration under a PR schedule in adult SHR. We determined if enhanced noradrenergic transmission at α2-adrenergic receptors within prefrontal cortex contributes to this neutral effect of adolescent atomoxetine treatment in adult SHR. Following treatment from postnatal days 28-55 with atomoxetine (0.3 mg/kg) or vehicle, adult male SHR and control rats from Wistar-Kyoto (WKY) and Wistar (WIS) strains were trained to self-administer 0.3 mg/kg cocaine. Self-administration performance was evaluated under a PR schedule of cocaine delivery following infusion of the α2-adrenergic receptor antagonist idazoxan (0 and 10-56 μg/side) directly into prelimbic cortex. Adult SHR attained higher PR break points and had greater numbers of active lever responses and infusions than WKY and WIS. Idazoxan dose-dependently increased PR break points and active lever responses in SHR following adolescent atomoxetine vs. vehicle treatment. Behavioral changes were negligible after idazoxan pretreatment in SHR following adolescent vehicle or in WKY and WIS following adolescent atomoxetine or vehicle. α2-Adrenergic receptor blockade in prelimbic cortex of SHR masked the expected neutral effect of adolescent atomoxetine on adult cocaine self-administration behavior. Moreover, greater efficacy of acute idazoxan challenge in adult SHR after adolescent atomoxetine relative to vehicle is consistent with the idea that chronic atomoxetine may downregulate presynaptic α2A-adrenergic autoreceptors in SHR.

High amylose resistant starch diet ameliorates oxidative stress, inflammation, and progression of chronic kidney disease

USDA-ARS?s Scientific Manuscript database

Inflammation is a major mediator of CKD progression and is partly driven by altered gut microbiome and intestinal barrier disruption, events which are caused by: urea influx in the intestine resulting in dominance of urease-possessing bacteria; disruption of epithelial barrier by urea-derived ammoni...

A resistant starch fiber diet ameliorates oxidative stress, inflammation, and progression of chronic kidney disease (CKD)

USDA-ARS?s Scientific Manuscript database

Inflammation is a constant feature and a major mediator of CKD progression. It is, in part, driven by altered gut microbiome and disruption of intestinal epithelial barrier, events which are primarily caused by: 1- urea influx in the intestine resulting in dominance of urease-possessing bacteria; 2-...

Factors Associated with Teacher Delivery of a Classroom-Based Tier 2 Prevention Program

ERIC Educational Resources Information Center

Sutherland, Kevin S; Conroy, Maureen A; McLeod, Bryce D; Algina, James; Kunemund, Rachel L

2018-01-01

Teachers sometimes struggle to deliver evidence based programs designed to prevent and ameliorate chronic problem behaviors of young children with integrity. Identifying factors associated with variations in the quantity and quality of delivery is thus an important goal for the field. This study investigated factors associated with teacher…

Physical activity and neural correlates of aging: A combined TMS/fMRI study

PubMed Central

McGregor, Keith M.; Zlatar, Zvinka; Kleim, Erin; Sudhyadhom, Atchar; Bauer, Andrew; Phan, Stephanie; Seeds, Lauren; Ford, Anastasia; Manini, Todd M.; White, Keith D.; Kleim, Jeffrey; Crosson, Bruce

2013-01-01

Aerobic exercise has been suggested to ameliorate aging-related decline in humans. Recently, evidence has indicated chronological aging is associated with decreases in measures of interhemispheric inhibition during unimanual movements, but that such decreases may be mitigated by long-term physical fitness. The present study investigated measures of ipsilateral (right) primary motor cortex activity during right-hand movements using functional magnetic resonance imaging and transcranial magnetic stimulation (TMS). Healthy, right-handed participant groups were comprised of 12 sedentary older adults, 12 physically active older adults, and 12 young adults. Active older adults and younger adults evidenced longer ipsilateral silent periods (iSP) and less positive BOLD of ipsilateral motor cortex (iM1) as compared to sedentary older adults. Across groups, duration of iSP from TMS was inversely correlated with BOLD activity in iM1 during unimanual movement. These findings suggest that increased physical activity may have a role in decreasing aging-related losses of interhemispheric inhibition. PMID:21440574

Sports-related brain injuries: connecting pathology to diagnosis.

PubMed

Pan, James; Connolly, Ian D; Dangelmajer, Sean; Kintzing, James; Ho, Allen L; Grant, Gerald

2016-04-01

Brain injuries are becoming increasingly common in athletes and represent an important diagnostic challenge. Early detection and management of brain injuries in sports are of utmost importance in preventing chronic neurological and psychiatric decline. These types of injuries incurred during sports are referred to as mild traumatic brain injuries, which represent a heterogeneous spectrum of disease. The most dramatic manifestation of chronic mild traumatic brain injuries is termed chronic traumatic encephalopathy, which is associated with profound neuropsychiatric deficits. Because chronic traumatic encephalopathy can only be diagnosed by postmortem examination, new diagnostic methodologies are needed for early detection and amelioration of disease burden. This review examines the pathology driving changes in athletes participating in high-impact sports and how this understanding can lead to innovations in neuroimaging and biomarker discovery.

State of the art in biobehavioral approaches to the management of chronic pain in childhood

PubMed Central

Simons, Laura E; Basch, Molly C

2016-01-01

Chronic pain in childhood is prevalent, persistent and significantly impactful on most domains of life. The chronic pain experience occurs within a complex biopsychosocial framework, with particular emphasis on the social context. Currently, psychological treatments involve a cognitive–behavioral therapy treatment plan, providing some combination of psychoeducation, self-regulation training, maladaptive cognition identification, behavioral exposure and parent involvement. New treatment areas are emerging, such as group- and internet-based cognitive–behavioral therapy, motivational interviewing, comorbid obesity intervention and intensive multidisciplinary rehabilitation. Preliminary studies of emerging treatments demonstrate encouraging results; however, treatment effectiveness hinges on accurate matching of patient to treatment modality. Overall, the current direction of the field promises many innovative breakthroughs to ameliorate suffering in youth with chronic pain. PMID:26678858

Altered CB receptor-signaling in prefrontal cortex from an animal model of depression is reversed by chronic fluoxetine.

PubMed

Rodríguez-Gaztelumendi, Antonio; Rojo, M Luisa; Pazos, Angel; Díaz, Alvaro

2009-03-01

Bilateral olfactory bulbectomy in the rat (OBX) induces behavioral, neurochemical, and structural abnormalities similar to those observed in human depression that are normalized after chronic, but not acute, treatment with antidepressants. In our study, OBX animals exhibited significant increases in both CB(1) receptor density ([(3)H]CP55490 binding) and functionality (stimulation of [(35)S]GTPgammaS binding by the cannabinoid (CB) agonist WIN 55212-2) at the prefrontal cortex (PFC). After chronic treatment with fluoxetine (10 mg/kg/day, 14 days, s.c.), OBX-induced hyperactivity in the open-field test was fully abolished. Interestingly, chronic fluoxetine fully reversed the enhanced CB(1)-receptor signaling in PFC observed following OBX. The CB agonist Delta(9)-tetrahydrocannabinol (5 mg/kg, i.p., 1 day) did not produce any behavioral effect in sham-operated animals but returned locomotor activity to control values in OBX rats. As both acute administration of Delta(9)-tetrahydrocannabinol and chronic fluoxetine elicited a similar behavioral effect in the OBX rat, it is not unlikely that the regionally selective enhancement of CB(1) receptor-signaling in the PFC could be related with the altered OBX behavior. Our findings reinforce the utility of this animal model to further investigating the implication of the endocannabinoid system in the modulation of emotional processes and its potential role in the adaptive responses to chronic antidepressants.

Silymarin ameliorates experimentally induced depressive like behavior in rats: Involvement of hippocampal BDNF signaling, inflammatory cytokines and oxidative stress response.

PubMed

Thakare, Vishnu N; Aswar, Manoj K; Kulkarni, Yogesh P; Patil, Rajesh R; Patel, Bhoomika M

2017-10-01

Silymarin is a polyphenolic flavonoid of Silybum marianum, exhibited neuroprotection and antidepressant like activity in acute restraint stressed mice. The main objective of the present study is to investigate possible antidepressant like activity of silymarin in experimentally induced depressive behavior in rats. The depressive behaviors were induced in rats by olfactory bulbectomized (OBX) technique. Wistar rats were administered with silymarin at a dose of 100mg/kg and 200mg/kg, by per oral in OBX and sham operated rats. Behavioral (ambulatory and rearing activity and immobility time), neurochemical [serotonin (5-HT), dopamine (DA), norepinephrine (NE) and brain derived neurotrophic factor (BDNF) level], biochemical (MDA formation, IL-6, TNF-α and antioxidants) changes in hippocampus and cerebral cortex along with serum corticosterone were investigated. Rats subjected to OBX elicited significant increase in immobility time, ambulatory and rearing behaviors, reduced BDNF level, 5-HT, DA, NE and antioxidant parameters along with increased serum corticosterone, MDA formation, IL-6, and TNF-α in hippocampus and cerebral cortex compared to sham operated rats. Administration of with silymarin significantly attenuated immobility time, ambulatory and rearing behaviors, serum corticosterone and improved BDNF expression, 5-HT, DA, NE and antioxidant paradigms in cerebral cortex as well as hippocampus. In addition, silymarin attenuated IL-6, and TNF-α significantly in hippocampus and cerebral cortex in OBX rats. Thus, silymarin exhibits anti-depressant-like activity in OBX rats due to alterations in several neurotransmitters, endocrine and immunologic systems, including BDNF, 5-HT, DA, NE, MDA formation, IL-6, and TNF-α in hippocampus and cerebral cortex as well as serum corticosterone. Copyright © 2017 Elsevier Inc. All rights reserved.

Motor cortex stimulation suppresses cortical responses to noxious hindpaw stimulation after spinal cord lesion in rats.

PubMed

Jiang, Li; Ji, Yadong; Voulalas, Pamela J; Keaser, Michael; Xu, Su; Gullapalli, Rao P; Greenspan, Joel; Masri, Radi

2014-01-01

Motor cortex stimulation (MCS) is a potentially effective treatment for chronic neuropathic pain. The neural mechanisms underlying the reduction of hyperalgesia and allodynia after MCS are not completely understood. To investigate the neural mechanisms responsible for analgesic effects after MCS. We test the hypothesis that MCS attenuates evoked blood oxygen-level dependent signals in cortical areas involved in nociceptive processing in an animal model of chronic neuropathic pain. We used adult female Sprague-Dawley rats (n = 10) that received unilateral electrolytic lesions of the right spinal cord at the level of C6 (SCL animals). In these animals, we performed magnetic resonance imaging (fMRI) experiments to study the analgesic effects of MCS. On the day of fMRI experiment, 14 days after spinal cord lesion, the animals were anesthetized and epidural bipolar platinum electrodes were placed above the left primary motor cortex. Two 10-min sessions of fMRI were performed before and after a session of MCS (50 μA, 50 Hz, 300 μs, for 30 min). During each fMRI session, the right hindpaw was electrically stimulated (noxious stimulation: 5 mA, 5 Hz, 3 ms) using a block design of 20 s stimulation off and 20 s stimulation on. A general linear model-based statistical parametric analysis was used to analyze whole brain activation maps. Region of interest (ROI) analysis and paired t-test were used to compare changes in activation before and after MCS in these ROI. MCS suppressed evoked blood oxygen dependent signals significantly (Family-wise error corrected P < 0.05) and bilaterally in 2 areas heavily implicated in nociceptive processing. These areas consisted of the primary somatosensory cortex and the prefrontal cortex. These findings suggest that, in animals with SCL, MCS attenuates hypersensitivity by suppressing activity in the primary somatosensory cortex and prefrontal cortex. Copyright © 2014. Published by Elsevier Inc.

Increased /sup 3/H-spiperone binding sites in mesolimbic area related to methamphetamine-induced behavioral hypersensitivity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Akiyama, K.; Sato, M.; Otsuki, S.

1982-02-01

The specific /sup 3/H-spiperone binding to membrane homogenates of the striatum, mesolimbic area, and frontal cortex was examined in two groups of rats pretreated once daily with saline or 4 mg/kg of methamphetamine (MAP) for 14 days. At 7 days following cessation of chronic pretreatment, all rats received an injection of 4 mg/kg of MAP and were decapitated 1 hr after the injection. In the chronic saline-pretreatment group, the single administration of MAP induced significant changes in the number (Bmax) of specific /sup 3/H-spiperone binding sites (a decrease in the striatum and an increase in the mesolimbic area and frontalmore » cortex), but no significant changes in the affinity (KD) in any brain area. The chronic MAP pretreatment markedly augmented the changes in Bmax in the striatum and mesolimbic area. The increase in specific /sup 3/H-spiperone binding sites in the mesolimbic area is discussed in relation to MAP-induced behavioral hypersensitivity.« less

Targeted Metabolomic Pathway Analysis and Validation Revealed Glutamatergic Disorder in the Prefrontal Cortex among the Chronic Social Defeat Stress Mice Model of Depression.

PubMed

Wang, Wei; Guo, Hua; Zhang, Shu-Xiao; Li, Juan; Cheng, Ke; Bai, Shun-Jie; Yang, De-Yu; Wang, Hai-Yang; Liang, Zi-Hong; Liao, Li; Sun, Lin; Xie, Peng

2016-10-07

Major depressive disorder (MDD) is a severe psychiatric disease that has critically affected life quality for millions of people. Chronic stress is gradually recognized as a primary pathogenesis risk factor of MDD. Despite the remarkable progress in mechanism research, the pathogenesis mechanism of MDD is still not well understood. Therefore, we conducted a liquid chromatography-tandem mass spectrometry (LC-MS/MS) detection of 25 major metabolites of tryptophanic, GABAergic, and catecholaminergic pathways in the prefontal cortex (PFC) of mice in chronic social defeat stress (CSDS). The depressed mice exhibit significant reduction of glutamate in the GABAergic pathway and an increase of L-DOPA and vanillylmandelic acid in catecholaminergic pathways. The data of real-time-quantitative polymerase chain reaction (RT-qPCR) and Western blotting analysis revealed an altered level of glutamatergic circuitry. The metabolomic and molecular data reveal that the glutamatergic disorder in mice shed lights to reveal a mechanism on depression-like and stress resilient phenotype.

Chronic cocaine disrupts neurovascular networks and cerebral function: optical imaging studies in rodents

NASA Astrophysics Data System (ADS)

Zhang, Qiujia; You, Jiang; Volkow, Nora D.; Choi, Jeonghun; Yin, Wei; Wang, Wei; Pan, Yingtian; Du, Congwu

2016-02-01

Cocaine abuse can lead to cerebral strokes and hemorrhages secondary to cocaine's cerebrovascular effects, which are poorly understood. We assessed cocaine's effects on cerebrovascular anatomy and function in the somatosensory cortex of the rat's brain. Optical coherence tomography was used for in vivo imaging of three-dimensional cerebral blood flow (CBF) networks and to quantify CBF velocities (CBFv), and multiwavelength laser-speckle-imaging was used to simultaneously measure changes in CBFv, oxygenated (Δ[HbO2]) and deoxygenated hemoglobin (Δ[HbR]) concentrations prior to and after an acute cocaine challenge in chronically cocaine exposed rats. Immunofluorescence techniques on brain slices were used to quantify microvasculature density and levels of vascular endothelial growth factor (VEGF). After chronic cocaine (2 and 4 weeks), CBFv in small vessels decreased, whereas vasculature density and VEGF levels increased. Acute cocaine further reduced CBFv and decreased Δ[HbO2] and this decline was larger and longer lasting in 4 weeks than 2 weeks cocaine-exposed rats, which indicates that risk for ischemia is heightened during intoxication and that it increases with chronic exposures. These results provide evidence of cocaine-induced angiogenesis in cortex. The CBF reduction after chronic cocaine exposure, despite the increases in vessel density, indicate that angiogenesis was insufficient to compensate for cocaine-induced disruption of cerebrovascular function.

Alterations in regional homogeneity of resting-state cerebral activity in patients with chronic prostatitis/chronic pelvic pain syndrome.

PubMed

Lin, Yusong; Bai, Yan; Liu, Peng; Yang, Xuejuan; Qin, Wei; Gu, Jianqin; Ding, Degang; Tian, Jie; Wang, Meiyun

2017-01-01

The purpose of this study was to explore the neural mechanism in Chronic prostatitis/Chronic pelvic pain syndrome (CP/CPPS) using resting-state functional magnetic resonance imaging. The functional magnetic resonance imaging was performed on 31 male CP/CPPS-patients and 31 age and education matched male healthy controls on a 3-T magnetic resonance imaging unit. A two-sample t-test was adopted to reveal the regional homogeneity between the patients and healthy controls. The mean regional homogeneity values in the alerted brain regions of patients were correlated with the clinical measurements by using Pearson's correlation analyses. The CP/CPPS-patients had significantly decreased regional homogeneity in the bilateral anterior cingulate cortices, insular cortices and right medial prefrontal cortex, while significantly increased regional homogeneity in the brainstem and right thalamus compared with the healthy controls. In the CP/CPPS-patients, the mean regional homogeneity value in the left anterior cingulate cortex, bilateral insular cortices and brainstem were respectively correlated with the National Institutes of Health Chronic Prostatitis Symptom Index total score and pain subscale. These brain regions are important in the pain modulation process. Therefore, an impaired pain modulatory system, either by decreased descending pain inhibition or enhanced pain facilitation, may explain the pain symptoms in CP/CPPS.

Transcranial direct current stimulation over the primary motor vs prefrontal cortex in refractory chronic migraine: A pilot randomized controlled trial.

PubMed

Andrade, Suellen Marinho; de Brito Aranha, Renata Emanuela Lyra; de Oliveira, Eliane Araújo; de Mendonça, Camila Teresa Ponce Leon; Martins, Wanessa Kallyne Nascimento; Alves, Nelson Torro; Fernández-Calvo, Bernardino

2017-07-15

Although transcranial direct current stimulation (tDCS) represents a therapeutic option for the prophylaxis of chronic migraine, the target area for application of the electrical current to the cortex has not yet been well established. Here we sought to determine whether a treatment protocol involving 12 sessions of 2mA, 20min anodal stimulation of the left primary motor (M1) or dorsolateral prefrontal cortex (DLPFC) could offer clinical benefits in the management of pain from migraine. Thirteen participants were assessed before and after treatment, using the Headache Impact Test-6, Visual Analogue Scale and Medical Outcomes Study 36 - Item Short - Form Health Survey. After treatment, group DLPFC exhibited a better performance compared with groups M1 and sham. On intragroup comparison, groups DLPFC and M1 exhibited a greater reduction in headache impact and pain intensity and a higher quality of life after treatment. No significant change was found in group sham. The participants in group M1 exhibited more adverse effects, especially headache, heartburn, and sleepiness, than did those in the other two groups. Transcranial direct current stimulation is a safe and efficacious technique for treating chronic migraine. However, it should be kept in mind that the site of cortical stimulation might modulate the patient's response to treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Structural brain correlates of unconstrained motor activity in people with schizophrenia.

PubMed

Farrow, Tom F D; Hunter, Michael D; Wilkinson, Iain D; Green, Russell D J; Spence, Sean A

2005-11-01

Avolition affects quality of life in chronic schizophrenia. We investigated the relationship between unconstrained motor activity and the volume of key executive brain regions in 16 male patients with schizophrenia. Wristworn actigraphy monitors were used to record motor activity over a 20 h period. Structural magnetic resonance imaging brain scans were parcellated and individual volumes for anterior cingulate cortex and dorsolateral prefrontal cortex extracted. Patients'total activity was positively correlated with volume of left anterior cingulate cortex. These data suggest that the volume of specific executive structures may affect (quantifiable) motor behaviours, having further implications for models of the 'will' and avolition.

Addiction Related Alteration in Resting-state Brain Connectivity

PubMed Central

Ma, Ning; Liu, Ying; Li, Nan; Wang, Chang-Xin; Zhang, Hao; Jiang, Xiao-Feng; Xu, Hu-Sheng; Fu, Xian-Ming; Hu, Xiaoping; Zhang, Da-Ren

2009-01-01

It is widely accepted that addictive drug use is related to abnormal functional organization in the user’s brain. The present study aimed to identify this type of abnormality within the brain networks implicated in addiction by resting-state functional connectivity measured with functional magnetic resonance imaging (fMRI). With fMRI data acquired during resting state from 14 chronic heroin users (12 of whom were being treated with methadone) and 13 non-addicted controls, we investigated the addiction related alteration in functional connectivity between the regions in the circuits implicated in addiction with seed-based correlation analysis. Compared with controls, chronic heroin users showed increased functional connectivity between nucleus accumbens and ventral/rostral anterior cingulate cortex (ACC), and orbital frontal cortex (OFC), between amygdala and OFC; and reduced functional connectivity between prefrontal cortex and OFC, and ACC. These observations of altered resting-state functional connectivity suggested abnormal functional organization in the addicted brain and may provide additional evidence supporting the theory of addiction that emphasizes enhanced salience value of a drug and its related cues but weakened cognitive control in the addictive state. PMID:19703568

Reversing pathological neural activity using targeted plasticity.

PubMed

Engineer, Navzer D; Riley, Jonathan R; Seale, Jonathan D; Vrana, Will A; Shetake, Jai A; Sudanagunta, Sindhu P; Borland, Michael S; Kilgard, Michael P

2011-02-03

Brain changes in response to nerve damage or cochlear trauma can generate pathological neural activity that is believed to be responsible for many types of chronic pain and tinnitus. Several studies have reported that the severity of chronic pain and tinnitus is correlated with the degree of map reorganization in somatosensory and auditory cortex, respectively. Direct electrical or transcranial magnetic stimulation of sensory cortex can temporarily disrupt these phantom sensations. However, there is as yet no direct evidence for a causal role of plasticity in the generation of pain or tinnitus. Here we report evidence that reversing the brain changes responsible can eliminate the perceptual impairment in an animal model of noise-induced tinnitus. Exposure to intense noise degrades the frequency tuning of auditory cortex neurons and increases cortical synchronization. Repeatedly pairing tones with brief pulses of vagus nerve stimulation completely eliminated the physiological and behavioural correlates of tinnitus in noise-exposed rats. These improvements persisted for weeks after the end of therapy. This method for restoring neural activity to normal may be applicable to a variety of neurological disorders.

Reversing pathological neural activity using targeted plasticity

PubMed Central

Engineer, Navzer D.; Riley, Jonathan R.; Seale, Jonathan D.; Vrana, Will A.; Shetake, Jai A.; Sudanagunta, Sindhu P.; Borland, Michael S.; Kilgard, Michael P.

2012-01-01

Brain changes in response to nerve damage or cochlear trauma can generate pathological neural activity that is believed to be responsible for many types of chronic pain and tinnitus1–3. Several studies have reported that the severity of chronic pain and tinnitus is correlated with the degree of map reorganization in somatosensory and auditory cortex, respectively1,4. Direct electrical or transcranial magnetic stimulation of sensory cortex can temporarily disrupt these phantom sensations5. However, there is as yet no direct evidence for a causal role of plasticity in the generation of pain or tinnitus. Here we report evidence that reversing the brain changes responsible can eliminate the perceptual impairment in an animal model of noise-induced tinnitus. Exposure to intense noise degrades the frequency tuning of auditory cortex neurons and increases cortical synchronization. Repeatedly pairing tones with brief pulses of vagus nerve stimulation completely eliminated the physiological and behavioural correlates of tinnitus in noise-exposed rats. These improvements persisted for weeks after the end of therapy. This method for restoring neural activity to normal may be applicable to a variety of neurological disorders. PMID:21228773

Imidacloprid toxicity impairs spatial memory of echolocation bats through neural apoptosis in hippocampal CA1 and medial entorhinal cortex areas.

PubMed

Hsiao, Chun-Jen; Lin, Ching-Lung; Lin, Tian-Yu; Wang, Sheue-Er; Wu, Chung-Hsin

2016-04-13

It has been reported that the decimation of honey bees was because of pesticides of imidacloprid. The imidacloprid is a wildly used neonicotinoid insecticide. However, whether imidacloprid toxicity interferes with the spatial memory of echolocation bats is still unclear. Thus, we compared the spatial memory of Formosan leaf-nosed bats, Hipposideros terasensis, before and after chronic treatment with a low dose of imidacloprid. We observed that stereotyped flight patterns of echolocation bats that received chronic imidacloprid treatment were quite different from their originally learned paths. We further found that neural apoptosis in hippocampal CA1 and medial entorhinal cortex areas of echolocation bats that received imidacloprid treatment was significantly enhanced in comparison with echolocation bats that received sham treatment. Thus, we suggest that imidacloprid toxicity may interfere with the spatial memory of echolocation bats through neural apoptosis in hippocampal CA1 and medial entorhinal cortex areas. The results provide direct evidence that pesticide toxicity causes a spatial memory disorder in echolocation bats. This implies that agricultural pesticides may pose severe threats to the survival of echolocation bats.

Patient-conducted anodal transcranial direct current stimulation of the motor cortex alleviates pain in trigeminal neuralgia

PubMed Central

2014-01-01

Background Transcranial direct current stimulation (tDCS) of the primary motor cortex has been shown to modulate pain and trigeminal nociceptive processing. Methods Ten patients with classical trigeminal neuralgia (TN) were stimulated daily for 20 minutes over two weeks using anodal (1 mA) or sham tDCS over the primary motor cortex (M1) in a randomized double-blind cross-over design. Primary outcome variable was pain intensity on a verbal rating scale (VRS 0–10). VRS and attack frequency were assessed for one month before, during and after tDCS. The impact on trigeminal pain processing was assessed with pain-related evoked potentials (PREP) and the nociceptive blink reflex (nBR) following electrical stimulation on both sides of the forehead before and after tDCS. Results Anodal tDCS reduced pain intensity significantly after two weeks of treatment. The attack frequency reduction was not significant. PREP showed an increased N2 latency and decreased peak-to-peak amplitude after anodal tDCS. No severe adverse events were reported. Conclusion Anodal tDCS over two weeks ameliorates intensity of pain in TN. It may become a valuable treatment option for patients unresponsive to conventional treatment. PMID:25424567

High frequency repetitive sensory stimulation improves temporal discrimination in healthy subjects.

PubMed

Erro, Roberto; Rocchi, Lorenzo; Antelmi, Elena; Palladino, Raffaele; Tinazzi, Michele; Rothwell, John; Bhatia, Kailash P

2016-01-01

High frequency electrical stimulation of an area of skin on a finger improves two-point spatial discrimination in the stimulated area, likely depending on plastic changes in the somatosensory cortex. However, it is unknown whether improvement also applies to temporal discrimination. Twelve young and ten elderly volunteers underwent the stimulation protocol onto the palmar skin of the right index finger. Somatosensory temporal discrimination threshold (STDT) was evaluated before and immediately after stimulation as well as 2.5h and 24h later. There was a significant reduction in somatosensory temporal threshold only on the stimulated finger. The effect was reversible, with STDT returning to the baseline values within 24h, and was smaller in the elderly than in the young participants. High frequency stimulation of the skin focally improves temporal discrimination in the area of stimulation. Given previous suggestions that the perceptual effects rely on plastic changes in the somatosensory cortex, our results are consistent with the idea that the timing of sensory stimuli is, at least partially, encoded in the primary somatosensory cortex. Such a protocol could potentially be used as a therapeutic intervention to ameliorate physiological decline in the elderly or in other disorders of sensorimotor integration. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Green Tea Polyphenols, Mimicking the Effects of Dietary Restriction, Ameliorate High-Fat Diet-Induced Kidney Injury via Regulating Autophagy Flux

PubMed Central

Xie, Xiao; Yi, Weijie; Zhang, Piwei; Wu, Nannan; Yan, Qiaoqiao; Yang, Hui; Tian, Chong; Xiang, Siyun; Du, Miying; Getachew Assefa, Eskedar; Zuo, Xuezhi; Ying, Chenjiang

2017-01-01

Epidemiological and experimental studies reveal that Western dietary patterns contribute to chronic kidney disease, whereas dietary restriction (DR) or dietary polyphenols such as green tea polyphenols (GTPs) can ameliorate the progression of kidney injury. This study aimed to investigate the renal protective effects of GTPs and explore the underlying mechanisms. Sixty Wistar rats were randomly divided into 6 groups: standard diet (STD), DR, high-fat diet (HFD), and three diets plus 200 mg/kg(bw)/day GTPs, respectively. After 18 weeks, HFD group exhibited renal injuries by increased serum cystatin C levels and urinary N-acetyl-β-d-glucosaminidase activity, which can be ameliorated by GTPs. Meanwhile, autophagy impairment as denoted by autophagy-lysosome related proteins, including LC3-II, Beclin-1, p62, cathepsin B, cathepsin D and LAMP-1, was observed in HFD group, whereas DR or GTPs promoted renal autophagy activities and GTPs ameliorated HFD-induced autophagy impairment. In vitro, autophagy flux suppression was detected in palmitic acid (PA)-treated human proximal tubular epithelial cells (HK-2), which was ameliorated by epigallocatechin-3-gallate (EGCG). Furthermore, GTPs (or EGCG) elevated phosphorylation of AMP-activated protein kinase in the kidneys of HFD-treated rats and in PA-treated HK-2 cells. These findings revealed that GTPs mimic the effects of DR to induce autophagy and exert a renal protective effect by alleviating HFD-induced autophagy suppression. PMID:28505110

Effects of inhaled particulate matter on the central nervous system in mice.

PubMed

Kim, So Young; Kim, Jin Ki; Park, So Hyeon; Kim, Byeong-Gon; Jang, An-Soo; Oh, Seung Ha; Lee, Jun Ho; Suh, Myung-Whan; Park, Moo Kyun

2018-06-04

Little is known regarding the adverse effects of chronic particulate matter (PM) inhalation on the central nervous system (CNS). The present study aimed to examine how PM exposure impacts on oxidative stress and inflammatory processes, as well as the expression of interneurons and perineuronal nets (PNNs) in the CNS. BALB/c mice (6-week-old females, n = 32) were exposed to 1 to 5 μm size diesel-extracted particles (DEPs) (100 μg/m 3 , 5 d/week, 5 h/day) and categorized into the following four groups: 1) 4-week DEP (n = 8); 2) 4-week control (n = 8), 3) 8-week DEP (n = 8); and 4) 8-week control (n = 8). The olfactory bulb, prefrontal cortex, temporal cortex, striatum, and cerebellum were harvested from the animals in each group. The expression of antioxidants (heme oxygenase 1 [HO-1] and superoxide dismutase 2 [SOD-2]), and markers of the unfolded protein response (X-box binding protein [XBP]-1S), inflammation (tumor necrosis factor-alpha [TNF-α]), and proliferation (neurotrophin-3 and brain-derived neurotrophic factor [BDNF]) were measured using reverse transcription polymerase chain reaction (PCR) and Western blotting. The expression levels of HO-1, SOD-2, XBP-1S, TNF-α, neurotrophin-3, and BDNF were compared among groups using the Mann-Whitney U test. The temporal cortex was immunostained for parvalbumin (PV) and Wisteria floribunda agglutinin (WFA). The numbers of PV- and WFA-positive cells were counted using a confocal microscope and analyzed with the Mann-Whitney U test. HO-1 expression was elevated in the prefrontal cortex, temporal cortex, striatum, and cerebellum of mice in the 8-week DEP group compared with the control group. Expression of SOD-2 and XBP-1S was elevated in the prefrontal cortex and striatum of the 8-week DEP group compared with the control group. TNF-α expression was elevated in the prefrontal cortex, temporal cortex, striatum, and cerebellum in the 4- and 8-week DEP groups compared with the control group. Neurotrophin-3 expression was decreased in the olfactory bulb and striatum of the 8-week DEP group compared with the control group. WFA density was increased in the 8-week DEP group compared with the control group. The PV and PV + WFA densities were decreased in the 4-week DEP group compared with the control group. Chronic DEP inhalation activated oxidative stress and inflammation in multiple brain regions. Chronic DEP inhalation increased PNNs and decreased the number of interneurons, which may contribute to PM exposure-related CNS dysfunction. Copyright © 2018 Elsevier B.V. All rights reserved.

Ameliorative effect of kolaviron, a biflavonoid complex from Garcinia kola seeds against scopolamine-induced memory impairment in rats: role of antioxidant defense system.

PubMed

Ishola, Ismail O; Adamson, Folasade M; Adeyemi, Olufunmilayo O

2017-02-01

In Alzheimer's disease (AD) basal forebrain cholinergic neurons appear to be targeted primarily in early stages of the disease. Scopolamine (muscarinic receptor antagonist) has been used for decades to induce working and reference memory impairment in rodents. In this study, we evaluated the protective effect of kolaviron, a biflavonoid complex isolated from Garcinia kola seeds extract against scopolamine-induced memory impairment/oxidative stress. Rats were pretreated with kolaviron (25, 50 or 100 mg/kg p.o.) for 3 consecutive days, scopolamine (3 mg/kg, i.p.) was administered 1 h post-treatment on day 3. Five minutes post-scopolamine injection, memory function was assessed using the Y-maze or Morris water maze tests (MWM) in rats. The rats were sacrificed and brains isolated on the 8th day after the MWM test for estimation of acetylcholinesterase activity and nitrosative/oxidative stress status. Scopolamine injection induced deficit (P < 0.05) in percentage alternation behaviour in the Y-maze test indicating memory impairment which was ameliorated by kolaviron in a dose-dependent manner. Also, pre-training treatment with kolaviron significantly improved spatial learning evidenced in the session-dependent and more efficient localization of the hidden platform in the MWM test. Moreover, scopolamine injection induced significant increase in lipid peroxidation (prefrontal cortex), nitrite generation (striatum and hippocampus) and a decrease in glutathione (prefrontal cortex, striatum and hippocampus) and superoxide dismutase (striatum and hippocampus) level which was attenuated by kolaviron pre-treatment. These findings showed that kolaviron possesses cognition enhancing effect through enhancement of antioxidant defense and cholinergic systems.

Seven Years of Recording from Monkey Cortex with a Chronically Implanted Multiple Microelectrode

PubMed Central

Krüger, Jürgen; Caruana, Fausto; Volta, Riccardo Dalla; Rizzolatti, Giacomo

2010-01-01

A brush of 64 microwires was chronically implanted in the ventral premotor cortex of a macaque monkey. Contrary to common approaches, the wires were inserted from the white matter side. This approach, by avoiding mechanical pressure on the dura and pia mater during penetration, disturbed only minimally the cortical recording site. With this approach isolated potentials and multiunit activity were recorded for more than 7 years in about one-third of electrodes. The indirect insertion method also provided an excellent stability within each recording session, and in some cases even allowed recording from the same neurons for several years. Histological examination of the implanted brain region shows only a very marginal damage to the recording area. Advantages and problems related to long-term recording are discussed. PMID:20577628

[Review of the effects of mindfulness meditation on mental and physical health and its mechanisms of action].

PubMed

Ngô, Thanh-Lan

2013-01-01

Interventions based on mindfulness have become increasingly popular. This article reviews the empirical literature on its effects on mental and physical health, discusses presumed mechanisms of action as well as its proposed neurobiological underpinning. Mindfulness is associated with increased well-being as well as reduced cognitive reactivity and behavioral avoidance. It seems to contribute to enhance immune functions, diminish inflammation, diminish the reactivity of the autonomic nervous system, increase telomerase activity, lead to higher levels of plasmatic melatonin and serotonin. It enhances the quality of life for patients suffering from chronic pain, fibromylagia and HIV infection. It facilitates adaptation to the diagnosis of cancer and diabetes. It seems to lead to symptomatic improvement in irritable bowel syndrome, chronic fatigue syndrome, hot flashes, insomnia, stress related hyperphagia. It diminishes craving in substance abuse. The proposed mechanism of action are enhanced metacognitive conscience, interoceptive exposure, experiential acceptance, self-management, attention control, memory, relaxation. Six mechanism of actions for which neurological underpinnings have been published are: attention regulation (anterior cingulate cortex), body awareness (insula, temporoparietal junction), emotion regulation (modulation of the amygdala by the lateral prefrontal cortex), cognitive re-evaluation (activation of the dorsal medial prefrontal cortex or diminished activity in prefrontal regions), exposure/extinction/reconsolidation (ventromedial prefrontal cortex, hippocampus, amygdala) and flexible self-concept (prefrontal median cortex, posterior cingulated cortex, insula, temporoparietal junction). The neurobiological effects of meditation are described. These are: (1) the deactivation of the default mode network that generates spontaneous thoughts, contributes to the maintenance of the autobiographical self and is associated with anxiety and depression; (2) the anterior cingulate cortex that underpins attention functions; (3) the anterior insula associated with the perception of visceral sensation, the detection of heartbeat and respiratory rate, and the affective response to pain; (4) the posterior cingulate cortex which helps to understand the context from which a stimulus emerges; (5) the temporoparietal junction which assumes a central role in empathy and compassion; (6) the amygdala implicated in fear responses. The article ends with a short review of the empirical basis supporting the efficacy for mindfulness based intervention and suggested directions for future research.

Effects of chronic Rhodiola Rosea supplementation on sport performance and antioxidant capacity in trained male: preliminary results.

PubMed

Parisi, A; Tranchita, E; Duranti, G; Ciminelli, E; Quaranta, F; Ceci, R; Cerulli, C; Borrione, P; Sabatini, S

2010-03-01

Rhodiola Rosea, is an adaptogen plant which has been reported to promote fatty acids utilisation, to ameliorate antioxidant function, and to improve body resistance to physical strenuous efforts. The purpose of the present study was to investigate the effects on physical performance as well as on the redox status of a chronic Rhodiola Rosea supplementation in a group of competitive athletes during endurance exercise. Following a chronic supplementation with Rhodiola Rosea for 4 weeks, 14 trained male athletes underwent a cardio-pulmonary exhaustion test and blood samples to evaluate their antioxidant status and other biochemical parameters. These data were compared with those coming from the same athletes after an intake of placebo. The evaluation of physical performance parameters showed that HR Max, Borg Scale level, VO(2) max and duration of the test were essentially unaffected by Rhodiola Rosea assumption. On the contrary, Rhodiola Rosea intake reduced, in a statistically significative manner, plasma free fatty acids levels. No effect on blood glucose was found. Blood antioxidant status and inflammatory parameters resulted unaffected by Rhodiola Rosea supplementation. Blood lactate and plasma creatine kinase levels were found significantly lower (P<0.05) in Rhodiola Rosea treated subjects when compared to the placebo treated group. Chronic Rhodiola Rosea supplementation is able to reduce both lactate levels and parameters of skeletal muscle damage after an exhaustive exercise session. Moreover this supplementation seems to ameliorate fatty acid consumption. Taken together those observation confirm that Rhodiola Rosea may increase the adaptogen ability to physical exercise.

Decreasing self-reported cognitive biases and increasing clinical insight through meta-cognitive training in patients with chronic schizophrenia.

PubMed

Gawęda, Łukasz; Krężołek, Martyna; Olbryś, Joanna; Turska, Agnieszka; Kokoszka, Andrzej

2015-09-01

The aim of this study was to assess the impact of meta-cognitive training (MCT) on cognitive biases, symptoms, clinical insight, and general functioning among low-level functioning persons diagnosed with chronic schizophrenia who were attending a daily Community Social Support Group Program; we compared the treatment-as-usual (TAU) condition with the MCT + TAU condition. Forty-four patients diagnosed with chronic schizophrenia were allocated to either the MCT + treatment-as-usual condition or the treatment-as-usual (TAU) condition. Delusion and hallucination severity, cognitive biases, clinical insight, and global functioning were assessed pre- and post-treatment (clinical trial NCT02187692). No significant changes were found in symptom severity as measured with the PSYRATS. Conversely, a medium to large effect size was observed for delusional ideation changes when assessed by the self-report measure (Paranoia Checklist). MCT was found to ameliorate cognitive biases as measured by the self-report scale at large effect size, however, no changes in jumping to conclusions (the Fish Task) and theory of mind deficits ("Reading the Mind in the Eyes" Test) were found in the behavioral tasks. MCT increased insight at large effect size. No changes in global functioning were found between the two conditions. Low intensity intervention. No follow-up assessment was provided. Only PSYRATS was assessed blind to patient allocation. MCT has a beneficial effect on low-functioning chronic schizophrenic patients in ameliorating cognitive biases and increasing clinical insight. Copyright © 2015 Elsevier Ltd. All rights reserved.

Protective effects of FTY720 on chronic allograft nephropathy by reducing late lymphocytic infiltration.

PubMed

Wang, Minghui; Liu, Shanying; Ouyang, Nengtai; Song, Erwei; Lutz, Jens; Heemann, Uwe

2004-09-01

Lymphocytic infiltration is obvious throughout early and late stages of chronic allograft nephropathy. Early infiltrating lymphocytes are involved in initial insults to kidney allografts, but the contribution of late infiltration to long-term allograft attrition is still controversial. Early application of FTY720 reduced the number of graft infiltrating lymphocytes, and inhibited acute rejection. The present study investigated the potential of FTY720 to reduce the number of infiltrating lymphocytes even at a late stage, and, thus, slow the pace of chronic allograft nephropathy. Fisher (F344) rat kidneys were orthotopically transplanted into Lewis recipients with an initial 10-day course of cyclosporine A (1.5 mg/kg/day). FTY720, at a dose of 0.5 mg/kg/day, or vehicle was administered to recipients either from weeks 12 to 24 or from 20 to 24 after transplantation. Animals were harvested 24 weeks after transplantation for histologic, immunohistologic, and molecular analysis. FTY720, either initiated at 12 or 20 weeks after transplantation, reduced urinary protein excretion, and significantly ameliorated glomerulosclerosis, interstitial fibrosis, tubular atrophy, and intimal proliferation of graft arteries at 24 weeks after transplantation. Furthermore FTY720 markedly suppressed lymphocyte infiltration and decreased mRNA levels of interleukin-10 (IL-10), transforming growth factor-beta (TGF-beta), and platelet-derived growth factor-B (PDGF-B) but enhanced the number of apoptotic cells in grafts. FTY720 ameliorated chronic allograft nephropathy even at advanced stages. Furthermore, our data suggest that this effect was achieved by a reduction of graft infiltrating lymphocytes.

Fluoxetine treatment ameliorates depression induced by perinatal arsenic exposure via a neurogenic mechanism

PubMed Central

Tyler, Christina R.; Solomon, Benjamin R.; Ulibarri, Adam L.; Allan, Andrea M.

2014-01-01

Several epidemiological studies have reported an association between arsenic exposure and increased rates of psychiatric disorders, including depression, in exposed populations. We have previously demonstrated that developmental exposure to low amounts of arsenic induces depression in adulthood along with several morphological and molecular aberrations, particularly associated with the hippocampus and the hypothalamic–pituitary–adrenal (HPA) axis. The extent and potential reversibility of this toxin-induced damage has not been characterized to date. In this study, we assessed the effects of fluoxetine, a selective serotonin reuptake inhibitor antidepressant, on adult animals exposed to arsenic during development. Perinatal arsenic exposure (PAE) induced depressive-like symptoms in a mild learned helplessness task and in the forced swim task after acute exposure to a predator odor (2,4,5-trimethylthiazoline, TMT). Chronic fluoxetine treatment prevented these behaviors in both tasks in arsenic-exposed animals and ameliorated arsenic-induced blunted stress responses, as measured by corticosterone (CORT) levels before and after TMT exposure. Morphologically, chronic fluoxetine treatment reversed deficits in adult hippocampal neurogenesis (AHN) after PAE, specifically differentiation and survival of neural progenitor cells. Protein expression of BDNF, CREB, the glucocorticoid receptor (GR), and HDAC2 was significantly increased in the dentate gyrus of arsenic animals after fluoxetine treatment. This study demonstrates that damage induced by perinatal arsenic exposure is reversible with chronic fluoxetine treatment resulting in restored resiliency to depression via a neurogenic mechanism. PMID:24952232

Fluoxetine ameliorates cognitive impairments induced by chronic cerebral hypoperfusion via down-regulation of HCN2 surface expression in the hippocampal CA1 area in rats.

PubMed

Luo, Pan; Zhang, Xiaoxue; Lu, Yun; Chen, Cheng; Li, Changjun; Zhou, Mei; Lu, Qing; Xu, Xulin; Shen, Guanxin; Guo, Lianjun

2016-01-01

Chronic cerebral hypoperfusion (CCH) causes cognitive impairments and increases the risk of Alzheimer's disease (AD) and vascular dementia (VD) through several biologically plausible pathways, yet the underlying neurobiological mechanisms are still poorly understood. In this study, we investigated whether fluoxetine, a selective serotonin reuptake inhibitor (SSRI), could play a neuroprotective role against chronic cerebral hypoperfusion injury and to clarify underlying mechanisms of its efficacy. Rats were subjected to permanent bilateral occlusion of the common carotid arteries (two-vessel occlusion, 2VO). Two weeks later, rats were treated with 30 mg/kg fluoxetine (intragastric injection, i.g.) for 6 weeks. Cognitive function was evaluated by Morris water maze (MWM) and novel objects recognition (NOR) test. Long-term potentiation (LTP) was used to address the underlying synaptic mechanisms. Western blotting was used to quantify the protein levels. Our results showed that fluoxetine treatment significantly improved the cognitive impairments caused by 2VO, accompanied with a reversion of 2VO-induced inhibitory of LTP. Furthermore, 2VO caused an up-regulation of hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) surface expressions in the hippocampal CA1 area and fluoxetine also effectively recovered the disorder of HCN2 surface expressions, which may be a possible mechanism that fluoxetine treatment ameliorates cognitive impairments in rats with CCH. Copyright © 2015 Elsevier Inc. All rights reserved.

[Treatment of chronic tinnitus with neuronavigated repetitive Transcranial Magnetic Stimulation (rTMS)].

PubMed

Kleinjung, T; Steffens, T; Langguth, B; Eichhammer, P; Marienhagen, J; Hajak, G; Strutz, J

2006-06-01

Idiopathic tinnitus is a frequent and debilitating disorder of largely unknown pathophysiology. Focal brain activation in the auditory cortex has recently been demonstrated in chronic tinnitus. Low-frequency rTMS can reduce cortical hyperexcitability. In 12 patients with chronic tinnitus, fusion of [18F]deoxyglucose-PET and structural MRI (T1, MPRAGE) scans allowed the area of increased metabolic activity in the auditory cortex to be exactly identified; this area was selected as the target for rTMS. A neuronavigational system adapted for TMS positioning enabled the relative positions of the figure-8 coil and the target area to be monitored. Repetitive TMS (110% motor threshold; 1 Hz; 2000 stimuli per day over 5 days) was performed using a placebo-controlled crossover design. A sham coil system was used for the placebo stimulation. Treatment outcome was assessed with a specific tinnitus questionnaire (Goebel and Hiller). In all 12 patients an asymmetrically increased metabolic activation of the gyrus of Heschl was detected. The tinnitus score was significantly improved after 5 days of active rTMS, an effect not seen after placebo stimulation. These preliminary results show that neuronavigated rTMS may improve our understanding and treatment of chronic tinnitus.

Perinatal Bisphenol A Exposure Induces Chronic Inflammation in Rabbit Offspring via Modulation of Gut Bacteria and Their Metabolites

PubMed Central

Veeramachaneni, D. N. Rao; Walters, William A.; Lozupone, Catherine; Palmer, Jennifer; Hewage, M. K. Kurundu; Bhatnagar, Rohil; Amir, Amnon; Kennett, Mary J.; Knight, Rob

2017-01-01

ABSTRACT Bisphenol A (BPA) accumulates in the maturing gut and liver in utero and is known to alter gut bacterial profiles in offspring. Gut bacterial dysbiosis may contribute to chronic colonic and systemic inflammation. We hypothesized that perinatal BPA exposure-induced intestinal (and liver) inflammation in offspring is due to alterations in the microbiome and colonic metabolome. The 16S rRNA amplicon sequencing analysis revealed differences in beta diversity with a significant reduction in the relative abundances of short-chain fatty acid (SCFA) producers such as Oscillospira and Ruminococcaceae due to BPA exposure. Furthermore, BPA exposure reduced fecal SCFA levels and increased systemic lipopolysaccharide (LPS) levels. BPA exposure-increased intestinal permeability was ameliorated by the addition of SCFA in vitro. Metabolic fingerprints revealed alterations in global metabolism and amino acid metabolism. Thus, our findings indicate that perinatal BPA exposure may cause gut bacterial dysbiosis and altered metabolite profiles, particularly SCFA profiles, leading to chronic colon and liver inflammation. IMPORTANCE Emerging evidence suggests that environmental toxicants may influence inflammation-promoted chronic disease susceptibility during early life. BPA, an environmental endocrine disruptor, can transfer across the placenta and accumulate in fetal gut and liver. However, underlying mechanisms for BPA-induced colonic and liver inflammation are not fully elucidated. In this report, we show how perinatal BPA exposure in rabbits alters gut microbiota and their metabolite profiles, which leads to colonic and liver inflammation as well as to increased gut permeability as measured by elevated serum lipopolysaccharide (LPS) levels in the offspring. Also, perinatal BPA exposure leads to reduced levels of gut bacterial diversity and bacterial metabolites (short-chain fatty acids [SCFA]) and elevated gut permeability—three common early biomarkers of inflammation-promoted chronic diseases. In addition, we showed that SCFA ameliorated BPA-induced intestinal permeability in vitro. Thus, our study results suggest that correcting environmental toxicant-induced bacterial dysbiosis early in life may reduce the risk of chronic diseases later in life. PMID:29034330

Effect of acute and repeated restraint stress on glucose oxidation to CO2 in hippocampal and cerebral cortex slices.

PubMed

Torres, I L; Gamaro, G D; Silveira-Cucco, S N; Michalowski, M B; Corrêa, J B; Perry, M L; Dalmaz, C

2001-01-01

It has been suggested that glucocorticoids released during stress might impair neuronal function by decreasing glucose uptake by hippocampal neurons. Previous work has demonstrated that glucose uptake is reduced in hippocampal and cerebral cortex slices 24 h after exposure to acute stress, while no effect was observed after repeated stress. Here, we report the effect of acute and repeated restraint stress on glucose oxidation to CO2 in hippocampal and cerebral cortex slices and on plasma glucose and corticosterone levels. Male adult Wistar rats were exposed to restraint 1 h/day for 50 days in the chronic model. In the acute model there was a single exposure. Immediately or 24 h after stress, the animals were sacrificed and the hippocampus and cerebral cortex were dissected, sliced, and incubated with Krebs buffer, pH 7.4, containing 5 mM glucose and 0.2 microCi D-[U-14C] glucose. CO2 production from glucose was estimated. Trunk blood was also collected, and both corticosterone and glucose were measured. The results showed that corticosterone levels after exposure to acute restraint were increased, but the increase was smaller when the animals were submitted to repeated stress. Blood glucose levels increased after both acute and repeated stress. However, glucose utilization, measured as CO2 production in hippocampal and cerebral cortex slices, was the same in stressed and control groups under conditions of both acute and chronic stress. We conclude that, although stress may induce a decrease in glucose uptake, this effect is not sufficient to affect the energy metabolism of these cells.

Antidepressant-like effects of oleoylethanolamide in a mouse model of chronic unpredictable mild stress.

PubMed

Jin, Peng; Yu, Hai-Ling; Tian-Lan; Zhang, Feng; Quan, Zhe-Shan

2015-06-01

Oleoylethanolamide (OEA) is an endocannabinoid analog that belongs to a family of endogenous acylethanolamides. Increasing evidence suggests that OEA may act as an endogenous neuroprotective factor and participate in the control of mental disorder-related behaviors. In this study, we examined whether OEA is effective against depression and investigated the role of circulating endogenous acylethanolamides during stress. Mice were subjected to 28days of chronic unpredictable mild stress (CUMS), and during the last 21days, treated with oral OEA (1.5-6mg/kg) or 6mg/kg fluoxetine. Sucrose preference and open field test activity were used to evaluate depression-like behaviors during CUMS and after OEA treatment. Weights of the prefrontal cortex and hippocampus were determined, and the adrenal index was measured. Furthermore, changes in serum adrenocorticotropic hormone (ACTH), corticosterone (CORT) and total antioxidant capacity (T-AOC), brain-derived neurotrophic factor (BDNF), and lipid peroxidation product malondialdehyde (MDA) levels, and superoxide dismutase (SOD) activities in the hippocampus and prefrontal cortex were detected. Our findings indicate that OEA normalized sucrose preferences, locomotion distances, rearing frequencies, prefrontal cortex and hippocampal atrophy, and adrenal indices. In addition, OEA reversed the abnormalities of BDNF and MDA levels and SOD activities in the hippocampus and prefrontal cortex, as well as changes in serum levels of ACTH, CORT, and T-AOC. The antidepressant effects of OEA may be related to the regulation of BDNF levels in the hippocampus and prefrontal cortex, antioxidant defenses, and normalizing hyperactivity in the hypothalamic-pituitary-adrenal axis (HPA). Copyright © 2015 Elsevier Inc. All rights reserved.

Chronic stress impairs prefrontal cortex-dependent response inhibition and spatial working memory.

PubMed

Mika, Agnieszka; Mazur, Gabriel J; Hoffman, Ann N; Talboom, Joshua S; Bimonte-Nelson, Heather A; Sanabria, Federico; Conrad, Cheryl D

2012-10-01

Chronic stress leads to neurochemical and structural alterations in the prefrontal cortex (PFC) that correspond to deficits in PFC-mediated behaviors. The present study examined the effects of chronic restraint stress on response inhibition (using a response-withholding task, the fixed-minimum interval schedule of reinforcement, or FMI), and working memory (using a radial arm water maze, RAWM). Adult male Sprague-Dawley rats were first trained on the RAWM and subsequently trained on FMI. After acquisition of FMI, rats were assigned to a restraint stress (6h/d/28d in wire mesh restrainers) or control condition. Immediately after chronic stress, rats were tested on FMI and subsequently on RAWM. FMI results suggest that chronic stress reduces response inhibition capacity and motivation to initiate the task on selective conditions when sucrose reward was not obtained on the preceding trial. RAWM results suggest that chronic stress produces transient deficits in working memory without altering previously consolidated reference memory. Behavioral measures from FMI failed to correlate with metrics from RAWM except for one in which changes in FMI timing imprecision negatively correlated with changes in RAWM working memory errors for the controls, a finding that was not observed following chronic stress. Fisher's r-to-z transformation revealed no significant differences between control and stress groups with correlation coefficients. These findings are the first to show that chronic stress impairs both response inhibition and working memory, two behaviors that have never been directly compared within the same animals after chronic stress, using FMI, an appetitive task, and RAWM, a nonappetitive task. PsycINFO Database Record (c) 2012 APA, all rights reserved.

Prefrontal tDCS Decreases Pain in Patients with Multiple Sclerosis

PubMed Central

Ayache, Samar S.; Palm, Ulrich; Chalah, Moussa A.; Al-Ani, Tarik; Brignol, Arnaud; Abdellaoui, Mohamed; Dimitri, Dalia; Sorel, Marc; Créange, Alain; Lefaucheur, Jean-Pascal

2016-01-01

Background: In the last few years, transcranial direct current stimulation (tDCS) has emerged as an appealing therapeutic option to improve brain functions. Promising data support the role of prefrontal tDCS in augmenting cognitive performance and ameliorating several neuropsychiatric symptoms, namely pain, fatigue, mood disturbances, and attentional impairment. Such symptoms are commonly encountered in patients with multiple sclerosis (MS). Objective: The main objective of the current work was to evaluate the tDCS effects over the left dorsolateral prefrontal cortex (DLPFC) on pain in MS patients.Our secondary outcomes were to study its influence on attention, fatigue, and mood. Materials and Methods: Sixteen MS patients with chronic neuropathic pain were enrolled in a randomized, sham-controlled, and cross-over study.Patients randomly received two anodal tDCS blocks (active or sham), each consisting of three consecutive daily tDCS sessions, and held apart by 3 weeks. Evaluations took place before and after each block. To evaluate pain, we used the Brief Pain Inventory (BPI) and the Visual Analog Scale (VAS). Attention was assessed using neurophysiological parameters and the Attention Network Test (ANT). Changes in mood and fatigue were measured using various scales. Results: Compared to sham, active tDCS yielded significant analgesic effects according to VAS and BPI global scales.There were no effects of any block on mood, fatigue, or attention. Conclusion: Based on our results, anodal tDCS over the left DLPFC appears to act in a selective manner and would ameliorate specific symptoms, particularly neuropathic pain. Analgesia might have occurred through the modulation of the emotional pain network. Attention, mood, and fatigue were not improved in this work. This could be partly attributed to the short protocol duration, the small sample size, and the heterogeneity of our MS cohort. Future large-scale studies can benefit from comparing the tDCS effects over different cortical sites, changing the stimulation montage, prolonging the duration of protocol, and coupling tDCS with neuroimaging techniques for a better understanding of its possible mechanism of action. PMID:27092048

High amylose resistant starch diet ameliorates oxidative stress, inflammation, and progression of chronic kidney disease (CKD)

USDA-ARS?s Scientific Manuscript database

Patients with advanced CKD exhibit profound changes in the composition and function of the gut microbiome. This is, in part, mediated by: I- heavy influx of urea in the intestinal tract leading to the dominance of urease-possessing bacteria and II- dietary restriction of potassium-rich fruits and ve...

[Ultrastructural pathology of oligodendrocytes in the white matter in continuous paranoid schizophrenia: a role for microglia].

PubMed

Uranova, N A; Vikhreva, O V; Rakhmanova, V I; Orlovskaya, D D

Previously the authors have reported the ultrastructural pathology and deficit of oligodendrocytes in gray and white matter of the prefrontal cortex in schizophrenia. The aim of the study was to determine of the effects of microglia on the ultrastructure of oligodendrocytes in the white matter underlying the prefrontal cortex in continuous schizophrenia. Postmortem morphometric electron microscopic study of oligodendrocytes in close apposition to microglia was performed in white matter underlying the prefrontal cortex (BA10). Eleven cases of chronic continuous schizophrenia and 11 normal controls were studied. Areas of oligodendrocytes, of their nuclei and cytoplasm, volume density (Vv) and the number of mitochondria, vacuoles of endoplasmic reticulum and lipofuscin granules were estimated. Group comparison was performed using ANCOVA. The schizophrenia group differed from the control group by paucity of ribosomes in the cytoplasm of oligodendrocytes, a significant decrease in Vv and the number of mitochondria and increase in the number of lipofuscin granules. Significant correlations between the parameters of lipofuscin granules, mitochondria and vacuoles were found only in the schizophrenia group. The number of lipofuscin granules were correlated positively with the illness duration. Dystrophic alterations of oligodendrocytes attached to microglial cells were found in the white matter of the prefrontal cortex in chronic paranoid schizophrenia as compared to controls. The data obtained suggest that microglia might contribute to abnormalities of energy, lipid and protein metabolism of oligodendrocytes in schizophrenia.

The Responsive Amygdala: Treatment-induced Alterations in Functional Connectivity in Pediatric Complex Regional Pain Syndrome

PubMed Central

Simons, LE; Pielech, M; Erpelding, N; Linnman, C; Moulton, E; Sava, S; Lebel, A; Serrano, P; Sethna, N; Berde, C; Becerra, L; Borsook, D

2014-01-01

The amygdala is a key brain region with efferent and afferent neural connections that involve complex behaviors such as pain, reward, fear and anxiety. This study evaluated resting state functional connectivity of the amygdala with cortical and subcortical regions in a group of chronic pain patients (pediatric complex regional pain syndrome) with age-gender matched controls before and after intensive physical-biobehavioral pain treatment. Our main findings include (1) enhanced functional connectivity from the amygdala to multiple cortical, subcortical, and cerebellar regions in patients compared to controls, with differences predominantly in the left amygdala in the pre-treated condition (disease state); (2) dampened hyperconnectivity from the left amygdala to the motor cortex, parietal lobe, and cingulate cortex after intensive pain rehabilitation treatment within patients with nominal differences observed among healthy controls from Time 1 to Time 2 (treatment effects); (3) functional connectivity to several regions key to fear circuitry (prefrontal cortex, bilateral middle temporal lobe, bilateral cingulate, hippocampus) correlated with higher pain-related fear scores and (4) decreases in pain-related fear associated with decreased connectivity between the amygdala and the motor and somatosensory cortex, cingulate, and frontal areas. Our data suggest that there are rapid changes in amygdala connectivity following an aggressive treatment program in children with chronic pain and intrinsic amygdala functional connectivity activity serving as a potential indicator of treatment response. PMID:24861582

Cortico-limbic morphology separates tinnitus from tinnitus distress

PubMed Central

Leaver, Amber M.; Seydell-Greenwald, Anna; Turesky, Ted K.; Morgan, Susan; Kim, Hung J.; Rauschecker, Josef P.

2012-01-01

Tinnitus is a common auditory disorder characterized by a chronic ringing or buzzing “in the ear.”Despite the auditory-perceptual nature of this disorder, a growing number of studies have reported neuroanatomical differences in tinnitus patients outside the auditory-perceptual system. Some have used this evidence to characterize chronic tinnitus as dysregulation of the auditory system, either resulting from inefficient inhibitory control or through the formation of aversive associations with tinnitus. It remains unclear, however, whether these “non-auditory” anatomical markers of tinnitus are related to the tinnitus signal itself, or merely to negative emotional reactions to tinnitus (i.e., tinnitus distress). In the current study, we used anatomical MRI to identify neural markers of tinnitus, and measured their relationship to a variety of tinnitus characteristics and other factors often linked to tinnitus, such as hearing loss, depression, anxiety, and noise sensitivity. In a new cohort of participants, we confirmed that people with chronic tinnitus exhibit reduced gray matter in ventromedial prefrontal cortex (vmPFC) compared to controls matched for age and hearing loss. This effect was driven by reduced cortical surface area, and was not related to tinnitus distress, symptoms of depression or anxiety, noise sensitivity, or other factors. Instead, tinnitus distress was positively correlated with cortical thickness in the anterior insula in tinnitus patients, while symptoms of anxiety and depression were negatively correlated with cortical thickness in subcallosal anterior cingulate cortex (scACC) across all groups. Tinnitus patients also exhibited increased gyrification of dorsomedial prefrontal cortex (dmPFC), which was more severe in those patients with constant (vs. intermittent) tinnitus awareness. Our data suggest that the neural systems associated with chronic tinnitus are different from those involved in aversive or distressed reactions to tinnitus. PMID:22493571

Chronic Intermittent Ethanol Exposure Enhances the Excitability and Synaptic Plasticity of Lateral Orbitofrontal Cortex Neurons and Induces a Tolerance to the Acute Inhibitory Actions of Ethanol

PubMed Central

Nimitvilai, Sudarat; Lopez, Marcelo F; Mulholland, Patrick J; Woodward, John J

2016-01-01

Alcoholism is associated with changes in brain reward and control systems, including the prefrontal cortex. In prefrontal areas, the orbitofrontal cortex (OFC) has been suggested to have an important role in the development of alcohol-abuse disorders and studies from this laboratory demonstrate that OFC-mediated behaviors are impaired in alcohol-dependent animals. However, it is not known whether chronic alcohol (ethanol) exposure alters the fundamental properties of OFC neurons. In this study, mice were exposed to repeated cycles of chronic intermittent ethanol (CIE) exposure to induce dependence and whole-cell patch-clamp electrophysiology was used to examine the effects of CIE treatment on lateral OFC (lOFC) neuron excitability, synaptic transmission, and plasticity. Repeated cycles of CIE exposure and withdrawal enhanced current-evoked action potential (AP) spiking and this was accompanied by a reduction in the after-hyperpolarization and a decrease in the functional activity of SK channels. CIE mice also showed an increase in the AMPA/NMDA ratio, and this was associated with an increase in GluA1/GluA2 AMPA receptor expression and a decrease in GluN2B NMDA receptor subunits. Following CIE treatment, lOFC neurons displayed a persistent long-term potentiation of glutamatergic synaptic transmission following a spike-timing-dependent protocol. Lastly, CIE treatment diminished the inhibitory effect of acute ethanol on AP spiking of lOFC neurons and reduced expression of the GlyT1 transporter. Taken together, these results suggest that chronic exposure to ethanol leads to enhanced intrinsic excitability and glutamatergic synaptic signaling of lOFC neurons. These alterations may contribute to the impairment of OFC-dependent behaviors in alcohol-dependent individuals. PMID:26286839

Neuron activity in rat hippocampus and motor cortex during discrimination reversal.

PubMed

Disterhoft, J F; Segal, M

1978-01-01

Chronic unit activity and gross movement were recorded from rats during two discrimination reversals in a classical appetitive conditioning situation. The anticipatory movement decreased in response to the former CS+ tone and increased to the previous CS- tone after each reversal. Hippocampus and motor cortex were differently related to these two kinds of behavioral change. Response rates of hippocampal neurons were more closely related to the increased movement response to the former CS- which now signaled food. Motor cortex neuron responses were more closely correlated with the decrease in movement responses to the former CS+ which became neutral after the reversal. It appeared that hippocampal neurons could have been involved in one cognitive aspect of the situation, motor cortex neurons in another. The data were related to current functional concepts of these brain regions.

G-Protein-Coupled Receptor Gpr17 Expression in Two Multiple Sclerosis Remyelination Models.

PubMed

Nyamoya, Stella; Leopold, Patrizia; Becker, Birte; Beyer, Cordian; Hustadt, Fabian; Schmitz, Christoph; Michel, Anne; Kipp, Markus

2018-06-05

In multiple sclerosis patients, demyelination is prominent in both the white and gray matter. Chronic clinical deficits are known to result from acute or chronic injury to the myelin sheath and inadequate remyelination. The underlying molecular mechanisms of remyelination and its failure remain currently unclear. Recent studies have recognized G protein-coupled receptor 17 (GPR17) as an important regulator of oligodendrocyte development and remyelination. So far, the relevance of GPR17 for myelin repair was mainly tested in remyelinating white matter lesions. The relevance of GPR17 for gray matter remyelination as well as remyelination of chronic white matter lesions was not addressed so far. Here, we provide a detailed characterization of GPR17 expression during experimental de- and remyelination. Experimental lesions with robust and limited endogenous remyelination capacity were established by either acute or chronic cuprizone-induced demyelination. Furthermore, remyelinating lesions were induced by the focal injection of lysophosphatidylcholine (LPC) into the corpus callosum. GPR17 expression was analyzed by complementary techniques including immunohistochemistry, in situ hybridization, and real-time PCR. In control animals, GPR17 + cells were evenly distributed in the corpus callosum and cortex and displayed a highly ramified morphology. Virtually all GPR17 + cells also expressed the oligodendrocyte-specific transcription factor OLIG2. After acute cuprizone-induced demyelination, robust endogenous remyelination was evident in the white matter corpus callosum but not in the gray matter cortex. Endogenous callosal remyelination was paralleled by a robust induction of GPR17 expression which was absent in the gray matter cortex. Higher numbers of GPR17 + cells were as well observed after LPC-induced focal white matter demyelination. In contrast, densities of GPR17 + cells were comparable to control animals after chronic cuprizone-induced demyelination indicating quiescence of this cell population. Our findings demonstrate that GPR17 expression induction correlates with acute demyelination and sufficient endogenous remyelination. This strengthens the view that manipulation of this receptor might be a therapeutic opportunity to support endogenous remyelination.

Melanocortin antagonism ameliorates muscle wasting and inflammation in chronic kidney disease.

PubMed

Cheung, Wai W; Mak, Robert H

2012-11-01

Aberrant melanocortin signaling has been implicated in the pathogenesis of wasting in chronic kidney disease (CKD). Previously, we demonstrated that agouti-related peptide (AgRP), a melenocortin-4 receptor antagonist, reduced CKD-associated cachexia in CKD mice. Our previous studies with AgRP utilized dual energy X-ray (DXA) densitometry to assess the body composition in mice (Cheung W, Kuo HJ, Markison S, Chen C, Foster AC, Marks DL, Mak RH. J Am Soc Nephrol 18: 2517-2524, 2007; Cheung W, Yu PX, Little BM, Cone RD, Marks DL, Mak RH. J Clin Invest 115: 1659-1665, 2005). DXA is unable to differentiate water content in mice, and fluid retention in CKD may lead to an overestimate of lean mass. In this study, we employed quantitative magnetic resonance technique to evaluate body composition change following central administration of AgRP in a CKD mouse model. AgRP treatment improved energy expenditure, total body mass, fat mass, and lean body mass in CKD mouse. We also investigated the effect of CKD-associated cachexia on the signaling pathways leading to wasting in skeletal muscle, as well as whether these changes can be ameliorated by central administration of AgRP. AgRP treatment caused an overall decrease in proinflammatory cytokines, which may be one important mechanism of its effects. Muscle wasting in CKD may be due to the activation of proteolytic pathways as well as inhibition of myogenesis and muscle regeneration processes. Our results suggest that these aberrant pathological pathways leading to muscle wasting in CKD mice were ameliorated by central administration of AgRP.

Dietary Changes Involving Bifidobacterium longum and Other Nutrients Delays Chronic Kidney Disease Progression.

PubMed

Iwashita, Yuko; Ohya, Masaki; Yashiro, Mitsuru; Sonou, Tomohiro; Kawakami, Kazuki; Nakashima, Yuri; Yano, Takuro; Iwashita, Yu; Mima, Toru; Negi, Shigeo; Kubo, Kaoru; Tomoda, Koichi; Odamaki, Toshitaka; Shigematsu, Takashi

2018-01-01

Recent studies suggest that prebiotic and/or probiotic treatments ameliorate kidney function in humans and animals by improving the gut environment. However, the gut microbiota and kidney disease interactions remain to be determined. This study investigated whether synbiotics modulate the gut microbiota and ameliorate kidney function using a rat model of chronic kidney disease (CKD). As uremic toxins are associated with CKD-related mineral and bone disorder, the secondary aim was to evaluate the relationship between synbiotics and secondary hyperparathyroidism (SHPT). 5/6 nephrectomy (Nx) rats were developed as the CKD model. Sham-operated (sham) rats were used as the control. To investigate the effectiveness of prebiotics (glutamine, dietary fiber, and oligosaccharide) and probiotics (Bifidobacterium longum strain; GFOB diet), rats were randomly assigned to 4 groups: Nx group fed the GFOB diet (n = 10); Nx group fed the control (CON) diet (n = 10); sham group fed the GFOB diet (n = 5); and sham group fed the control diet (n = 5). Blood, feces, and kidney samples were collected and analyzed. Serum creatinine (Cre) and blood urea nitrogen in the Nx GFOB group were significantly lower than those in the Nx CON group. Serum indoxyl sulfate in the Nx GFOB group was lower than that in the Nx CON group, and significantly correlated with serum Cre. Inorganic phosphorus and intact parathyroid hormone in the Nx GFOB group were significantly lower than those in the Nx CON group. Improving the gut environment using synbiotics ameliorated kidney function and might be a pharmacological treatment for SHPT without any serious adverse events. © 2018 S. Karger AG, Basel.

Antidepressant-like effect of flaxseed secoisolariciresinol diglycoside in ovariectomized mice subjected to unpredictable chronic stress.

PubMed

Ma, Xing; Wang, Rui; Zhao, Xin; Zhang, Chong; Sun, Jiao; Li, Jianxin; Zhang, Lu; Shao, Tuo; Ruan, Lina; Chen, Liang; Xu, Ying; Pan, Jianchun

2013-03-01

Secoisolariciresinol diglycoside (SDG), a predominant lignan in flaxseed, has antioxidant activity as a dietary supplement. The purpose of the present study was to investigate the antidepressant-like effect and the possible mechanism of flaxseed SDG when the ovariectomized mice were exposed to the unpredictable chronic mild stress procedure. Chronic stress induced the increases in immobility time in mouse model of despair tests, but administration with SDG (80 and 160 mg/kg, p.o.) for 21 days inhibited these behavioral changes caused by stress in both forced swimming and tail suspension tests. These doses that affected the immobile response did not affect locomotor activity. Moreover, the changes in the serum corticosterone and adrenocorticotropic hormone (ACTH) levels were also measured to explore the SDG-associated regulation of hypothalamus-pituitary-adrenals (HPA) axis. The results indicated that the chronic stress-induced increases in the serum corticosterone and ACTH were reversed by treatment with high doses of SDG. Chronic treatment with SDG also affected the body weight of mice and IL-6, IL1β levels in the frontal cortex. In addition, chronic stress procedure induced a decrease in brain-derived neurotrophic factor (BDNF) expression in the frontal cortex of mice; while treatment with SDG reversed this reduction of BDNF. All these results provide compelling evidence that the behavioral effects of flaxseed SDG in the ovariectomized mice might be related to their modulating effects on the neuroendocrine-immune network and neurotrophin factor expression.

Developing brain networks of attention.

PubMed

Posner, Michael I; Rothbart, Mary K; Voelker, Pascale

2016-12-01

Attention is a primary cognitive function critical for perception, language, and memory. We provide an update on brain networks related to attention, their development, training, and pathologies. An executive attention network, also called the cingulo-opercular network, allows voluntary control of behavior in accordance with goals. Individual differences among children in self-regulation have been measured by a higher order factor called effortful control, which is related to the executive network and to the size of the anterior cingulate cortex. Brain networks of attention arise in infancy and are related to individual differences, including pathology during childhood. Methods of training attention may improve performance and ameliorate pathology.

Sympathetic regulation and anterior cingulate cortex volume are altered in a rat model of chronic back pain.

PubMed

Touj, Sara; Houle, Sébastien; Ramla, Djamel; Jeffrey-Gauthier, Renaud; Hotta, Harumi; Bronchti, Gilles; Martinoli, Maria-Grazia; Piché, Mathieu

2017-06-03

Chronic pain is associated with autonomic disturbance. However, specific effects of chronic back pain on sympathetic regulation remain unknown. Chronic pain is also associated with structural changes in the anterior cingulate cortex (ACC), which may be linked to sympathetic dysregulation. The aim of this study was to determine whether sympathetic regulation and ACC surface and volume are affected in a rat model of chronic back pain, in which complete Freund Adjuvant (CFA) is injected in back muscles. Sympathetic regulation was assessed with renal blood flow (RBF) changes induced by electrical stimulation of a hind paw, while ACC structure was examined by measuring cortical surface and volume. RBF changes and ACC volume were compared between control rats and rats injected with CFA in back muscles segmental (T10) to renal sympathetic innervation or not (T2). In rats with CFA, chronic inflammation was observed in the affected muscles in addition to increased nuclear factor-kappa B (NF-kB) protein expression in corresponding spinal cord segments (p=0.01) as well as decreased ACC volume (p<0.05). In addition, intensity-dependent decreases in RBF during hind paw stimulation were attenuated by chronic pain at T2 (p's<0.05) and T10 (p's<0.05), but less so at T10 compared with T2 (p's<0.05). These results indicate that chronic back pain alters sympathetic functions through non-segmental mechanisms, possibly by altering descending regulatory pathways from ACC. Yet, segmental somato-sympathetic reflexes may compete with non-segmental processes depending on the back region affected by pain and according to the segmental organization of the sympathetic nervous system. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Unpredictable chronic mild stress differentially impairs social and contextual discrimination learning in two inbred mouse strains.

PubMed

van Boxelaere, Michiel; Clements, Jason; Callaerts, Patrick; D'Hooge, Rudi; Callaerts-Vegh, Zsuzsanna

2017-01-01

Alterations in the social and cognitive domain are considered important indicators for increased disability in many stress-related disorders. Similar impairments have been observed in rodents chronically exposed to stress, mimicking potential endophenotypes of stress-related psychopathologies such as major depression disorder (MDD), anxiety, conduct disorder, and posttraumatic stress disorder (PTSD). Data from numerous studies suggest that deficient plasticity mechanisms in hippocampus (HC) and prefrontal cortex (PFC) might underlie these social and cognitive deficits. Specifically, stress-induced deficiencies in neural plasticity have been associated with a hypodopaminergic state and reduced neural plasticity persistence. Here we assessed the effects of unpredictable chronic mild stress (UCMS) on exploratory, social and cognitive behavior of females of two inbred mouse strains (C57BL/6J and DBA/2J) that differ in their dopaminergic profile. Exposure to chronic stress resulted in impaired circadian rhythmicity, sociability and social cognition in both inbred strains, but differentially affected activity patterns and contextual discrimination performance. These stress-induced behavioral impairments were accompanied by reduced expression levels of brain derived neurotrophic factor (BDNF) in the prefrontal cortex. The strain-specific cognitive impairment was coexistent with enhanced plasma corticosterone levels and reduced expression of genes related to dopamine signaling in hippocampus. These results underline the importance of assessing different strains with multiple test batteries to elucidate the neural and genetic basis of social and cognitive impairments related to chronic stress.

Multiple faces of pain: effects of chronic pain on the brain regulation of facial expression

PubMed Central

Vachon-Presseau, Etienne; Roy, Mathieu; Woo, Choong-Wan; Kunz, Miriam; Martel, Marc-Olivier; Sullivan, Michael J.; Jackson, Philip L.; Wager, Tor D.; Rainville, Pierre

2018-01-01

Pain behaviors are shaped by social demands and learning processes, and chronic pain has been previously suggested to affect their meaning. In this study, we combined functional magnetic resonance imaging with in-scanner video recording during thermal pain stimulations and use multilevel mediation analyses to study the brain mediators of pain facial expressions and the perception of pain intensity (self-reports) in healthy individuals and patients with chronic back pain (CBP). Behavioral data showed that the relation between pain expression and pain report was disrupted in CBP. In both patients with CBP and healthy controls, brain activity varying on a trial-by-trial basis with pain facial expressions was mainly located in the primary motor cortex and completely dissociated from the pattern of brain activity varying with pain intensity ratings. Stronger activity was observed in CBP specifically during pain facial expressions in several nonmotor brain regions such as the medial prefrontal cortex, the precuneus, and the medial temporal lobe. In sharp contrast, no moderating effect of chronic pain was observed on brain activity associated with pain intensity ratings. Our results demonstrate that pain facial expressions and pain intensity ratings reflect different aspects of pain processing and support psychosocial models of pain suggesting that distinctive mechanisms are involved in the regulation of pain behaviors in chronic pain. PMID:27411160

Chronic lead intoxication affects glial and neural systems and induces hypoactivity in adult rat.

PubMed

Sansar, Wafa; Ahboucha, Samir; Gamrani, Halima

2011-10-01

Lead is an environmental toxin and its effects are principally manifested in the brain. Glial and neuronal changes have been described during development following chronic or acute lead intoxication, however, little is known about the effects of chronic lead intoxication in adults. In this study we evaluated immunohistochemically the glial and dopaminergic systems in adult male Wistar rats. 0.5% (v/v) lead acetate in drinking water was administrated chronically over a 3-month period. Hypertrophic immunoreactive astrocytes were observed in the frontal cortex and other brain structures of the treated animals. Analysis of the astroglial features showed increased number of astrocyte cell bodies and processes in treated rats, an increase confirmed by Western blot. Particular distribution of glial fibrillary acidic protein immunoreactivity was observed within the blood vessel walls in which dense immunoreactive glial processes emanate from astrocytes. Glial changes in the frontal cortex were concomitant with reduced tyrosine hydroxylase immunoreactive neuronal processes, which seem to occur as a consequence of significantly reduced dopaminergic neurons within the nucleus of origin in the substantia nigra. These glial and neuronal changes following lead intoxication may affect animal behavior as evidenced by reduced locomotor activity in an open field test. These findings demonstrate that chronic lead exposure induces astroglial changes, which may compromise neuronal function and consequently animal behavior. Copyright © 2010 Elsevier GmbH. All rights reserved.

Enhanced Brain Responses to Pain-Related Words in Chronic Back Pain Patients and Their Modulation by Current Pain.

PubMed

Ritter, Alexander; Franz, Marcel; Puta, Christian; Dietrich, Caroline; Miltner, Wolfgang H R; Weiss, Thomas

2016-08-10

Previous functional magnetic resonance imaging (fMRI) studies in healthy controls (HC) and pain-free migraine patients found activations to pain-related words in brain regions known to be activated while subjects experience pain. The aim of the present study was to identify neural activations induced by pain-related words in a sample of chronic back pain (CBP) patients experiencing current chronic pain compared to HC. In particular, we were interested in how current pain influences brain activations induced by pain-related adjectives. Subjects viewed pain-related, negative, positive, and neutral words; subjects were asked to generate mental images related to these words during fMRI scanning. Brain activation was compared between CBP patients and HC in response to the different word categories and examined in relation to current pain in CBP patients. Pain-related words vs. neutral words activated a network of brain regions including cingulate cortex and insula in subjects and patients. There was stronger activation in medial and dorsolateral prefrontal cortex (DLPFC) and anterior midcingulate cortex in CPB patients than in HC. The magnitude of activation for pain-related vs. negative words showed a negative linear relationship to CBP patients' current pain. Our findings confirm earlier observations showing that pain-related words activate brain networks similar to noxious stimulation. Importantly, CBP patients show even stronger activation of these structures while merely processing pain-related words. Current pain directly influences on this activation.

Losartan ameliorates dystrophic epidermolysis bullosa and uncovers new disease mechanisms

PubMed Central

Nyström, Alexander; Thriene, Kerstin; Mittapalli, Venugopal; Kern, Johannes S; Kiritsi, Dimitra; Dengjel, Jörn; Bruckner-Tuderman, Leena

2015-01-01

Genetic loss of collagen VII causes recessive dystrophic epidermolysis bullosa (RDEB)—a severe skin fragility disorder associated with lifelong blistering and disabling progressive soft tissue fibrosis. Causative therapies for this complex disorder face major hurdles, and clinical implementation remains elusive. Here, we report an alternative evidence-based approach to ameliorate fibrosis and relieve symptoms in RDEB. Based on the findings that TGF-β activity is elevated in injured RDEB skin, we targeted TGF-β activity with losartan in a preclinical setting. Long-term treatment of RDEB mice efficiently reduced TGF-β signaling in chronically injured forepaws and halted fibrosis and subsequent fusion of the digits. In addition, proteomics analysis of losartan- vs. vehicle-treated RDEB skin uncovered changes in multiple proteins related to tissue inflammation. In line with this, losartan reduced inflammation and diminished TNF-α and IL-6 expression in injured forepaws. Collectively, the data argue that RDEB fibrosis is a consequence of a cascade encompassing tissue damage, TGF-β-mediated inflammation, and matrix remodeling. Inhibition of TGF-β activity limits these unwanted outcomes and thereby substantially ameliorates long-term symptoms. PMID:26194911

Implementation Integrity of Practice-Based Coaching: Preliminary Results from the BEST in CLASS Efficacy Trial

ERIC Educational Resources Information Center

Sutherland, Kevin S.; Conroy, Maureen A.; Vo, Abigail; Ladwig, Crystal

2015-01-01

The purpose of this article is to describe the practice-based coaching model used in BEST in CLASS, a Tier-2 classroom-based intervention comprised of evidence-based instructional practices designed to prevent and ameliorate the chronic problem behaviors of young children at risk for the development of emotional/behavioral disorders. Following a…

BEST in CLASS: A Classroom-Based Model for Ameliorating Problem Behavior in Early Childhood Settings

ERIC Educational Resources Information Center

Vo, Abigail; Sutherland, Kevin S.; Conroy, Maureen A.

2012-01-01

As more young children enter school settings to attend early childhood programs, early childhood teachers and school psychologists have been charged with supporting a growing number of young children with chronic problem behaviors that put them at risk for the development of emotional/behavioral disorders (EBDs). There is a need for effective,…

Topical atorvastatin ameliorates 12-O-tetradecanoylphorbol-13-acetate induced skin inflammation by reducing cutaneous cytokine levels and NF-κB activation.

PubMed

Kulkarni, Nagaraj M; Muley, Milind M; Jaji, Mallikarjun S; Vijaykanth, G; Raghul, J; Reddy, Neetin Kumar D; Vishwakarma, Santosh L; Rajesh, Navin B; Mookkan, Jeyamurugan; Krishnan, Uma Maheswari; Narayanan, Shridhar

2015-06-01

Atorvastatin is a 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor used in the treatment of atherosclerosis and dyslipidemia. Studies have evaluated the utility of statins in the treatment of skin inflammation but with varied results. In the present study, we investigated the effect of atorvastatin on TNF-α release and keratinocyte proliferation in vitro and in acute and chronic 12-O-tetradecanoylphorbol-13-acetate (TPA) induced skin inflammation in vivo. Atorvastatin significantly inhibited lipopolysacharide induced TNF-α release in THP-1 cells and keratinocyte proliferation in HaCaT cells. In an acute study, topical atorvastatin showed dose dependent reduction in TPA induced skin inflammation with highest efficacy observed at 500 µg/ear dose. In chronic study, topical atorvastatin significantly reduced TPA induced ear thickness, ear weight, cutaneous cytokines, MPO activity and improved histopathological features comparable to that of dexamethasone. Atorvastatin also inhibited TPA stimulated NF-κB activation in mouse ear. In conclusion, our results suggest that atorvastatin ameliorates TPA induced skin inflammation in mice at least in part, due to inhibition of cytokine release and NF-κB activation and may be beneficial for the treatment skin inflammation like psoriasis.

Lithium ameliorates altered glycogen synthase kinase-3 and behavior in a mouse model of fragile X syndrome.

PubMed

Yuskaitis, Christopher J; Mines, Marjelo A; King, Margaret K; Sweatt, J David; Miller, Courtney A; Jope, Richard S

2010-02-15

Fragile X syndrome (FXS), the most common form of inherited mental retardation and a genetic cause of autism, results from mutated fragile X mental retardation-1 (Fmr1). This study examined the effects on glycogen synthase kinase-3 (GSK3) of treatment with a metabotropic glutamate receptor (mGluR) antagonist, MPEP, and the GSK3 inhibitor, lithium, in C57Bl/6 Fmr1 knockout mice. Increased mGluR signaling may contribute to the pathology of FXS, and the mGluR5 antagonist MPEP increased inhibitory serine-phosphorylation of brain GSK3 selectively in Fmr1 knockout mice but not in wild-type mice. Inhibitory serine-phosphorylation of GSK3 was lower in Fmr1 knockout, than wild-type, mouse brain regions and was increased by acute or chronic lithium treatment, which also increased hippocampal brain-derived neurotrophic factor levels. Fmr1 knockout mice displayed alterations in open-field activity, elevated plus-maze, and passive avoidance, and these differences were ameliorated by chronic lithium treatment. These findings support the hypothesis that impaired inhibition of GSK3 contributes to the pathogenesis of FXS and support GSK3 as a potential therapeutic target.

Omega-3 fatty acid supplementation decreases DNA damage in brain of rats subjected to a chemically induced chronic model of Tyrosinemia type II.

PubMed

Carvalho-Silva, Milena; Gomes, Lara M; Scaini, Giselli; Rebelo, Joyce; Damiani, Adriani P; Pereira, Maiara; Andrade, Vanessa M; Gava, Fernanda F; Valvassori, Samira S; Schuck, Patricia F; Ferreira, Gustavo C; Streck, Emilio L

2017-08-01

Tyrosinemia type II is an inborn error of metabolism caused by a mutation in a gene encoding the enzyme tyrosine aminotransferase leading to an accumulation of tyrosine in the body, and is associated with neurologic and development difficulties in numerous patients. Because the accumulation of tyrosine promotes oxidative stress and DNA damage, the main aim of this study was to investigate the possible antioxidant and neuroprotective effects of omega-3 treatment in a chemically-induced model of Tyrosinemia type II in hippocampus, striatum and cerebral cortex of rats. Our results showed chronic administration of L-tyrosine increased the frequency and the index of DNA damage, as well as the 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in the hippocampus, striatum and cerebral cortex. Moreover, omega-3 fatty acid treatment totally prevented increased DNA damage in the striatum and hippocampus, and partially prevented in the cerebral cortex, whereas the increase in 8-OHdG levels was totally prevented by omega-3 fatty acid treatment in hippocampus, striatum and cerebral cortex. In conclusion, the present study demonstrated that the main accumulating metabolite in Tyrosinemia type II induce DNA damage in hippocampus, striatum and cerebral cortex, possibly mediated by free radical production, and the supplementation with omega-3 fatty acids was able to prevent this damage, suggesting that could be involved in the prevention of oxidative damage to DNA in this disease. Thus, omega-3 fatty acids supplementation to Tyrosinemia type II patients may represent a new therapeutic approach and a possible adjuvant to the curren t treatment of this disease.

[Effects of Betel shisanwei ingredients pill on AC-cAMP-PKA signal transduction pathways in hippocampus and prefrontal cortex of depressive rats].

PubMed

Tong, Hai-Ying; Wu, Jisiguleng; Bai, Liang-Feng; Bao, Wu-Ye; Hu, Rilebagen; Li, Jing; Zhang, Yue

2014-05-01

To observe the effects of Mongolian pharmaceutical Betel shisanwei ingredients pill on AC-cAMP-PKA signal transduction pathways in hippocampus and prefrontal cortex of depressive rats. Sixty male Wistar rats were randomly divided into six groups according to the sugar consumption test (10 rats in each group), normal control group,model group,fluoxetine group (3.3 mg x kg(-1)) and low dose, medium dose and high dose group (0.25, 0.5, 1 g x kg(-1)) of Betel shisanwei ingredients pill. Except the normal control,the other groups were treated with the chronic unpredictable mild stress stimulation combined with lonely raising for 28 days. 10 mL x kg(-1) of drugs were given to each rat once daily,continuously for 28 days. The AC activity of the hippocampus and prefrontal cortex were determined by radiation immunity analysis (RIA), while cAMP and PKA quantity were determinated by Enzyme-linked immunosorbent (ELISA). The AC activity, cAMP and PKA quantity of hippocampus and prefrontal of mouse model of Chronic stress depression decreased significantly than those of control group (P < 0.05 or P < 0.01). However, the AC activity, cAMP and PKA quantity of rat hippocampus and prefrontal cortex in the fluoxetine group and the Mongolian pharmaceutical Betel shisanwei ingredients pill group indecreased significantly than those of model group (P < 0.01 or P < 0.05). Especially for the high dose group of Mongolian pharmaceutical Betel shisanwei ingredients pill. The AC-cAMP-PKA signal transduction pathways in hippocampus and prefrontal cortex of depression model of rats is down-regulated, whereas Mongolian pharmaceutical Betel shisanwei ingredients pill could up-regulated it to resist depression.

Changes in oxidative metabolism and memory and learning in an cerebral hypoperfusion model in rats.

PubMed

Castaño Guerrero, Y; González Fraguela, M E; Fernández Verdecia, I; Horruitiner Gutiérrez, I; Piedras Carpio, S

2013-01-01

Chronic hypoperfusion in rats produces memory and learning impairments due to permanent occlusion of commun carotid arteries (POCCA). Molecular mechanisms leading to behavioural disorders have been poorly studied. For this reason, the aim of the present study was to characterise oxidative metabolism disorders and their implications in memory and learning impairments. Superoxide dismutase (SOD) and catalase (CAT) activities were determined in cortex, hippocampus and striatum homogenates at 24 hours and at 22 days after the lesion. Haematoxylin-eosin staining and glial fibrillary acidic protein (GFAP) immunoreactivity were performed on coronal sections. Behavioural impairments were explored using the Morris water maze (MWM). Escape latencies were determined in all behavioural studies. The lesion induced a significant increase (P<.01) in CAT activity in the cortex at 24 hours, while SOD activity was significantly higher (P<.01) in the cortex and hippocampus at 22 days. An intense vacuolization was observed in the cortex and striatum as a result of the lesion. A neuronal loss in the striatum and hippocampus was observed. The glial reaction increased in the cortex and striatum. Visual alterations were observed in the lesion group with the lowest evolution time (P<.001). Escape latencies, corresponding to MWM schemes for long-term and short-term memory evaluation increased significantly (P<.05) in both groups of lesioned animals. It was concluded that changes in SOD and CAT activities indicate a possible implication of oxidative imbalance in the pathology associated with chronic cerebral hypoperfusion. In addition, the POCCA model in rats is useful for understanding mechanisms by which cerebral hypoperfusion produces memory and learning impairments. Copyright © 2011 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Neuregulin 1 Deficiency Modulates Adolescent Stress-Induced Dendritic Spine Loss in a Brain Region-Specific Manner and Increases Complement 4 Expression in the Hippocampus.

PubMed

Clarke, David J; Chohan, Tariq W; Kassem, Mustafa S; Smith, Kristie L; Chesworth, Rose; Karl, Tim; Kuligowski, Michael P; Fok, Sandra Y; Bennett, Maxwell R; Arnold, Jonathon C

2018-03-16

One neuropathological feature of schizophrenia is a diminished number of dendritic spines in the prefrontal cortex and hippocampus. The neuregulin 1 (Nrg1) system is involved in the plasticity of dendritic spines, and chronic stress decreases dendritic spine densities in the prefrontal cortex and hippocampus. Here, we aimed to assess whether Nrg1 deficiency confers vulnerability to the effects of adolescent stress on dendritic spine plasticity. We also assessed other schizophrenia-relevant neurobiological changes such as microglial cell activation, loss of parvalbumin (PV) interneurons, and induction of complement factor 4 (C4). Adolescent male wild-type (WT) and Nrg1 heterozygous mice were subjected to chronic restraint stress before their brains underwent Golgi impregnation or immunofluorescent staining of PV interneurons, microglial cells, and C4. Stress in WT mice promoted dendritic spine loss and microglial cell activation in the prefrontal cortex and the hippocampus. However, Nrg1 deficiency rendered mice resilient to stress-induced dendritic spine loss in the infralimbic cortex and the CA3 region of the hippocampus without affecting stress-induced microglial cell activation in these brain regions. Nrg1 deficiency and adolescent stress combined to trigger increased dendritic spine densities in the prelimbic cortex. In the hippocampal CA1 region, Nrg1 deficiency accentuated stress-induced dendritic spine loss. Nrg1 deficiency increased C4 protein and decreased C4 mRNA expression in the hippocampus, and the number of PV interneurons in the basolateral amygdala. This study demonstrates that Nrg1 modulates the impact of stress on the adolescent brain in a region-specific manner. It also provides first evidence of a link between Nrg1 and C4 systems in the hippocampus.

Disrupted functional connectivity of the pain network in fibromyalgia.

PubMed

Cifre, Ignacio; Sitges, Carolina; Fraiman, Daniel; Muñoz, Miguel Ángel; Balenzuela, Pablo; González-Roldán, Ana; Martínez-Jauand, Mercedes; Birbaumer, Niels; Chialvo, Dante R; Montoya, Pedro

2012-01-01

To investigate the impact of chronic pain on brain dynamics at rest. Functional connectivity was examined in patients with fibromyalgia (FM) (n = 9) and healthy controls (n = 11) by calculating partial correlations between low-frequency blood oxygen level-dependent fluctuations extracted from 15 brain regions. Patients with FM had more positive and negative correlations within the pain network than healthy controls. Patients with FM displayed enhanced functional connectivity of the anterior cingulate cortex (ACC) with the insula (INS) and basal ganglia (p values between .01 and .05), the secondary somatosensory area with the caudate (CAU) (p = .012), the primary motor cortex with the supplementary motor area (p = .007), the globus pallidus with the amygdala and superior temporal sulcus (both p values < .05), and the medial prefrontal cortex with the posterior cingulate cortex (PCC) and CAU (both p values < .05). Functional connectivity of the ACC with the amygdala and periaqueductal gray (PAG) matter (p values between .001 and .05), the thalamus with the INS and PAG (both p values < .01), the INS with the putamen (p = .038), the PAG with the CAU (p = .038), the secondary somatosensory area with the motor cortex and PCC (both p values < .05), and the PCC with the superior temporal sulcus (p = .002) was also reduced in FM. In addition, significant negative correlations were observed between depression and PAG connectivity strength with the thalamus (r = -0.64, p = .003) and ACC (r = -0.60, p = .004). These findings demonstrate that patients with FM display a substantial imbalance of the connectivity within the pain network during rest, suggesting that chronic pain may also lead to changes in brain activity during internally generated thought processes such as occur at rest.

Xiao-Yao-San, a Chinese Medicine Formula, Ameliorates Chronic Unpredictable Mild Stress Induced Polycystic Ovary in Rat

PubMed Central

Sun, Hao-Yu; Li, Quan; Liu, Yu-Ying; Wei, Xiao-Hong; Pan, Chun-Shui; Fan, Jing-Yu; Han, Jing-Yan

2017-01-01

Chronic stress induces endocrine disturbance, which contributes to the development of polycystic ovary syndrome (PCOS), a condition that remains a challenge for clinicians to cope with. The present study investigated the effect of Xiao-Yao-San (XYS), a traditional Chinese medicine formula used for treatment of gynecological disease, on the chronic stress-induced polycystic ovary and its underlying mechanism. Female Sprague-Dwaley rats underwent a 3 weeks chronic unpredictable mild stress (CUMS) procedure to establish the PCOS model, followed by 4 weeks treatment with XYS (0.505 g/kg or 1.01 g/kg) by gavage. Granulosa cells were exposed to noradrenaline (1 mM) in vitro for 24 h, followed by incubation with or without XYS-treated rat serum for 24 h. Post-treatment with XYS ameliorated CUMS-induced irregular estrous cycles and follicles development abnormalities, decrease of estradiol and progesterone level as well as increase of luteinizing hormone in serum, reduced cystic follicles formation and the apoptosis and autophagy of granulosa cells, attenuated the increase in dopamine beta hydroxylase and c-fos level in locus coeruleus, the noradrenaline level in serum and ovarian tissue, and the expression of beta 2 adrenergic receptor in ovarian tissue. Besides, XYS alleviated the reduction of phosphorylation of ribosomal protein S6 kinase polypeptide I and protein kinase B, as well as the increase of microtubule-associated protein light chain 3-I to microtubule-associated protein light chain 3-II conversion both in vivo and in vitro. This study demonstrated XYS as a potential strategy for CUMS induced polycystic ovary, and suggested that the beneficial role of XYS was correlated with the regulation of the sympathetic nerve activity. PMID:29018356

INTRARENAL GHRELIN RECEPTOR INHIBITION AMELIORATES ANGIOTENSIN II-DEPENDENT HYPERTENSION IN RATS.

PubMed

Kemp, Brandon A; Howell, Nancy L; Padia, Shetal H

2018-06-20

The intrarenal ghrelin receptor (GR) is localized to collecting duct (CD) cells where it increases αENaC-dependent sodium reabsorption in rodents. We hypothesized that chronic GR inhibition with intrarenal GR siRNA lowers blood pressure (BP) in Angiotensin II-dependent hypertension via reductions in αENaC-dependent sodium reabsorption. Uninephrectomized Sprague-Dawley rats (N=121) received subcutaneous osmotic pumps for chronic systemic delivery of Angiotensin II or vehicle (5% dextrose in water). Rats also received intrarenal infusion of vehicle, GR siRNA, or scrambled (SCR) siRNA. In rats receiving intrarenal vehicle or intrarenal SCR siRNA, systemic Angiotensin II infusion increased sodium retention and BP on day 1, and BP remained elevated throughout the 5-day study. These rats also demonstrated increased CD GR expression after 5 days of infusion. However, intrarenal GR siRNA infusion prevented Angiotensin II-mediated sodium retention on day 1, induced a continuously negative cumulative sodium balance compared with Angiotensin II alone, and reduced BP chronically. Glomerular filtration rate and renal blood flow remained unchanged in GR siRNA-infused rats. Systemic Angiotensin II infusion also increased serum aldosterone levels, CD αENaC and pSGK1 expression in rats with intrarenal SCR siRNA; however these effects were not observed in the presence of intrarenal GR siRNA, despite exposure to the same systemic Angiotensin II. These data demonstrate that chronic inhibition of intrarenal GR activity significantly reduces αENaC -dependent sodium retention, resulting in a negative cumulative sodium balance, thereby ameliorating Angiotensin II-induced hypertension in rats. Renal GRs represent a novel therapeutic target for the treatment of hypertension and other sodium-retaining states.

Bacopa monnieri (Brahmi) Enhanced Cognitive Function and Prevented Cognitive Impairment by Increasing VGLUT2 Immunodensity in Prefrontal Cortex of Sub-Chronic Phencyclidine Rat Model of Schizophrenia.

PubMed

Piyabhan, Pritsana; Wetchateng, Thanitsara

2015-04-01

Glutamatergic hypofunction is affected in schizophrenia. The decrement ofpresynaptic glutamatergic marker remarkably vesicular glutamate transporter type 1 (VGLUT1) indicates the deficit ofglutamatergic and cognitive function in schizophrenic brain. However there have been afew studies in VGLUT2. Brahmi, a traditional herbal medicine, might be a new frontier of cognitive deficit treatment and prevention in schizophrenia by changing cerebral VGLUT2 density. To study cognitive enhancement- and neuroprotective-effects of Brahmi on novel object recognition task and cerebral VGLUT2 immunodensity in sub-chronic phencyclidine (PCP) rat model of schizophrenia. Cognitive enhancement effect study; rats were assigned to three groups; Group-1: Control, Group-2: PCP administration and Group-3: PCP + Brahmi. Neuroprotective effect study; rats were assigned to three groups; Group-1: Control, Group-2: PCP administration and Group-3: Brahmi + PCP Discrimination ratio (DR) representing cognitive ability was obtained from novel object recognition task. VGLUT2 immunodensity was measured in prefrontal cortex, striatum, cornu ammonis fields 1 (CA1) and 2/3 (CA2/3) of hippocampus using immunohistochemistry. DR was significantly reduced in PCP group compared with control. This occurred alongside VGLUT2 reduction in prefrontal cortex, but not in striatum, CA1 or CA2/3. Both PCP + Brahmi and Brahmi + PCP groups showed an increased DR score up to normal, which occurred alongside a significantly increased VGLUT2 immunodensity in the prefrontal cortex, compared with PCP group. The decrement of VGLUT2 density in prefrontal cortex resulted in cognitive deficit in rats receiving PCP. Interestingly, receiving Brahmi after PCP administration can restore this cognitive deficit by increasing VGLUT2 density in prefrontal cortex. This investigation is defined as Brahmi's cognitive enhancement effect. Additionally, receiving Brahmi before PCP administration can also prevent cognitive impairment by elevating VGLUT2 density in prefrontal cortex. This observation indicates neuroprotective effect of Brahmi. Therefore, Brahmi could be a new frontier of restoration and prevention of cognitive deficit in schizophrenia.

Medicinal plants and natural products in amelioration of arsenic toxicity: a short review.

PubMed

Bhattacharya, Sanjib

2017-12-01

Chronic arsenic toxicity (arsenicosis) is considered a serious public health menace worldwide, as there is no specific, safe, and efficacious therapeutic management of arsenicosis. To collate the studies on medicinal plants and natural products with arsenic toxicity ameliorative effect, active pre-clinically and/or clinically. Literature survey was carried out by using Google, Scholar Google and Pub-Med. Only the scientific journal articles found on the internet for last two decades were considered. Minerals and semi-synthetic or synthetic analogs of natural products were excluded. Literature study revealed that 34 medicinal plants and 14 natural products exhibited significant protection from arsenic toxicity, mostly in preclinical trials and a few in clinical studies. This research could lead to development of a potentially useful agent in clinical management of arsenicosis in humans.

Music-supported therapy induces plasticity in the sensorimotor cortex in chronic stroke: a single-case study using multimodal imaging (fMRI-TMS).

PubMed

Rojo, Nuria; Amengual, Julian; Juncadella, Montserrat; Rubio, Francisco; Camara, Estela; Marco-Pallares, Josep; Schneider, Sabine; Veciana, Misericordia; Montero, Jordi; Mohammadi, Bahram; Altenmüller, Eckart; Grau, Carles; Münte, Thomas F; Rodriguez-Fornells, Antoni

2011-01-01

Music-Supported Therapy (MST) has been developed recently in order to improve the use of the affected upper extremity after stroke. This study investigated the neuroplastic mechanisms underlying effectiveness in a patient with chronic stroke. MST uses musical instruments, a midi piano and an electronic drum set emitting piano sounds, to retrain fine and gross movements of the paretic upper extremity. Data are presented from a patient with a chronic stroke (20 months post-stroke) with residual right-sided hemiparesis who took part in 20 MST sessions over the course of 4 weeks. Post-therapy, a marked improvement of movement quality, assessed by 3D movement analysis, was observed. Moreover, functional magnetic resonance imaging (fMRI) of a sequential hand movement revealed distinct therapy-related changes in the form of a reduction of excess contralateral and ipsilateral activations. This was accompanied by changes in cortical excitability evidenced by transcranial magnetic stimulation (TMS). Functional MRI in a music listening task suggests that one of the effects of MST is the task-dependent coupling of auditory and motor cortical areas. The MST appears to be a useful neurorehabilitation tool in patients with chronic stroke and leads to neural reorganization in the sensorimotor cortex.

Impaired Limbic Cortico-Striatal Structure and Sustained Visual Attention in a Rodent Model of Schizophrenia

PubMed Central

Barnes, Samuel A.; Sawiak, Stephen J.; Caprioli, Daniele; Jupp, Bianca; Buonincontri, Guido; Mar, Adam C.; Harte, Michael K.; Fletcher, Paul C.; Robbins, Trevor W.; Neill, Jo C.

2015-01-01

Background: N-methyl-d-aspartate receptor (NMDAR) dysfunction is thought to contribute to the pathophysiology of schizophrenia. Accordingly, NMDAR antagonists such as phencyclidine (PCP) are used widely in experimental animals to model cognitive impairment associated with this disorder. However, it is unclear whether PCP disrupts the structural integrity of brain areas relevant to the profile of cognitive impairment in schizophrenia. Methods: Here we used high-resolution magnetic resonance imaging and voxel-based morphometry to investigate structural alterations associated with sub-chronic PCP treatment in rats. Results: Sub-chronic exposure of rats to PCP (5mg/kg twice daily for 7 days) impaired sustained visual attention on a 5-choice serial reaction time task, notably when the attentional load was increased. In contrast, sub-chronic PCP had no significant effect on the attentional filtering of a pre-pulse auditory stimulus in an acoustic startle paradigm. Voxel-based morphometry revealed significantly reduced grey matter density bilaterally in the hippocampus, anterior cingulate cortex, ventral striatum, and amygdala. PCP-treated rats also exhibited reduced cortical thickness in the insular cortex. Conclusions: These findings demonstrate that sub-chronic NMDA receptor antagonism is sufficient to produce highly-localized morphological abnormalities in brain areas implicated in the pathogenesis of schizophrenia. Furthermore, PCP exposure resulted in dissociable impairments in attentional function. PMID:25552430

Fluoxetine regulates mTOR signalling in a region-dependent manner in depression-like mice.

PubMed

Liu, Xiao-Long; Luo, Liu; Mu, Rong-Hao; Liu, Bin-Bin; Geng, Di; Liu, Qing; Yi, Li-Tao

2015-11-02

Previous studies have demonstrated that the mammalian target of rapamycin (mTOR) signaling pathway has an important role in ketamine-induced, rapid antidepressant effects despite the acute administration of fluoxetine not affecting mTOR phosphorylation in the brain. However, the effects of long-term fluoxetine treatment on mTOR modulation have not been assessed to date. In the present study, we examined whether fluoxetine, a type of commonly used antidepressant agent, alters mTOR signaling following chronic administration in different brain regions, including the frontal cortex, hippocampus, amygdala and hypothalamus. We also investigated whether fluoxetine enhanced synaptic protein levels in these regions via the activation of the mTOR signaling pathway and its downstream regulators, p70S6K and 4E-BP-1. The results indicated that chronic fluoxetine treatment attenuated the chronic, unpredictable, mild stress (CUMS)-induced mTOR phosphorylation reduction in the hippocampus and amygdala of mice but not in the frontal cortex or the hypothalamus. Moreover, the CUMS-decreased PSD-95 and synapsin I levels were reversed by fluoxetine, and these effects were blocked by rapamycin only in the hippocampus. In conclusion, our findings suggest that chronic treatment with fluoxetine can induce synaptic protein expression by activating the mTOR signaling pathway in a region-dependent manner and mainly in the hippocampus.

Systemic inhibition of Janus kinase induces browning of white adipose tissue and ameliorates obesity-related metabolic disorders.

PubMed

Qurania, Kikid Rucira; Ikeda, Koji; Wardhana, Donytra Arby; Barinda, Agian Jeffilano; Nugroho, Dhite Bayu; Kuribayashi, Yuko; Rahardini, Elda Putri; Rinastiti, Pranindya; Ryanto, Gusty Rizky Teguh; Yagi, Keiko; Hirata, Ken-Ichi; Emoto, Noriaki

2018-07-07

Browning of white adipose tissue is a promising strategy to tackle obesity. Recently, Janus kinase (JAK) inhibition was shown to induce white-to-brown metabolic conversion of adipocytes in vitro; however effects of JAK inhibition on browning and systemic metabolic health in vivo remain to be elucidated. Here, we report that systemic administration of JAK inhibitor (JAKi) ameliorated obesity-related metabolic disorders. Administration of JAKi in mice fed a high-fat diet increased UCP-1 and PRDM16 expression in white adipose tissue, indicating the browning of white adipocyte. Food intake was increased in JAKi-treated mice, while the body weight and adiposity was similar between the JAKi- and vehicle-treated mice. In consistent with the browning, thermogenic capacity was enhanced in mice treated with JAKi. Chronic inflammation in white adipose tissue was not ameliorated by JAKi-treatment. Nevertheless, insulin sensitivity was well preserved in JAKi-treated mice comparing with that in vehicle-treated mice. Serum levels of triglyceride and free fatty acid were significantly reduced by JAKi-treatment, which is accompanied by ameliorated hepatosteatosis. Our data demonstrate that systemic administration of JAKi has beneficial effects in preserving metabolic health, and thus inhibition of JAK signaling has therapeutic potential for the treatment of obesity and its-related metabolic disorders. Copyright © 2018 Elsevier Inc. All rights reserved.

Amygdala stimulation promotes recovery of behavioral performance in a spatial memory task and increases GAP-43 and MAP-2 in the hippocampus and prefrontal cortex of male rats.

PubMed

Mercerón-Martínez, D; Almaguer-Melian, W; Alberti-Amador, E; Bergado, J A

2018-06-19

The relationships between affective and cognitive processes are an important issue of present neuroscience. The amygdala, the hippocampus and the prefrontal cortex appear as main players in these mechanisms. We have shown that post-training electrical stimulation of the basolateral amygdala (BLA) speeds the acquisition of a motor skill, and produces a recovery in behavioral performance related to spatial memory in fimbria-fornix (FF) lesioned animals. BLA electrical stimulation rises bdnf RNA expression, BDNF protein levels, and arc RNA expression in the hippocampus. In the present paper we have measured the levels of one presynaptic protein (GAP-43) and one postsynaptic protein (MAP-2) both involved in synaptogenesis to assess whether structural neuroplastic mechanisms are involved in the memory enhancing effects of BLA stimulation. A single train of BLA stimulation produced in healthy animals an increase in the levels of GAP-43 and MAP-2 that lasted days in the hippocampus and the prefrontal cortex. In FF-lesioned rats, daily post-training stimulation of the BLA ameliorates the memory deficit of the animals and induces an increase in the level of both proteins. These results support the hypothesis that the effects of amygdala stimulation on memory recovery are sustained by an enhanced formation of new synapses. Copyright © 2018. Published by Elsevier Inc.

Botulinum Toxin Injections Reduce Associative Plasticity in Patients with Primary Dystonia

PubMed Central

Kojovic, Maja; Caronni, Antonio; Bologna, Matteo; Rothwell, John C.; Bhatia, Kailash P.; Edwards, Mark J.

2014-01-01

Botulinum toxin injections ameliorate dystonic symptoms by blocking the neuromuscular junction and weakening dystonic contractions. We asked if botulinum toxin injections in dystonia patients might also affect the integrity of sensorimotor cortical plasticity, one of the key pathophysiological features of dystonia. We applied a paired associative stimulation protocol, known to induce long-term potentiation–like changes in the primary motor cortex hand area to 12 patients with cervical dystonia before and 1 and 3 months after botulinum toxin injections to the neck muscles. Primary motor cortex excitability was probed by measuring transcranial magnetic stimulation-evoked motor evoked potentials before and after paired associative stimulation. We also measured the input–output curve, short-interval intracortical inhibition, intracortical facilitation, short afferent inhibition, and long afferent inhibition in hand muscles and the clinical severity of dystonia. Before botulinum toxin injections, paired associative stimulation significantly facilitated motor evoked potentials in hand muscles. One month after injections, this effect was abolished, with partial recovery after 3 months. There were significant positive correlations between the facilitation produced by paired associative stimulation and (1) the time elapsed since botulinum toxin injections and (2) the clinical dystonia score. One effect of botulinum toxin injection treatment is to modulate afferent input from the neck. We propose that subsequent reorganization of the motor cortex representation of hand muscles may explain the effect of botulinum toxin on motor cortical plasticity. PMID:21469207

Protective effect of stilbenes containing extract-fraction from Cajanus cajan L. on Abeta(25-35)-induced cognitive deficits in mice.

PubMed

Ruan, Can-Jun; Si, Jian-Yong; Zhang, Li; Chen, Di-Hua; Du, Guan-Hua; Su, Lan

2009-12-25

Cajanus cajan (L.) is a traditional Chinese herb medicine which contains a lot of potential active components. In the present study, we identified the effects of the stilbenes containing extract-fraction from C. cajan L. (sECC) on Abeta(25-35)-induced cognitive deficits, oxidative stress and cholinergic dysfunction in mice. Mice were treated with sECC (100 and 200mg/kg/d) for 1-week, and then received a single intracerebroventricular (i.c.v.) injection of Abeta(25-35) (5mug/mice). Behavioral changes and neuron apoptosis in mice were evaluated using Morris water maze and TUNEL tests. Furthermore, superoxide dismutase (SOD), choline acetyl transferase (ChAT) and acetylcholine esterase (AchE) activity in hippocampus and cortex were analyzed by spectrophotometric method. The data showed that consumption of sECC (200mg/kg) significantly ameliorated the cognitive deficits and neuron apoptosis caused by i.c.v. injection of Abeta(25-35). At the same time, the decreased SOD and ChAT activity in hippocampus and cortex were markedly increased by sECC (200mg/kg). sECC has no effect on AchE activity in hippocampus and cortex. These findings suggest that sECC may be a potential candidate for the development of therapeutic agents to manage cognitive impairment associated with Alzheimer's disease (AD) through increasing the activity of ChAT and anti-oxidative mechanism.

N-Oleoyl-glycine reduces nicotine reward and withdrawal in mice.

PubMed

Donvito, Giulia; Piscitelli, Fabiana; Muldoon, Pretal; Jackson, Asti; Vitale, Rosa Maria; D'Aniello, Enrico; Giordano, Catia; Ignatowska-Jankowska, Bogna M; Mustafa, Mohammed A; Guida, Francesca; Petrie, Gavin N; Parker, Linda; Smoum, Reem; Sim-Selley, Laura; Maione, Sabatino; Lichtman, Aron H; Damaj, M Imad; Di Marzo, Vincenzo; Mechoulam, Raphael

2018-03-19

Cigarette smokers with brain damage involving the insular cortex display cessation of tobacco smoking, suggesting that this region may contribute to nicotine addiction. In the present study, we speculated that molecules in the insular cortex that are sensitive to experimental traumatic brain injury (TBI) in mice might provide leads to ameliorate nicotine addiction. Using targeted lipidomics, we found that TBI elicited substantial increases of a largely uncharacterized lipid, N-acyl-glycine, N-oleoyl-glycine (OlGly), in the insular cortex of mice. We then evaluated whether intraperitoneal administration of OlGly would alter withdrawal responses in nicotine-dependent mice as well as the rewarding effects of nicotine, as assessed in the conditioned place preference paradigm (CPP). Systemic administration of OlGly reduced mecamylamine-precipitated withdrawal responses in nicotine-dependent mice and prevented nicotine CPP. However, OlGly did not affect morphine CPP, demonstrating a degree of selectivity. Our respective in vitro and in vivo observations that OlGly activated peroxisome proliferator-activated receptor alpha (PPAR-α) and the PPAR-α antagonist GW6471 prevented the OlGly-induced reduction of nicotine CPP in mice suggests that this lipid acts as a functional PPAR-α agonist to attenuate nicotine reward. These findings raise the possibility that the long chain fatty acid amide OlGly may possess efficacy in treating nicotine addiction. Copyright © 2018. Published by Elsevier Ltd.

Treatment with NZ-419 (5-Hydroxy-1-methylimidazoline-2,4-dione), a novel intrinsic antioxidant, against the progression of chronic kidney disease at stages 3 and 4 in rats.

PubMed

Ienaga, Kazuharu; Yokozawa, Takako

2010-01-01

For rats, glomerular filtration rate (GFR) and its relative GFR (ratio to normal GFR(0)) were estimated in order to classify their chronic kidney disease (CKD) into 5 stages like those in humans. The adenine-loaded rats, which were used to show the intrinsic antioxidant and creatinine (Cr) metabolite, NZ-419 (5-hydroxy-1- methylimidazolidine-2,4-dione), when taken orally, prevented the progression of chronic renal failure (CRF), were used as a model to reach the severest stage 5. In this report, we show that, by using both a tubular lesion and a glomerular lesion models (adenine-loaded and 5/6 nephrectomized rats, respectively), peroral NZ-419 might be a common tool to prevent the progression of CRF at CKD stages 3 and 4 under the condition that most rats in the control group still remained at stage 4 (0.15

Chronic ethanol consumption inhibits glucokinase transcriptional activity by Atf3 and triggers metabolic syndrome in vivo.

PubMed

Kim, Ji Yeon; Hwang, Joo-Yeon; Lee, Dae Yeon; Song, Eun Hyun; Park, Keon Jae; Kim, Gyu Hee; Jeong, Eun Ae; Lee, Yoo Jeong; Go, Min Jin; Kim, Dae Jin; Lee, Seong Su; Kim, Bong-Jo; Song, Jihyun; Roh, Gu Seob; Gao, Bin; Kim, Won-Ho

2014-09-26

Chronic ethanol consumption induces pancreatic β-cell dysfunction through glucokinase (Gck) nitration and down-regulation, leading to impaired glucose tolerance and insulin resistance, but the underlying mechanism remains largely unknown. Here, we demonstrate that Gck gene expression and promoter activity in pancreatic β-cells were suppressed by chronic ethanol exposure in vivo and in vitro, whereas expression of activating transcription factor 3 (Atf3) and its binding to the putative Atf/Creb site (from -287 to -158 bp) on the Gck promoter were up-regulated. Furthermore, in vitro ethanol-induced Atf3 inhibited the positive effect of Pdx-1 on Gck transcriptional regulation, enhanced recruitment of Hdac1/2 and histone H3 deacetylation, and subsequently augmented the interaction of Hdac1/Pdx-1 on the Gck promoter, which were diminished by Atf3 siRNA. In vivo Atf3-silencing reversed ethanol-mediated Gck down-regulation and β-cell dysfunction, followed by the amelioration of impaired glucose tolerance and insulin resistance. Together, we identified that ethanol-induced Atf3 fosters β-cell dysfunction via Gck down-regulation and that its loss ameliorates metabolic syndrome and could be a potential therapeutic target in treating type 2 diabetes. The Atf3 gene is associated with the induction of type 2 diabetes and alcohol consumption-induced metabolic impairment and thus may be the major negative regulator for glucose homeostasis. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Chronic Social Stress and Ethanol Increase Expression of KLF11, a Cell Death Mediator, in Rat Brain.

PubMed

Duncan, Jeremy; Wang, Niping; Zhang, Xiao; Johnson, Shakevia; Harris, Sharonda; Zheng, Baoying; Zhang, Qinli; Rajkowska, Grazyna; Miguel-Hidalgo, Jose Javier; Sittman, Donald; Ou, Xiao-Ming; Stockmeier, Craig A; Wang, Jun Ming

2015-07-01

Major depressive disorder and alcoholism are significant health burdens that can affect executive functioning, cognitive ability, job responsibilities, and personal relationships. Studies in animal models related to depression or alcoholism reveal that the expression of Krüppel-like factor 11 (KLF11, also called TIEG2) is elevated in frontal cortex, which suggests that KLF11 may play a role in stress- or ethanol-induced psychiatric conditions. KLF11 is a transcriptional activator of monoamine oxidase A and B, but also serves other functions in cell cycle regulation and apoptotic cell death. In the present study, immunohistochemistry was used to quantify intensity of nuclear KLF11, combined with an unbiased stereological approach to assess nuclei in fronto-limbic, limbic, and other brain regions of rats exposed chronically to social defeat or ethanol. KLF11 immunoreactivity was increased significantly in the medial prefrontal cortex, frontal cortex, and hippocampus of both stressed rats and rats fed ethanol. However, expression of KLF11 protein was not significantly affected in the thalamus, hypothalamus, or amygdala in either treatment group compared to respective control rats. Triple-label immunofluorescence revealed that KLF11 protein was localized in nuclei of neurons and astrocytes. KLF11 was also co-localized with the immunoreactivity of cleaved caspase-3. In addition, Western blot analysis revealed a significant reduction in anti-apoptotic protein, Bcl-xL, but an increase of caspase-3 expression in the frontal cortex of ethanol-treated rats compared to ethanol-preferring controls. Thus, KLF11 protein is up-regulated following chronic exposure to stress or ethanol in a region-specific manner and may contribute to pro-apoptotic signaling in ethanol-treated rats. Further investigation into the KLF11 signaling cascade as a mechanism for neurotoxicity and cell death in depression and alcoholism may provide novel pharmacological targets to lessen brain damage and maximize neuroprotection in these disorders.

Altered functional connectivity between the insula and the cingulate cortex in patients with temporomandibular disorder: a pilot study.

PubMed

Ichesco, Eric; Quintero, Andres; Clauw, Daniel J; Peltier, Scott; Sundgren, Pia M; Gerstner, Geoffrey E; Schmidt-Wilcke, Tobias

2012-03-01

Among the most common chronic pain conditions, yet poorly understood, are temporomandibular disorders (TMDs), with a prevalence estimate of 3-15% for Western populations. Although it is increasingly acknowledged that central nervous system mechanisms contribute to pain amplification and chronicity in TMDs, further research is needed to unravel neural correlates that might abet the development of chronic pain. The insular cortex (IC) and cingulate cortex (CC) are both critically involved in the experience of pain. The current study sought specifically to investigate IC-CC functional connectivity in TMD patients and healthy controls (HCs), both during resting state and during the application of a painful stimulus. Eight patients with TMD, and 8 age- and sex-matched HCs were enrolled in the present study. Functional magnetic resonance imaging data during resting state and during the performance of a pressure pain stimulus to the temple were acquired. Predefined seed regions were placed in the IC (anterior and posterior insular cortices) and the extracted signal was correlated with brain activity throughout the whole brain. Specifically, we were interested whether TMD patients and HCs would show differences in IC-CC connectivity, both during resting state and during the application of a painful stimulus to the face. As a main finding, functional connectivity analyses revealed an increased functional connectivity between the left anterior IC and pregenual anterior cingulate cortex (ACC) in TMD patients, during both resting state and applied pressure pain. Within the patient group, there was a negative correlation between the anterior IC-ACC connectivity and clinical pain intensity as measured by a visual analog scale. Since the pregenual region of the ACC is critically involved in antinociception, we hypothesize that an increase in anterior IC-ACC connectivity is indicative of an adaptation of the pain modulatory system early in the chronification process. © 2011 American Headache Society.

The analgesic effect of therapeutic rTMS is not mediated or predicted by comorbid psychiatric or sleep disorders

PubMed Central

Lindholm, Pauliina; Lamusuo, Salla; Taiminen, Tero; Virtanen, Arja; Pertovaara, Antti; Forssell, Heli; Hagelberg, Nora; Jääskeläinen, Satu

2016-01-01

Abstract Background: Mechanisms underlying alleviation of neuropathic pain by repetitive transcranial magnetic stimulation (rTMS) of primary motor cortex (M1) and right secondary somatosensory cortex (S2) are only partly known. Patients with chronic neuropathic pain often have comorbidities like depression and sleep problems. Through functional connectivity, rTMS of M1 and S2 may activate dorsolateral prefrontal cortex, the target for treating depression with rTMS. Thus, the analgesic effect of rTMS could be mediated indirectly via improvement of psychiatric comorbidities or sleep. We examined whether rTMS has an independent analgesic effect or whether its clinical benefits depend on effects on mood or sleep. We also evaluated if comorbid psychiatric or sleep disorders predict the treatment outcome. Methods: Sixteen patients with chronic drug-resistant neuropathic orofacial pain participated in this randomized controlled crossover rTMS study. Patients’ psychiatric history was evaluated by a specialist in psychiatry. Intensity and interference of pain, mood, and the quality of sleep and life were evaluated at baseline and after 2 active (primary somatosensory cortex [S1]/M1 and S2) and placebo rTMS treatments. A logistic regression analysis was done to investigate predictors of treatment outcome. Results: The analgesic effect of the right S2 stimulation was not associated with improvement of psychiatric conditions or sleep, whereas S1/M1 stimulation improved sleep without significant analgesic effect (P = 0.013–0.046 in sleep scores). Psychiatric and sleep disorders were more common in patients than in the general population (P = 0.000–0.001 in sleep scores), but these comorbidities did not predict the rTMS treatment outcome. Conclusion: We conclude that rTMS to the right S2 does not exert its beneficial analgesic effects in chronic neuropathic orofacial pain via indirect improvement of comorbid psychiatric or sleep disorders. PMID:27858874

Signals from the ventrolateral thalamus to the motor cortex during locomotion

PubMed Central

Marlinski, Vladimir; Nilaweera, Wijitha U.; Zelenin, Pavel V.; Sirota, Mikhail G.

2012-01-01

The activity of the motor cortex during locomotion is profoundly modulated in the rhythm of strides. The source of modulation is not known. In this study we examined the activity of one of the major sources of afferent input to the motor cortex, the ventrolateral thalamus (VL). Experiments were conducted in chronically implanted cats with an extracellular single-neuron recording technique. VL neurons projecting to the motor cortex were identified by antidromic responses. During locomotion, the activity of 92% of neurons was modulated in the rhythm of strides; 67% of cells discharged one activity burst per stride, a pattern typical for the motor cortex. The characteristics of these discharges in most VL neurons appeared to be well suited to contribute to the locomotion-related activity of the motor cortex. In addition to simple locomotion, we examined VL activity during walking on a horizontal ladder, a task that requires vision for correct foot placement. Upon transition from simple to ladder locomotion, the activity of most VL neurons exhibited the same changes that have been reported for the motor cortex, i.e., an increase in the strength of stride-related modulation and shortening of the discharge duration. Five modes of integration of simple and ladder locomotion-related information were recognized in the VL. We suggest that, in addition to contributing to the locomotion-related activity in the motor cortex during simple locomotion, the VL integrates and transmits signals needed for correct foot placement on a complex terrain to the motor cortex. PMID:21994259

How does visual language affect crossmodal plasticity and cochlear implant success?

PubMed Central

Lyness, C.R.; Woll, B.; Campbell, R.; Cardin, V.

2013-01-01

Cochlear implants (CI) are the most successful intervention for ameliorating hearing loss in severely or profoundly deaf children. Despite this, educational performance in children with CI continues to lag behind their hearing peers. From animal models and human neuroimaging studies it has been proposed the integrative functions of auditory cortex are compromised by crossmodal plasticity. This has been argued to result partly from the use of a visual language. Here we argue that ‘cochlear implant sensitive periods’ comprise both auditory and language sensitive periods, and thus cannot be fully described with animal models. Despite prevailing assumptions, there is no evidence to link the use of a visual language to poorer CI outcome. Crossmodal reorganisation of auditory cortex occurs regardless of compensatory strategies, such as sign language, used by the deaf person. In contrast, language deprivation during early sensitive periods has been repeatedly linked to poor language outcomes. Language sensitive periods have largely been ignored when considering variation in CI outcome, leading to ill-founded recommendations concerning visual language in CI habilitation. PMID:23999083

The effects of sesquiterpenes-rich extract of Alpinia oxyphylla Miq. on amyloid-β-induced cognitive impairment and neuronal abnormalities in the cortex and hippocampus of mice.

PubMed

Shi, Shao-Huai; Zhao, Xu; Liu, Bing; Li, Huan; Liu, Ai-Jing; Wu, Bo; Bi, Kai-Shun; Jia, Ying

2014-01-01

As a kind of medicine which can also be used as food, Alpinia oxyphylla Miq. has a long clinical history in China. A variety of studies demonstrated the significant neuroprotective activity effects of chloroform (CF) extract from the fruits of Alpinia oxyphylla. In order to further elucidate the possible mechanisms of CF extract which mainly contains sesquiterpenes with neuroprotection on the cognitive ability, mice were injected with Aβ(1-42) and later with CF in this study. The results showed that the long-term treatment of CF enhanced the cognitive performances in behavior tests, increased activities of glutathione peroxidase (GSH-px) and decreased the level of malondialdehyde (MDA), acetylcholinesterase (AChE), and amyloid-β (Aβ), and reversed the activation of microglia, degeneration of neuronal acidophilia, and nuclear condensation in the cortex and hippocampus. These results demonstrate that CF ameliorates learning and memory deficits by attenuating oxidative stress and regulating the activation of microglia and degeneration of neuronal acidophilia to reinforce cholinergic functions.

The Effects of Sesquiterpenes-Rich Extract of Alpinia oxyphylla Miq. on Amyloid-β-Induced Cognitive Impairment and Neuronal Abnormalities in the Cortex and Hippocampus of Mice

PubMed Central

Shi, Shao-Huai; Zhao, Xu; Liu, Bing; Li, Huan; Liu, Ai-Jing; Wu, Bo; Bi, Kai-Shun

2014-01-01

As a kind of medicine which can also be used as food, Alpinia oxyphylla Miq. has a long clinical history in China. A variety of studies demonstrated the significant neuroprotective activity effects of chloroform (CF) extract from the fruits of Alpinia oxyphylla. In order to further elucidate the possible mechanisms of CF extract which mainly contains sesquiterpenes with neuroprotection on the cognitive ability, mice were injected with Aβ 1−42 and later with CF in this study. The results showed that the long-term treatment of CF enhanced the cognitive performances in behavior tests, increased activities of glutathione peroxidase (GSH-px) and decreased the level of malondialdehyde (MDA), acetylcholinesterase (AChE), and amyloid-β (Aβ), and reversed the activation of microglia, degeneration of neuronal acidophilia, and nuclear condensation in the cortex and hippocampus. These results demonstrate that CF ameliorates learning and memory deficits by attenuating oxidative stress and regulating the activation of microglia and degeneration of neuronal acidophilia to reinforce cholinergic functions. PMID:25180067

Swertisin ameliorates pre-pulse inhibition deficits and cognitive impairment induced by MK-801 in mice.

PubMed

Oh, Hee Kyong; Jeon, Se Jin; Lee, Sunhee; Lee, Hyung Eun; Kim, Eunji; Park, Se Jin; Kim, Ha Neul; Jung, Won Yong; Cheong, Jae Hoon; Jang, Dae Sik; Ryu, Jong Hoon

2017-02-01

Swertisin, a plant-derived C-glucosylflavone, is known to have antidiabetic, anti-inflammatory and antioxidant effects. In the present study, we investigated in mice the effects of swertisin on glutamatergic dysfunction induced by dizocilpine (MK-801), a non-competitive N-methyl-D-aspartate receptor antagonist. In the Acoustic Startle Response test, their MK-801-induced (given 0.2 mg/kg i.p.) pre-pulse inhibition deficit was significantly attenuated by the administration of swertisin (30 mg/kg p.o.). In the Novel Object Recognition Test, the recognition memory impairments that were induced by MK-801 (0.2 mg/kg, given i.p.) were also reversed by administration of swertisin (30 mg/kg p.o.). In addition, swertisin normalized the MK-801-induced elevation of phosphorylation levels of Akt and GSK-3β signaling molecules in the prefrontal cortex. These results indicated that swertisin may be useful in managing the symptoms of schizophrenia, including sensorimotor gating disruption and cognitive impairment, and that these behavioral outcomes may be related to Akt-GSK-3β signaling in the prefrontal cortex.

Neuroprotection and mechanisms of atractylenolide III in preventing learning and memory impairment induced by chronic high-dose homocysteine administration in rats.

PubMed

Zhao, H; Ji, Z-H; Liu, C; Yu, X-Y

2015-04-02

Studies demonstrated that chronic high-dose homocysteine administration induced learning and memory impairment in animals. Atractylenolide III (Aen-III), a neuroprotective constituent of Atractylodis macrocephalae Koidz, was isolated in our previous study. In this study, we investigated potential benefits of Aen-III in preventing learning and memory impairment following chronic high-dose homocysteine administration in rats. Results showed that administration of Aen-III significantly ameliorated learning and memory impairment induced by chronic high-dose homocysteine administration in rats, decreased homocysteine-induced reactive oxygen species (ROS) formation and restored homocysteine-induced decrease of phosphorylated protein kinase C expression level. Moreover, Aen-III protected primary cultured neurons from apoptotic death induced by homocysteine treatment. This study provides the first evidence for the neuroprotective effect of Aen-III in preventing learning and impairment induced by chronic administration of homocysteine. Aen-III may have therapeutic potential in treating homocysteine-mediated cognitive impairment and neuronal injury. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

N-acetylcysteine (NAC) ameliorates Epstein-Barr virus latent membrane protein 1 induced chronic inflammation.

PubMed

Gao, Xiao; Lampraki, Eirini-Maria; Al-Khalidi, Sarwah; Qureshi, Muhammad Asif; Desai, Rhea; Wilson, Joanna Beatrice

2017-01-01

Chronic inflammation results when the immune system responds to trauma, injury or infection and the response is not resolved. It can lead to tissue damage and dysfunction and in some cases predispose to cancer. Some viruses (including Epstein-Barr virus (EBV)) can induce inflammation, which may persist even after the infection has been controlled or cleared. The damage caused by inflammation, can itself act to perpetuate the inflammatory response. The latent membrane protein 1 (LMP1) of EBV is a pro-inflammatory factor and in the skin of transgenic mice causes a phenotype of hyperplasia with chronic inflammation of increasing severity, which can progress to pre-malignant and malignant lesions. LMP1 signalling leads to persistent deregulated expression of multiple proteins throughout the mouse life span, including TGFα S100A9 and chitinase-like proteins. Additionally, as the inflammation increases, numerous chemokines and cytokines are produced which promulgate the inflammation. Deposition of IgM, IgG, IgA and IgE and complement activation form part of this process and through genetic deletion of CD40, we show that this contributes to the more tissue-destructive aspects of the phenotype. Treatment of the mice with N-acetylcysteine (NAC), an antioxidant which feeds into the body's natural redox regulatory system through glutathione synthesis, resulted in a significantly reduced leukocyte infiltrate in the inflamed tissue, amelioration of the pathological features and delay in the inflammatory signature measured by in vivo imaging. Reducing the degree of inflammation achieved through NAC treatment, had the knock on effect of reducing leukocyte recruitment to the inflamed site, thereby slowing the progression of the pathology. These data support the idea that NAC could be considered as a treatment to alleviate chronic inflammatory pathologies, including post-viral disease. Additionally, the model described can be used to effectively monitor and accurately measure therapies for chronic inflammation.

Protective effect of adipose-derived mesenchymal stem cells against acute kidney injury induced by ischemia-reperfusion in Sprague-Dawley rats.

PubMed

Sheashaa, Hussein; Lotfy, Ahmed; Elhusseini, Fatma; Aziz, Azza Abdel; Baiomy, Azza; Awad, Samah; Alsayed, Aziza; El-Gilany, Abdel-Hady; Saad, Mohamed-Ahdy A A; Mahmoud, Khaled; Zahran, Faten; Salem, Dalia A; Sarhan, Ahmed; Ghaffar, Hassan Abdel; Sobh, Mohamed

2016-05-01

Acute kidney injury (AKI) is a complex clinical condition associated with significant morbidity and mortality and lacking effective management. Ischemia-reperfusion injury (IRI) remains one of the leading causes of AKI in native and transplanted kidneys. The aim of this study was to evaluate the efficacy of adipose-derived mesenchymal stem cells (ADSCs) in the prevention of renal IRI in rats. The study was conducted on male Sprague-Dawley rats (n=72) weighing 250-300 g. Rats were randomly assigned to three main groups: i) Sham-operated control group (n=24); ii) positive control group, in which rats were subjected to IRI and were administered culture media following 4 h of IRI (n=24); and iii) ADSC group (n=24), in which rats were administered 1×10 6 ADSCs via the tail vein following 4 h of IRI. Each main group was further divided according to the timing after IRI into four equal-sized subgroups. Renal function was tested via the measurement of serum creatinine levels and creatinine clearance. In addition, malondialdehyde (MDA) levels were determined in serum and renal tissue homogenate as an indicator of oxidative stress. Histopathological changes were analyzed in different regions of the kidney, namely the cortex, outer stripe of the outer medulla (OSOM), inner stripe of the outer medulla (ISOM) and inner medulla. In each region, the scoring system considered active injury changes, regenerative changes and chronic changes. The ADSCs were assessed and their differentiation capability was verified. IRI resulted in a significant increase in serum creatinine, serum and tissue MDA levels and a significant reduction in creatinine clearance compared with those in sham-operated rats,. These changes were attenuated by the use of ADSCs. The prominent histopathological changes in the cortex, ISOM and OSOM were reflected in the injury score, which was significantly evident in the positive control group. The use of ADSCs was associated with significantly lowered injury scores at days 1 and 3; however, no significant effect was observed on day 7. These results indicate that the use of ADSCs ameliorates renal injury and dysfunction associated with IRI in rats.

Resistant starch alters gut microbiome and metabolomic profiles concurrent with amelioration of chronic kidney disease in rats

PubMed Central

Kieffer, Dorothy A.; Piccolo, Brian D.; Vaziri, Nosratola D.; Liu, Shuman; Lau, Wei L.; Khazaeli, Mahyar; Nazertehrani, Sohrab; Moore, Mary E.; Marco, Maria L.; Martin, Roy J.

2016-01-01

Patients and animals with chronic kidney disease (CKD) exhibit profound alterations in the gut environment including shifts in microbial composition, increased fecal pH, and increased blood levels of gut microbe-derived metabolites (xenometabolites). The fermentable dietary fiber high amylose maize-resistant starch type 2 (HAMRS2) has been shown to alter the gut milieu and in CKD rat models leads to markedly improved kidney function. The aim of the present study was to identify specific cecal bacteria and cecal, blood, and urinary metabolites that associate with changes in kidney function to identify potential mechanisms involved with CKD amelioration in response to dietary resistant starch. Male Sprague-Dawley rats with adenine-induced CKD were fed a semipurified low-fiber diet or a high-fiber diet [59% (wt/wt) HAMRS2] for 3 wk (n = 9 rats/group). The cecal microbiome was characterized, and cecal contents, serum, and urine metabolites were analyzed. HAMRS2-fed rats displayed decreased cecal pH, decreased microbial diversity, and an increased Bacteroidetes-to-Firmicutes ratio. Several uremic retention solutes were altered in the cecal contents, serum, and urine, many of which had strong correlations with specific gut bacteria abundances, i.e., serum and urine indoxyl sulfate were reduced by 36% and 66%, respectively, in HAMRS2-fed rats and urine p-cresol was reduced by 47% in HAMRS2-fed rats. Outcomes from this study were coincident with improvements in kidney function indexes and amelioration of CKD outcomes previously reported for these rats, suggesting an important role for microbial-derived factors and gut microbe metabolism in regulating host kidney function. PMID:26841824

Resistant starch alters gut microbiome and metabolomic profiles concurrent with amelioration of chronic kidney disease in rats.

PubMed

Kieffer, Dorothy A; Piccolo, Brian D; Vaziri, Nosratola D; Liu, Shuman; Lau, Wei L; Khazaeli, Mahyar; Nazertehrani, Sohrab; Moore, Mary E; Marco, Maria L; Martin, Roy J; Adams, Sean H

2016-05-01

Patients and animals with chronic kidney disease (CKD) exhibit profound alterations in the gut environment including shifts in microbial composition, increased fecal pH, and increased blood levels of gut microbe-derived metabolites (xenometabolites). The fermentable dietary fiber high amylose maize-resistant starch type 2 (HAMRS2) has been shown to alter the gut milieu and in CKD rat models leads to markedly improved kidney function. The aim of the present study was to identify specific cecal bacteria and cecal, blood, and urinary metabolites that associate with changes in kidney function to identify potential mechanisms involved with CKD amelioration in response to dietary resistant starch. Male Sprague-Dawley rats with adenine-induced CKD were fed a semipurified low-fiber diet or a high-fiber diet [59% (wt/wt) HAMRS2] for 3 wk (n = 9 rats/group). The cecal microbiome was characterized, and cecal contents, serum, and urine metabolites were analyzed. HAMRS2-fed rats displayed decreased cecal pH, decreased microbial diversity, and an increased Bacteroidetes-to-Firmicutes ratio. Several uremic retention solutes were altered in the cecal contents, serum, and urine, many of which had strong correlations with specific gut bacteria abundances, i.e., serum and urine indoxyl sulfate were reduced by 36% and 66%, respectively, in HAMRS2-fed rats and urine p-cresol was reduced by 47% in HAMRS2-fed rats. Outcomes from this study were coincident with improvements in kidney function indexes and amelioration of CKD outcomes previously reported for these rats, suggesting an important role for microbial-derived factors and gut microbe metabolism in regulating host kidney function. Copyright © 2016 the American Physiological Society.

Colonic microbiota can promote rapid local improvement of murine colitis by thioguanine independently of T lymphocytes and host metabolism

PubMed Central

Oancea, I; Movva, R; Das, I; Aguirre de Cárcer, D; Schreiber, V; Yang, Y; Purdon, A; Harrington, B; Proctor, M; Wang, R; Sheng, Y; Lobb, M; Lourie, R; Ó Cuív, P; Duley, J A; Begun, J; Florin, T H J

2017-01-01

Objective Mercaptopurine (MP) and pro-drug azathioprine are ‘first-line’ oral therapies for maintaining remission in IBD. It is believed that their pharmacodynamic action is due to a slow cumulative decrease in activated lymphocytes homing to inflamed gut. We examined the role of host metabolism, lymphocytes and microbiome for the amelioration of colitis by the related thioguanine (TG). Design C57Bl/6 mice with or without specific genes altered to elucidate mechanisms responsible for TG's actions were treated daily with oral or intrarectal TG, MP or water. Disease activity was scored daily. At sacrifice, colonic histology, cytokine message, caecal luminal and mucosal microbiomes were analysed. Results Oral and intrarectal TG but not MP rapidly ameliorated spontaneous chronic colitis in Winnie mice (point mutation in Muc2 secretory mucin). TG ameliorated dextran sodium sulfate-induced chronic colitis in wild-type (WT) mice and in mice lacking T and B lymphocytes. Remarkably, colitis improved without immunosuppressive effects in the absence of host hypoxanthine (guanine) phosphoribosyltransferase (Hprt)-mediated conversion of TG to active drug, the thioguanine nucleotides (TGN). Colonic bacteria converted TG and less so MP to TGN, consistent with intestinal bacterial conversion of TG to so reduce inflammation in the mice lacking host Hprt. TG rapidly induced autophagic flux in epithelial, macrophage and WT but not Hprt−/− fibroblast cell lines and augmented epithelial intracellular bacterial killing. Conclusions Treatment by TG is not necessarily dependent on the adaptive immune system. TG is a more efficacious treatment than MP in Winnie spontaneous colitis. Rapid local bacterial conversion of TG correlated with decreased intestinal inflammation and immune activation. PMID:27411368

"More than skin deep": stress neurobiology and mental health consequences of racial discrimination.

PubMed

Berger, Maximus; Sarnyai, Zoltán

2015-01-01

Ethnic minority groups across the world face a complex set of adverse social and psychological challenges linked to their minority status, often involving racial discrimination. Racial discrimination is increasingly recognized as an important contributing factor to health disparities among non-dominant ethnic minorities. A growing body of literature has recognized these health disparities and has investigated the relationship between racial discrimination and poor health outcomes. Chronically elevated cortisol levels and a dysregulated hypothalamic-pituitary-adrenal (HPA) axis appear to mediate effects of racial discrimination on allostatic load and disease. Racial discrimination seems to converge on the anterior cingulate cortex (ACC) and may impair the function of the prefrontal cortex (PFC), hence showing substantial similarities to chronic social stress. This review provides a summary of recent literature on hormonal and neural effects of racial discrimination and a synthesis of potential neurobiological pathways by which discrimination affects mental health.

Chronic smoking and alcoholism change expression of selective genes in the human prefrontal cortex.

PubMed

Flatscher-Bader, Traute; Wilce, Peter A

2006-05-01

Alcoholism is commonly associated with chronic smoking. A number of gene expression profiles of regions within the human mesocorticolimbic system have identified potential alcohol-sensitive genes; however, the influence of smoking on these changes was not taken into account. This study addressed the impact of alcohol and smoking on the expression of 4 genes, previously identified as alcoholism-sensitive, in the human prefrontal cortex (PFC). mRNA expression of apolipoprotein D, tissue inhibitor of the metalloproteinase 3, high-affinity glial glutamate transporter and midkine, was measured in the PFC of alcoholic subjects and controls with and without smoking comorbidity using real-time polymerase chain reaction. The results show that alcohol affects transcription of some of these genes. Additionally, smoking has a marked influence on gene expression. This study emphasizes the need for careful case selection in future gene expression studies to delineate the adaptive molecular process associated with smoking and alcohol.

Effect of chronic restraint stress on inhibitory gating in the auditory cortex of rats.

PubMed

Ma, Lanlan; Li, Wai; Li, Sibin; Wang, Xuejiao; Qin, Ling

2017-05-01

A fundamental adaptive mechanism of auditory function is inhibitory gating (IG), which refers to the attenuation of neural responses to repeated sound stimuli. IG is drastically impaired in individuals with emotional and cognitive impairments (i.e. posttraumatic stress disorder). The objective of this study was to test whether chronic stress impairs the IG of the auditory cortex (AC). We used the standard two-tone stimulus paradigm and examined the parametric qualities of IG in the AC of rats by recording the electrophysiological signals of a single-unit and local field potential (LFP) simultaneously. The main results of this study were that most of the AC neurons showed a weaker response to the second tone than to the first tone, reflecting an IG of the repeated input. A fast negative wave of LFP showed consistent IG across the sampled AC sites, whereas a slow positive wave of LFP had less IG effect. IG was diminished following chronic restraint stress at both, the single-unit and LFP level, due to the increase in response to the second tone. This study provided new evidence that chronic stress disrupts the physiological function of the AC. Lay Summary The effects of chronic stress on IG were investigated by recording both, single-unit spike and LFP activities, in the AC of rats. In normal rats, most of the single-unit and N25 LFP activities in the AC showed an IG effect. IG was diminished following chronic restraint stress at both, the single-unit and LFP level.

Blonanserin Ameliorates Phencyclidine-Induced Visual-Recognition Memory Deficits: the Complex Mechanism of Blonanserin Action Involving D3-5-HT2A and D1-NMDA Receptors in the mPFC

PubMed Central

Hida, Hirotake; Mouri, Akihiro; Mori, Kentaro; Matsumoto, Yurie; Seki, Takeshi; Taniguchi, Masayuki; Yamada, Kiyofumi; Iwamoto, Kunihiro; Ozaki, Norio; Nabeshima, Toshitaka; Noda, Yukihiro

2015-01-01

Blonanserin differs from currently used serotonin 5-HT2A/dopamine-D2 receptor antagonists in that it exhibits higher affinity for dopamine-D2/3 receptors than for serotonin 5-HT2A receptors. We investigated the involvement of dopamine-D3 receptors in the effects of blonanserin on cognitive impairment in an animal model of schizophrenia. We also sought to elucidate the molecular mechanism underlying this involvement. Blonanserin, as well as olanzapine, significantly ameliorated phencyclidine (PCP)-induced impairment of visual-recognition memory, as demonstrated by the novel-object recognition test (NORT) and increased extracellular dopamine levels in the medial prefrontal cortex (mPFC). With blonanserin, both of these effects were antagonized by DOI (a serotonin 5-HT2A receptor agonist) and 7-OH-DPAT (a dopamine-D3 receptor agonist), whereas the effects of olanzapine were antagonized by DOI but not by 7-OH-DPAT. The ameliorating effect was also antagonized by SCH23390 (a dopamine-D1 receptor antagonist) and H-89 (a protein kinase A (PKA) inhibitor). Blonanserin significantly remediated the decrease in phosphorylation levels of PKA at Thr197 and of NR1 (an essential subunit of N-methyl-D-aspartate (NMDA) receptors) at Ser897 by PKA in the mPFC after a NORT training session in the PCP-administered mice. There were no differences in the levels of NR1 phosphorylated at Ser896 by PKC in any group. These results suggest that the ameliorating effect of blonanserin on PCP-induced cognitive impairment is associated with indirect functional stimulation of the dopamine-D1-PKA-NMDA receptor pathway following augmentation of dopaminergic neurotransmission due to inhibition of both dopamine-D3 and serotonin 5-HT2A receptors in the mPFC. PMID:25120077

The sirtuin family's role in aging and age-associated pathologies.

PubMed

Hall, Jessica A; Dominy, John E; Lee, Yoonjin; Puigserver, Pere

2013-03-01

The 7 mammalian sirtuin proteins compose a protective cavalry of enzymes that can be invoked by cells to aid in the defense against a vast array of stressors. The pathologies associated with aging, such as metabolic syndrome, neurodegeneration, and cancer, are either caused by or exacerbated by a lifetime of chronic stress. As such, the activation of sirtuin proteins could provide a therapeutic approach to buffer against chronic stress and ameliorate age-related decline. Here we review experimental evidence both for and against this proposal, as well as the implications that isoform-specific sirtuin activation may have for healthy aging in humans.

Treatment of chronic kidney diseases with histone deacetylase inhibitors

PubMed Central

Liu, Na; Zhuang, Shougang

2015-01-01

Histone deacetylases (HDACs) induce deacetylation of both histone and non-histone proteins and play a critical role in the modulation of physiological and pathological gene expression. Pharmacological inhibition of HDAC has been reported to attenuate progression of renal fibrogenesis in obstructed kidney and reduce cyst formation in polycystic kidney disease. HDAC inhibitors (HDACis) are also able to ameliorate renal lesions in diabetes nephropathy, lupus nephritis, aristolochic acid nephropathy, and transplant nephropathy. The beneficial effects of HDACis are associated with their anti-fibrosis, anti-inflammation, and immunosuppressant effects. In this review, we summarize recent advances on the treatment of various chronic kidney diseases with HDACis in pre-clinical models. PMID:25972812

Unpredictable chronic mild stress differentially impairs social and contextual discrimination learning in two inbred mouse strains

PubMed Central

van Boxelaere, Michiel; Clements, Jason; Callaerts, Patrick; D’Hooge, Rudi

2017-01-01

Alterations in the social and cognitive domain are considered important indicators for increased disability in many stress-related disorders. Similar impairments have been observed in rodents chronically exposed to stress, mimicking potential endophenotypes of stress-related psychopathologies such as major depression disorder (MDD), anxiety, conduct disorder, and posttraumatic stress disorder (PTSD). Data from numerous studies suggest that deficient plasticity mechanisms in hippocampus (HC) and prefrontal cortex (PFC) might underlie these social and cognitive deficits. Specifically, stress-induced deficiencies in neural plasticity have been associated with a hypodopaminergic state and reduced neural plasticity persistence. Here we assessed the effects of unpredictable chronic mild stress (UCMS) on exploratory, social and cognitive behavior of females of two inbred mouse strains (C57BL/6J and DBA/2J) that differ in their dopaminergic profile. Exposure to chronic stress resulted in impaired circadian rhythmicity, sociability and social cognition in both inbred strains, but differentially affected activity patterns and contextual discrimination performance. These stress-induced behavioral impairments were accompanied by reduced expression levels of brain derived neurotrophic factor (BDNF) in the prefrontal cortex. The strain-specific cognitive impairment was coexistent with enhanced plasma corticosterone levels and reduced expression of genes related to dopamine signaling in hippocampus. These results underline the importance of assessing different strains with multiple test batteries to elucidate the neural and genetic basis of social and cognitive impairments related to chronic stress. PMID:29166674

The effects of chronic intracortical microstimulation on neural tissue and fine motor behavior.

PubMed

Rajan, Alexander T; Boback, Jessica L; Dammann, John F; Tenore, Francesco V; Wester, Brock A; Otto, Kevin J; Gaunt, Robert A; Bensmaia, Sliman J

2015-12-01

One approach to conveying sensory feedback in neuroprostheses is to electrically stimulate sensory neurons in the cortex. For this approach to be viable, it is critical that intracortical microstimulation (ICMS) causes minimal damage to the brain. Here, we investigate the effects of chronic ICMS on the neuronal tissue across a variety of stimulation regimes in non-human primates. We also examine each animal's ability to use their hand--the cortical representation of which is targeted by the ICMS--as a further assay of possible neuronal damage. We implanted electrode arrays in the primary somatosensory cortex of three Rhesus macaques and delivered ICMS four hours per day, five days per week, for six months. Multiple regimes of ICMS were delivered to investigate the effects of stimulation parameters on the tissue and behavior. Parameters included current amplitude (10-100 μA), pulse train duration (1, 5 s), and duty cycle (1/1, 1/3). We then performed a range of histopathological assays on tissue near the tips of both stimulated and unstimulated electrodes to assess the effects of chronic ICMS on the tissue and their dependence on stimulation parameters. While the implantation and residence of the arrays in the cortical tissue did cause significant damage, chronic ICMS had no detectable additional effect; furthermore, the animals exhibited no impairments in fine motor control. Chronic ICMS may be a viable means to convey sensory feedback in neuroprostheses as it does not cause significant damage to the stimulated tissue.

The effects of chronic intracortical microstimulation on neural tissue and fine motor behavior

NASA Astrophysics Data System (ADS)

Rajan, Alexander T.; Boback, Jessica L.; Dammann, John F.; Tenore, Francesco V.; Wester, Brock A.; Otto, Kevin J.; Gaunt, Robert A.; Bensmaia, Sliman J.

2015-12-01

Objective. One approach to conveying sensory feedback in neuroprostheses is to electrically stimulate sensory neurons in the cortex. For this approach to be viable, it is critical that intracortical microstimulation (ICMS) causes minimal damage to the brain. Here, we investigate the effects of chronic ICMS on the neuronal tissue across a variety of stimulation regimes in non-human primates. We also examine each animal’s ability to use their hand—the cortical representation of which is targeted by the ICMS—as a further assay of possible neuronal damage. Approach. We implanted electrode arrays in the primary somatosensory cortex of three Rhesus macaques and delivered ICMS four hours per day, five days per week, for six months. Multiple regimes of ICMS were delivered to investigate the effects of stimulation parameters on the tissue and behavior. Parameters included current amplitude (10-100 μA), pulse train duration (1, 5 s), and duty cycle (1/1, 1/3). We then performed a range of histopathological assays on tissue near the tips of both stimulated and unstimulated electrodes to assess the effects of chronic ICMS on the tissue and their dependence on stimulation parameters. Main results. While the implantation and residence of the arrays in the cortical tissue did cause significant damage, chronic ICMS had no detectable additional effect; furthermore, the animals exhibited no impairments in fine motor control. Significance. Chronic ICMS may be a viable means to convey sensory feedback in neuroprostheses as it does not cause significant damage to the stimulated tissue.

Chronic treatment with AMPA receptor potentiator Org 26576 increases neuronal cell proliferation and survival in adult rodent hippocampus.

PubMed

Su, Xiaowei W; Li, Xiao-Yuan; Banasr, Mounira; Koo, Ja Wook; Shahid, Mohammed; Henry, Brian; Duman, Ronald S

2009-10-01

Currently available antidepressants upregulate hippocampal neurogenesis and prefrontal gliogenesis after chronic administration, which could block or reverse the effects of stress. Allosteric alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators (ARPs), which have novel targets compared to current antidepressants, have been shown to have antidepressant properties in neurogenic and behavioral models. This study analyzed the effect of the ARP Org 26576 on the proliferation, survival, and differentiation of neurons and glia in the hippocampus and prelimbic cortex of adult rats. Male Sprague-Dawley rats received acute (single day) or chronic (21 day) twice-daily intraperitoneal injections of Org 26576 (1-10 mg/kg). Bromodeoxyuridine (BrdU) immunohistochemistry was conducted 24 h or 28 days after the last drug injection for the analysis of cell proliferation or survival, respectively. Confocal immunofluorescence analysis was used to determine the phenotype of surviving cells. Acute administration of Org 26576 did not increase neuronal cell proliferation. However, chronic administration of Org 26576 increased progenitor cell proliferation in dentate gyrus (approximately 40%) and in prelimbic cortex (approximately 35%) at the 10-mg/kg dosage. Cells born in response to chronic Org 26576 in dentate gyrus exhibited increased rates of survival (approximately 30%) with the majority of surviving cells expressing a neuronal phenotype. Findings suggest that Org 26576 may have antidepressant properties, which may be attributed, in part, to upregulation of hippocampal neurogenesis and prelimbic cell proliferation.

Reboxetine Improves Auditory Attention and Increases Norepinephrine Levels in the Auditory Cortex of Chronically Stressed Rats

PubMed Central

Pérez-Valenzuela, Catherine; Gárate-Pérez, Macarena F.; Sotomayor-Zárate, Ramón; Delano, Paul H.; Dagnino-Subiabre, Alexies

2016-01-01

Chronic stress impairs auditory attention in rats and monoamines regulate neurotransmission in the primary auditory cortex (A1), a brain area that modulates auditory attention. In this context, we hypothesized that norepinephrine (NE) levels in A1 correlate with the auditory attention performance of chronically stressed rats. The first objective of this research was to evaluate whether chronic stress affects monoamines levels in A1. Male Sprague–Dawley rats were subjected to chronic stress (restraint stress) and monoamines levels were measured by high performance liquid chromatographer (HPLC)-electrochemical detection. Chronically stressed rats had lower levels of NE in A1 than did controls, while chronic stress did not affect serotonin (5-HT) and dopamine (DA) levels. The second aim was to determine the effects of reboxetine (a selective inhibitor of NE reuptake) on auditory attention and NE levels in A1. Rats were trained to discriminate between two tones of different frequencies in a two-alternative choice task (2-ACT), a behavioral paradigm to study auditory attention in rats. Trained animals that reached a performance of ≥80% correct trials in the 2-ACT were randomly assigned to control and stress experimental groups. To analyze the effects of chronic stress on the auditory task, trained rats of both groups were subjected to 50 2-ACT trials 1 day before and 1 day after of the chronic stress period. A difference score (DS) was determined by subtracting the number of correct trials after the chronic stress protocol from those before. An unexpected result was that vehicle-treated control rats and vehicle-treated chronically stressed rats had similar performances in the attentional task, suggesting that repeated injections with vehicle were stressful for control animals and deteriorated their auditory attention. In this regard, both auditory attention and NE levels in A1 were higher in chronically stressed rats treated with reboxetine than in vehicle-treated animals. These results indicate that NE has a key role in A1 and attention of stressed rats during tone discrimination. PMID:28082872

Alterations of apparent diffusion coefficient (ADC) in the brain of rats chronically exposed to lead acetate.

PubMed

López-Larrubia, Pilar; Cauli, Omar

2011-03-15

Diffusion-weighted imaging (DWI) allows the assessment of the water apparent diffusion coefficient (ADC), a measure of tissue water diffusivity which is altered during different pathological conditions such as cerebral oedema. By means of DWI, we repeatedly measured in the same rats apparent diffusion coefficient ADC in different brain areas (motor cortex (MCx), somato-sensory cortex (SCx), caudate-putamen (CPu), hippocampus (Hip), mesencephalic reticular formation (RF), corpus callosum (CC) and cerebellum (Cb)) after 1 week, 4 and 12 weeks of lead acetate exposure via drinking water (50 or 500 ppm). After 12 weeks of lead exposure rats received albumin-Evans blue complex administration and were sacrificed 1h later. Blood-brain barrier permeability and water tissue content were determined in order to evaluate their relationship with ADC changes. Chronic exposure to lead acetate (500 ppm) for 4 weeks increased ADC values in Hip, RF and Cb but no in other brain areas. After 12 weeks of lead acetate exposure at 500 ppm ADC is significantly increased also in CPu and CC. Brain areas displaying high ADC values after lead exposure showed also an increased water content and increased BBB permeability to Evans blue-albumin complex. Exposure to 50 ppm for 12 weeks increased ADC values and BBB permeability in the RF and Cb. In summary, chronic lead exposure induces cerebral oedema in the adult brain depending on the brain area and the dose of exposure. RF and Cb appeared the most sensitive brain areas whereas cerebral cortex appears resistant to lead-induced cerebral oedema. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Chronic intraventricular administration of lysergic acid diethylamide (LSD) affects the sensitivity of cortical cells to monocular deprivation.

PubMed

McCall, M A; Tieman, D G; Hirsch, H V

1982-11-04

In kittens, but not in adult cats, depriving one eye of pattern vision by suturing the lids shut (monocular deprivation or MD) for one week reduces the proportion of binocular units in the visual cortex. A sensitivity of cortical units in adult cats to MD can be produced by infusing exogenous monoamines into the visual cortex. Since LSD interacts with monoamines, we have examined the effects of chronic administration of LSD on the sensitivity to MD for cortical cells in adult cats. Cats were assigned randomly to one of four conditions: MD/LSD, MD/No-LSD, No-MD/LSD, No-MD/No-LSD. An osmotic minipump delivered either LSD or the vehicle solution alone during a one-week period of MD. The animals showed no obvious anomalies during the administration of the drug. After one week the response properties of single units in area 17 of the visual cortex were studied without knowledge of the contents of the individual minipumps. With the exception of ocular dominance, the response properties of units recorded in all animals did not differ from normal. In the control animals (MD/No-LSD, No-MD/LSD, No-MD/No-LSD) the average proportion of binocular cells was 78%; similar to that observed for normal adult cats. However, in the experimental animals, which received LSD during the period of MD, only 52% of the cells were binocular. Our results suggest that chronic intraventricular administration of LSD affects either directly or indirectly the sensitivity of cortical neurons to MD.

The AT{sub 1} Receptor Antagonist, L-158,809, Prevents or Ameliorates Fractionated Whole-Brain Irradiation-Induced Cognitive Impairment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Robbins, Mike E.; Brain Tumor Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC; Payne, Valerie B.S.

2009-02-01

Purpose: We hypothesized that administration of the angiotensin type 1 (AT1) receptor antagonist, L-158,809, to young adult male rats would prevent or ameliorate fractionated whole-brain irradiation (WBI)-induced cognitive impairment. Materials and Methods: Groups of 80 young adult male Fischer 344 x Brown Norway (F344xBN) rats, 12-14 weeks old, received either: (1) fractionated WBI; 40 Gy of {gamma} rays in 4 weeks, 2 fractions/week, (2) sham-irradiation; (3) WBI plus L-158,809 (20 mg/L drinking water) starting 3 days prior, during, and for 14, 28, or 54 weeks postirradiation; and (4) sham-irradiation plus L-158,809 for 14, 28, or 54 weeks postirradiation. An additionalmore » group of rats (n = 20) received L-158,809 before, during, and for 5 weeks postirradiation, after which they received normal drinking water up to 28 weeks postirradiation. Results: Administration of L-158,809 before, during, and for 28 or 54 weeks after fractionated WBI prevented or ameliorated the radiation-induced cognitive impairment observed 26 and 52 weeks postirradiation. Moreover, giving L-158,809 before, during, and for only 5 weeks postirradiation ameliorated the significant cognitive impairment observed 26 weeks postirradiation. These radiation-induced cognitive impairments occurred without any changes in brain metabolites or gross histologic changes assessed at 28 and 54 weeks postirradiation, respectively. Conclusions: Administering L-158,809 before, during, and after fractionated WBI can prevent or ameliorate the chronic, progressive, cognitive impairment observed in rats at 26 and 52 weeks postirradiation. These findings offer the promise of improving the quality of life for brain tumor patients.« less

Piracetam Attenuates LPS-Induced Neuroinflammation and Cognitive Impairment in Rats.

PubMed

Tripathi, Alok; Paliwal, Pankaj; Krishnamurthy, Sairam

2017-11-01

The present study was performed to investigate the effect of piracetam on neuroinflammation induced by lipopolysaccharide (LPS) and resulting changes in cognitive behavior. Neuroinflammation was induced by a single dose of LPS solution infused into each of the lateral cerebral ventricles in concentrations of 1 μg/μl, at a rate of 1 μl/min over a 5-min period, with a 5-min waiting period between the two infusions. Piracetam in doses of 50, 100, and 200 mg/kg i.p. was administered 30 min before LPS infusion and continued for 9 days. On ninth day, the behavioral test for memory and anxiety was done followed by blood collection and microdissection of the hippocampus (HIP) and prefrontal cortex brain regions. Piracetam attenuated the LPS-induced decrease in coping strategy to novel environment indicating anxiolytic activity. It also reversed the LPS-induced changes in the known arm and novel arm entries in the Y-maze test indicating amelioration of spatial memory impairment. Further, piracetam moderated LPS-induced decrease in the mitochondrial complex enzyme activities (I, II, IV, and V) and mitochondrial membrane potential. It ameliorated changes in hippocampal lipid peroxidation and nitrite levels including the activity of superoxide dismutase. Piracetam region specifically ameliorated LPS-induced increase in the level of IL-6 in HIP indicating anti-neuroinflammatory effect. Further, piracetam reduced HIP Aβ (1-40) and increased blood Aβ level suggesting efflux of Aβ from HIP to blood. Therefore, the present study indicates preclinical evidence for the use of piracetam in the treatment of neuroinflammatory disorders.

DEP domain-containing mTOR-interacting protein suppresses lipogenesis and ameliorates hepatic steatosis and acute-on-chronic liver injury in alcoholic liver disease.

PubMed

Chen, Hanqing; Shen, Feng; Sherban, Alex; Nocon, Allison; Li, Yu; Wang, Hua; Xu, Ming-Jiang; Rui, Xianliang; Han, Jinyan; Jiang, Bingbing; Lee, Donghwan; Li, Na; Keyhani-Nejad, Farnaz; Fan, Jian-Gao; Liu, Feng; Kamat, Amrita; Musi, Nicolas; Guarente, Leonard; Pacher, Pal; Gao, Bin; Zang, Mengwei

2018-02-19

Alcoholic liver disease (ALD) is characterized by lipid accumulation and liver injury. However, how chronic alcohol consumption causes hepatic lipid accumulation remains elusive. The present study demonstrates that activation of the mechanistic target of rapamycin complex 1 (mTORC1) plays a causal role in alcoholic steatosis, inflammation, and liver injury. Chronic-plus-binge ethanol feeding led to hyperactivation of mTORC1, as evidenced by increased phosphorylation of mTOR and its downstream kinase S6 kinase 1 (S6K1) in hepatocytes. Aberrant activation of mTORC1 was likely attributed to the defects of the DEP domain-containing mTOR-interacting protein (DEPTOR) and the nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 1 (SIRT1) in the liver of chronic-plus-binge ethanol-fed mice and in the liver of patients with ALD. Conversely, adenoviral overexpression of hepatic DEPTOR suppressed mTORC1 signaling and ameliorated alcoholic hepatosteatosis, inflammation, and acute-on-chronic liver injury. Mechanistically, the lipid-lowering effect of hepatic DEPTOR was attributable to decreased proteolytic processing, nuclear translocation, and transcriptional activity of the lipogenic transcription factor sterol regulatory element-binding protein-1 (SREBP-1). DEPTOR-dependent inhibition of mTORC1 also attenuated alcohol-induced cytoplasmic accumulation of the lipogenic regulator lipin 1 and prevented alcohol-mediated inhibition of fatty acid oxidation. Pharmacological intervention with rapamycin alleviated the ability of alcohol to up-regulate lipogenesis, to down-regulate fatty acid oxidation, and to induce steatogenic phenotypes. Chronic-plus-binge ethanol feeding led to activation of SREBP-1 and lipin 1 through S6K1-dependent and independent mechanisms. Furthermore, hepatocyte-specific deletion of SIRT1 disrupted DEPTOR function, enhanced mTORC1 activity, and exacerbated alcoholic fatty liver, inflammation, and liver injury in mice. The dysregulation of SIRT1-DEPTOR-mTORC1 signaling is a critical determinant of ALD pathology; targeting SIRT1 and DEPTOR and selectively inhibiting mTORC1-S6K1 signaling may have therapeutic potential for treating ALD in humans. (Hepatology 2018). © 2018 by the American Association for the Study of Liver Diseases.

Antioxidant treatment ameliorates experimental diabetes-induced depressive-like behaviour and reduces oxidative stress in brain and pancreas.

PubMed

Réus, Gislaine Z; Dos Santos, Maria Augusta B; Abelaira, Helena M; Titus, Stephanie E; Carlessi, Anelise S; Matias, Beatriz I; Bruchchen, Livia; Florentino, Drielly; Vieira, Andriele; Petronilho, Fabricia; Ceretta, Luciane B; Zugno, Alexandra I; Quevedo, João

2016-03-01

Studies have shown a relationship between diabetes mellitus (DM) and the development of major depressive disorder. Alterations in oxidative stress are associated with the pathophysiology of both diabetes mellitus and major depressive disorder. This study aimed to evaluate the effects of antioxidants N-acetylcysteine and deferoxamine on behaviour and oxidative stress parameters in diabetic rats. To this aim, after induction of diabetes by a single dose of alloxan, Wistar rats were treated with N-acetylcysteine or deferoxamine for 14 days, and then depressive-like behaviour was evaluated. Oxidative stress parameters were assessed in the prefrontal cortex, hippocampus, amygdala, nucleus accumbens and pancreas. Diabetic rats displayed depressive-like behaviour, and treatment with N-acetylcysteine reversed this alteration. Carbonyl protein levels were increased in the prefrontal cortex, hippocampus and pancreas of diabetic rats, and both N-acetylcysteine and deferoxamine reversed these alterations. Lipid damage was increased in the prefrontal cortex, hippocampus, amygdala and pancreas; however, treatment with N-acetylcysteine or deferoxamine reversed lipid damage only in the hippocampus and pancreas. Superoxide dismutase activity was decreased in the amygdala, nucleus accumbens and pancreas of diabetic rats. In diabetic rats, there was a decrease in catalase enzyme activity in the prefrontal cortex, amygdala, nucleus accumbens and pancreas, but an increase in the hippocampus. Treatment with antioxidants did not have an effect on the activity of antioxidant enzymes. In conclusion, animal model of diabetes produced depressive-like behaviour and oxidative stress in the brain and periphery. Treatment with antioxidants could be a viable alternative to treat behavioural and biochemical alterations induced by diabetes. Copyright © 2015 John Wiley & Sons, Ltd.

Cortical grey matter volume reduction in people with schizophrenia is associated with neuro-inflammation

PubMed Central

Zhang, Y; Catts, V S; Sheedy, D; McCrossin, T; Kril, J J; Shannon Weickert, C

2016-01-01

Cortical grey matter volume deficits and neuro-inflammation exist in patients with schizophrenia, although it is not clear whether elevated cytokines contribute to the cortical volume reduction. We quantified cortical and regional brain volumes in fixed postmortem brains from people with schizophrenia and matched controls using stereology. Interleukin (IL)-6, IL-1β, IL-8 and SERPINA3 messenger RNAs (mRNAs) were quantified in the contralateral fresh frozen orbitofrontal cortex. We found a small, but significant reduction in cortical grey matter (1.3% F(1,85)=4.478, P=0.037) and superior frontal gyrus (6.5% F(1,80)=5.700, P=0.019) volumes in individuals with schizophrenia compared with controls. Significantly reduced cortical grey matter (9.2% F(1,24)=8.272, P=0.008) and superior frontal gyrus (13.9% F(1,20)=5.374, P=0.031) volumes were found in cases with schizophrenia and ‘high inflammation' status relative to schizophrenia cases with ‘low inflammation' status in the prefrontal cortex. The expression of inflammatory mRNAs in the orbitofrontal cortex was significantly correlated with those in dorsolateral prefrontal cortex (all r>0.417, all P<0.022), except for IL-8. Moreover, average daily and lifetime antipsychotic intake negatively correlated with cortical grey matter and superior frontal gyrus volumes (all r<−0.362, all P<0.05). The results suggest that the reduction in cortical grey matter volume in people with schizophrenia is exaggerated in those who have high expression of inflammatory cytokines. Further, antipsychotic medication intake does not appear to ameliorate the reduction in brain volume. PMID:27959331

Brain Hemispheric Differences in the Neurochemical Effects of Lead, Prenatal Stress, and the Combination and Their Amelioration by Behavioral Experience

PubMed Central

Cory-Slechta, Deborah A.

2013-01-01

Brain lateralization, critical to mediation of cognitive functions and to “multitasking,” is disrupted in conditions such as attention deficit disorder and schizophrenia. Both low-level lead (Pb) exposure and prenatal stress (PS) have been associated with mesocorticolimbic system–mediated executive-function cognitive and attention deficits. Mesocorticolimbic systems demonstrate significant laterality. Thus, altered brain lateralization could play a role in this behavioral toxicity. This study examined laterality of mesocorticolimbic monoamines (frontal cortex, nucleus accumbens, striatum, midbrain) and amino acids (frontal cortex) in male and female rats subjected to lifetime Pb exposure (0 or 50 ppm in drinking water), PS (restraint stress on gestational days 16–17), or the combination with and without repeated learning behavioral experience. Control males exhibited prominent laterality, particularly in midbrain and also in frontal cortex and striatum; females exhibited less laterality, and this was primarily striatal. Lateralized Pb ± PS induced neurotransmitter changes were assessed only in males because of limited sample sizes of Pb + PS females. In males, Pb ± PS changes occurred in left hemisphere of frontal cortex and right hemisphere of midbrain. Behavioral experience modified the laterality of Pb ± PS–induced neurotransmitter changes in a region-dependent manner. Notably, behavioral experience eliminated Pb ± PS neurotransmitter changes in males. These findings underscore the critical need to evaluate both sexes and brain hemispheres for the mechanistic understanding of sex-dependent differences in neuro- and behavioral toxicity. Furthermore, assessment of central nervous system mechanisms in the absence of behavioral experience, shown here for males, may constitute less relevant models of human health effects. PMID:23358193

Improving ideomotor limb apraxia by electrical stimulation of the left posterior parietal cortex.

PubMed

Bolognini, Nadia; Convento, Silvia; Banco, Elisabetta; Mattioli, Flavia; Tesio, Luigi; Vallar, Giuseppe

2015-02-01

Limb apraxia, a deficit of planning voluntary gestures, is most frequently caused by damage to the left hemisphere, where, according to an influential neurofunctional model, gestures are planned, before being executed through the motor cortex of the hemisphere contralateral to the acting hand. We used anodal transcranial direct current stimulation delivered to the left posterior parietal cortex (PPC), the right motor cortex (M1), and a sham stimulation condition, to modulate the ability of six left-brain-damaged patients with ideomotor apraxia, and six healthy control subjects, to imitate hand gestures, and to perform skilled hand movements using the left hand. Transcranial direct current stimulation delivered to the left PPC reduced the time required to perform skilled movements, and planning, but not execution, times in imitating gestures, in both patients and controls. In patients, the amount of decrease of planning times brought about by left PPC transcranial direct current stimulation was influenced by the size of the parietal lobe damage, with a larger parietal damage being associated with a smaller improvement. Of interest from a clinical perspective, left PPC stimulation also ameliorated accuracy in imitating hand gestures in patients. Instead, transcranial direct current stimulation to the right M1 diminished execution, but not planning, times in both patients and healthy controls. In conclusion, by using a transcranial stimulation approach, we temporarily improved ideomotor apraxia in the left hand of left-brain-damaged patients, showing a role of the left PPC in planning gestures. This evidence opens up novel perspectives for the use of transcranial direct current stimulation in the rehabilitation of limb apraxia. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Mitochondrial dysfunction in brain cortex mitochondria of STZ-diabetic rats: effect of l-Arginine.

PubMed

Ortiz, M Del Carmen; Lores-Arnaiz, Silvia; Albertoni Borghese, M Florencia; Balonga, Sabrina; Lavagna, Agustina; Filipuzzi, Ana Laura; Cicerchia, Daniela; Majowicz, Monica; Bustamante, Juanita

2013-12-01

Mitochondrial dysfunction has been implicated in many diseases, including diabetes. It is well known that oxygen free radical species are produced endogenously by mitochondria, and also nitric oxide (NO) by nitric oxide synthases (NOS) associated to mitochondrial membranes, in consequence these organelles constitute main targets for oxidative damage. The aim of this study was to analyze mitochondrial physiology and NO production in brain cortex mitochondria of streptozotocin (STZ) diabetic rats in an early stage of diabetes and the potential effect of L-arginine administration. The diabetic condition was characterized by a clear hyperglycaemic state with loose of body weight after 4 days of STZ injection. This hyperglycaemic state was associated with mitochondrial dysfunction that was evident by an impairment of the respiratory activity, increased production of superoxide anion and a clear mitochondrial depolarization. In addition, the alteration in mitochondrial physiology was associated with a significant decrease in both NO production and nitric oxide synthase type I (NOS I) expression associated to the mitochondrial membranes. An increased level of thiobarbituric acid-reactive substances (TBARS) in brain cortex homogenates from STZ-diabetic rats indicated the presence of lipid peroxidation. L-arginine treatment to diabetic rats did not change blood glucose levels but significantly ameliorated the oxidative stress evidenced by lower TBARS and a lower level of superoxide anion. This effect was paralleled by improvement of mitochondrial respiratory function and a partial mitochondrial repolarization.In addition, the administration of L-arginine to diabetic rats prevented the decrease in NO production and NOSI expression. These results could indicate that exogenously administered L-arginine may have beneficial effects on mitochondrial function, oxidative stress and NO production in brain cortex mitochondria of STZ-diabetic rats.

Changes in Male Rat Sexual Behavior and Brain Activity Revealed by Functional Magnetic Resonance Imaging in Response to Chronic Mild Stress.

PubMed

Chen, Guotao; Yang, Baibing; Chen, Jianhuai; Zhu, Leilei; Jiang, Hesong; Yu, Wen; Zang, Fengchao; Chen, Yun; Dai, Yutian

2018-02-01

Non-organic erectile dysfunction (noED) at functional imaging has been related to abnormal brain activity and requires animal models for further research on the associated molecular mechanisms. To develop a noED animal model based on chronic mild stress and investigate brain activity changes. We used 6 weeks of chronic mild stress to induce depression. The sucrose consumption test was used to assess the hedonic state. The apomorphine test and sexual behavior test were used to select male rats with ED. Rats with depression and ED were considered to have noED. Blood oxygen level-dependent-based resting-state functional magnetic resonance imaging (fMRI) studies were conducted on these rats, and the amplitude of low-frequency fluctuations and functional connectivity were analyzed to determine brain activity changes. The sexual behavior test and resting-state fMRI were used for outcome measures. The induction of depression was confirmed by the sucrose consumption test. A low intromission ratio and increased mount and intromission latencies were observed in male rats with depression. No erection was observed in male rats with depression during the apomorphine test. Male rats with depression and ED were considered to have noED. The possible central pathologic mechanism shown by fMRI involved the amygdaloid body, dorsal thalamus, hypothalamus, caudate-putamen, cingulate gyrus, insular cortex, visual cortex, sensory cortex, motor cortex, and cerebellum. Similar findings have been found in humans. The present study provided a novel noED rat model for further research on the central mechanism of noED. The present study developed a novel noED rat model and analyzed brain activity changes based at fMRI. The observed brain activity alterations might not extend to humans. The present study developed a novel noED rat model with brain activity alterations related to sexual arousal and erection, which will be helpful for further research involving the central mechanism of noED. Chen G, Yang B, Chen J, et al. Changes in Male Rat Sexual Behavior and Brain Activity Revealed by Functional Magnetic Resonance Imaging in Response to Chronic Mild Stress. J Sex Med 2018;15:136-147. Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Motor Cortex Excitability and BDNF Levels in Chronic Musculoskeletal Pain According to Structural Pathology

PubMed Central

Caumo, Wolnei; Deitos, Alícia; Carvalho, Sandra; Leite, Jorge; Carvalho, Fabiana; Dussán-Sarria, Jairo Alberto; Lopes Tarragó, Maria da Graça; Souza, Andressa; Torres, Iraci Lucena da Silva; Fregni, Felipe

2016-01-01

The central sensitization syndrome (CSS) encompasses disorders with overlapping symptoms in a structural pathology spectrum ranging from persistent nociception [e.g., osteoarthritis (OA)] to an absence of tissue injuries such as the one presented in fibromyalgia (FM) and myofascial pain syndrome (MPS). First, we hypothesized that these syndromes present differences in their cortical excitability parameters assessed by transcranial magnetic stimulation (TMS), namely motor evoked potential (MEP), cortical silent period (CSP), short intracortical inhibition (SICI) and short intracortical facilitation (SICF). Second, considering that the presence of tissue injury could be detected by serum neurotrophins, we hypothesized that the spectrum of structural pathology (i.e., from persistent nociception like in OA, to the absence of tissue injury like in FM and MPS), could be detected by differential efficiency of their descending pain inhibitory system, as assessed by the conditioned pain modulation (CPM) paradigm. Third, we explored whether brain-derived neurotrophic factor (BDNF) had an influence on the relationship between motor cortex excitability and structural pathology. This cross-sectional study pooled baseline data from three randomized clinical trials. We included females (n = 114), aged 19–65 years old with disability by chronic pain syndromes (CPS): FM (n = 19), MPS (n = 54), OA (n = 27) and healthy subjects (n = 14). We assessed the serum BDNF, the motor cortex excitability by parameters the TMS measures and the change on numerical pain scale [NPS (0–10)] during CPM-task. The adjusted mean (SD) on the SICI observed in the absence of tissue injury was 56.36% lower than with persistent nociceptive input [0.31(0.18) vs. 0.55 (0.32)], respectively. The BDNF was inversely correlated with the SICI and with the change on NPS (0–10)during CPM-task. These findings suggest greater disinhibition in the motor cortex and the descending pain inhibitory system in FM and MPS than in OA and healthy subjects. Likewise, the inter-hemispheric disinhibition as well as the dysfunction in the descending pain modulatory system is higher in chronic pain without tissue injury compared to a structural lesion. In addition, they suggest that a greater level of serum BDNF may be involved in the processes that mediate the disinhibition of motor cortex excitability, as well as the function of descending inhibitory pain modulation system, independently of the physiopathology mechanism of musculoskeletal pain syndromes. PMID:27471458

Chronic variable stress improves glucose tolerance in rats with sucrose-induced prediabetes

PubMed Central

Packard, Amy E. B.; Ghosal, Sriparna; Herman, James P.; Woods, Stephen C.; Ulrich-Lai, Yvonne M.

2014-01-01

The incidence of type-2 diabetes (T2D) and the burden it places on individuals, as well as society as a whole, compels research into the causes, factors and progression of this disease. Epidemiological studies suggest that chronic stress exposure may contribute to the development and progression of T2D in human patients. To address the interaction between chronic stress and the progression of T2D, we developed a dietary model of the prediabetic state in rats utilizing unlimited access to 30% sucrose solution (in addition to unlimited access to normal chow and water), which led to impaired glucose tolerance despite elevated insulin levels. We then investigated the effects of a chronic variable stress paradigm (CVS; twice daily exposure to an unpredictable stressor for 2 weeks) on metabolic outcomes in this prediabetic model. Chronic stress improved glucose tolerance in prediabetic rats following a glucose challenge. Importantly, pair-fed control groups revealed that the beneficial effect of chronic stress did not result from the decreased food intake or body weight gain that occurred during chronic stress. The present work suggests that chronic stress in rodents can ameliorate the progression of diet-induced prediabetic disease independent of chronic stress-induced decreases in food intake and body weight. PMID:25001967

Complete reorganization of the motor cortex of adult rats following long-term spinal cord injuries.

PubMed

Tandon, Shashank; Kambi, Niranjan; Mohammed, Hisham; Jain, Neeraj

2013-07-01

Understanding brain reorganization following long-term spinal cord injuries is important for optimizing recoveries based on residual function as well as developing brain-controlled assistive devices. Although it has been shown that the motor cortex undergoes partial reorganization within a few weeks after peripheral and spinal cord injuries, it is not known if the motor cortex of rats is capable of large-scale reorganization after longer recovery periods. Here we determined the organization of the rat (Rattus norvegicus) motor cortex at 5 or more months after chronic lesions of the spinal cord at cervical levels using intracortical microstimulation. The results show that, in the rats with the lesions, stimulation of neurons in the de-efferented forelimb motor cortex no longer evokes movements of the forelimb. Instead, movements of the body parts in the adjacent representations, namely the whiskers and neck were evoked. In addition, at many sites, movements of the ipsilateral forelimb were observed at threshold currents. The extent of representations of the eye, jaw and tongue movements was unaltered by the lesion. Thus, large-scale reorganization of the motor cortex leads to complete filling-in of the de-efferented cortex by neighboring representations following long-term partial spinal cord injuries at cervical levels in adult rats. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Platelet-Rich Fibrin Lysate Can Ameliorate Dysfunction of Chronically UVA-Irradiated Human Dermal Fibroblasts.

PubMed

Wirohadidjojo, Yohanes Widodo; Budiyanto, Arief; Soebono, Hardyanto

2016-09-01

To determine whether platelet-rich fibrin lysate (PRF-L) could restore the function of chronically ultraviolet-A (UVA)-irradiated human dermal fibroblasts (HDFs), we isolated and sub-cultured HDFs from six different human foreskins. HDFs were divided into two groups: those that received chronic UVA irradiation (total dosages of 10 J cm⁻²) and those that were not irradiated. We compared the proliferation rates, collagen deposition, and migration rates between the groups and between chronically UVA-irradiated HDFs in control and PRF-L-treated media. Our experiment showed that chronic UVA irradiation significantly decreased (p<0.05) the proliferation rates, migration rates, and collagen deposition of HDFs, compared to controls. Compared to control media, chronically UVA-irradiated HDFs in 50% PRF-L had significantly increased proliferation rates, migration rates, and collagen deposition (p<0.05), and the migration rates and collagen deposition of chronically UVA-irradiated HDFs in 50% PRF-L were equal to those of normal fibroblasts. Based on this experiment, we concluded that PRF-L is a good candidate material for treating UVA-induced photoaging of skin, although the best method for its clinical application remains to be determined.

Chronic cocaine disrupts mesocortical learning mechanisms

PubMed Central

Buchta, William C.; Riegel, Arthur C.

2016-01-01

The addictive power of drugs of abuse such as cocaine comes from their ability to hijack natural reward and plasticity mechanisms mediated by dopamine signaling in the brain. Reward learning involves burst firing of midbrain dopamine neurons in response to rewards and cues predictive of reward. The resulting release of dopamine in terminal regions is thought to act as a teaching signaling to areas such as the prefrontal cortex and striatum. In this review, we posit that a pool of extrasynaptic dopaminergic D1-like receptors activated in response to dopamine neuron burst firing serve to enable synaptic plasticity in the prefrontal cortex in response to rewards and their cues. We propose that disruptions in these mechanisms following chronic cocaine use contribute to addiction pathology, in part due to the unique architecture of the mesocortical pathway. By blocking dopamine reuptake in the cortex, cocaine elevates dopamine signaling at these extra-synaptic receptors, prolonging D1-receptor activation and the subsequent activation of intracellular signaling cascades, and thus inducing long-lasting maladaptive plasticity. These cellular adaptations may account for many of the changes in cortical function observed in drug addicts, including an enduring vulnerability to relapse. Therefore, understanding and targeting these neuroadaptations may provide cognitive benefits and help prevent relapse in human drug addicts. PMID:25704202

The Antiparkinsonian and Antidyskinetic Mechanisms of Mucuna pruriens in the MPTP-Treated Nonhuman Primate

PubMed Central

Lieu, Christopher A.; Venkiteswaran, Kala; Gilmour, Timothy P.; Rao, Anand N.; Petticoffer, Andrew C.; Gilbert, Erin V.; Deogaonkar, Milind; Manyam, Bala V.; Subramanian, Thyagarajan

2012-01-01

Chronic treatment with levodopa (LD) in Parkinson's disease (PD) can cause drug induced dyskinesias. Mucuna pruriens endocarp powder (MPEP) contains several compounds including natural LD and has been reported to not cause drug-induced dyskinesias. We evaluated the effects of Mucuna pruriens to determine if its underlying mechanistic actions are exclusively due to LD. We first compared MPEP with and without carbidopa (CD), and LD+CD in hemiparkinsonian (HP) monkeys. Each treatment ameliorated parkinsonism. We then compared the neuronal firing properties of the substantia nigra reticulata (SNR) and subthalamic nucleus (STN) in HP monkeys with MPEP+CD and LD+CD to evaluate basal ganglia circuitry alterations. Both treatments decreased SNR firing rate compared to HP state. However, LD+CD treatments significantly increased SNR bursting firing patterns that were not seen with MPEP+CD treatments. No significant changes were seen in STN firing properties. We then evaluated the effects of a water extract of MPEP. Oral MPWE ameliorated parkinsonism without causing drug-induced dyskinesias. The distinctive neurophysiological findings in the basal ganglia and the ability to ameliorate parkinsonism without causing dyskinesias strongly suggest that Mucuna pruriens acts through a novel mechanism that is different from that of LD. PMID:22997535

The Antiparkinsonian and Antidyskinetic Mechanisms of Mucuna pruriens in the MPTP-Treated Nonhuman Primate.

PubMed

Lieu, Christopher A; Venkiteswaran, Kala; Gilmour, Timothy P; Rao, Anand N; Petticoffer, Andrew C; Gilbert, Erin V; Deogaonkar, Milind; Manyam, Bala V; Subramanian, Thyagarajan

2012-01-01

Chronic treatment with levodopa (LD) in Parkinson's disease (PD) can cause drug induced dyskinesias. Mucuna pruriens endocarp powder (MPEP) contains several compounds including natural LD and has been reported to not cause drug-induced dyskinesias. We evaluated the effects of Mucuna pruriens to determine if its underlying mechanistic actions are exclusively due to LD. We first compared MPEP with and without carbidopa (CD), and LD+CD in hemiparkinsonian (HP) monkeys. Each treatment ameliorated parkinsonism. We then compared the neuronal firing properties of the substantia nigra reticulata (SNR) and subthalamic nucleus (STN) in HP monkeys with MPEP+CD and LD+CD to evaluate basal ganglia circuitry alterations. Both treatments decreased SNR firing rate compared to HP state. However, LD+CD treatments significantly increased SNR bursting firing patterns that were not seen with MPEP+CD treatments. No significant changes were seen in STN firing properties. We then evaluated the effects of a water extract of MPEP. Oral MPWE ameliorated parkinsonism without causing drug-induced dyskinesias. The distinctive neurophysiological findings in the basal ganglia and the ability to ameliorate parkinsonism without causing dyskinesias strongly suggest that Mucuna pruriens acts through a novel mechanism that is different from that of LD.

Histological Evaluation of a Chronically-implanted Electrocorticographic Electrode Grid in a Non-human Primate

PubMed Central

Degenhart, Alan D.; Eles, James; Dum, Richard; Mischel, Jessica L.; Smalianchuk, Ivan; Endler, Bridget; Ashmore, Robin C.; Tyler-Kabara, Elizabeth C.; Hatsopoulos, Nicholas G.; Wang, Wei; Batista, Aaron P.; Cui, X. Tracy

2016-01-01

Electrocorticography (ECoG), used as a neural recording modality for brain-machine interfaces (BMIs), potentially allows for field potentials to be recorded from the surface of the cerebral cortex for long durations without suffering the host-tissue reaction to the extent that it is common with intracortical microelectrodes. Though the stability of signals obtained from chronically-implanted ECoG electrodes has begun receiving attention, to date little work has characterized the effects of long-term implantation of ECoG electrodes on underlying cortical tissue. We implanted a high-density ECoG electrode grid subdurally over cortical motor areas of a Rhesus macaque for 666 days. Histological analysis revealed minimal damage to the cortex underneath the implant, though the grid itself was encapsulated in collagenous tissue. We observed macrophages and foreign body giant cells at the tissue-array interface, indicative of a stereotypical foreign body response. Despite this encapsulation, cortical modulation during reaching movements was observed more than 18 months post-implantation. These results suggest that ECoG may provide a means by which stable chronic cortical recordings can be obtained with comparatively little tissue damage, facilitating the development of clinically-viable brain-machine interface systems. PMID:27351722

Histological evaluation of a chronically-implanted electrocorticographic electrode grid in a non-human primate

NASA Astrophysics Data System (ADS)

Degenhart, Alan D.; Eles, James; Dum, Richard; Mischel, Jessica L.; Smalianchuk, Ivan; Endler, Bridget; Ashmore, Robin C.; Tyler-Kabara, Elizabeth C.; Hatsopoulos, Nicholas G.; Wang, Wei; Batista, Aaron P.; Cui, X. Tracy

2016-08-01

Objective. Electrocorticography (ECoG), used as a neural recording modality for brain-machine interfaces (BMIs), potentially allows for field potentials to be recorded from the surface of the cerebral cortex for long durations without suffering the host-tissue reaction to the extent that it is common with intracortical microelectrodes. Though the stability of signals obtained from chronically implanted ECoG electrodes has begun receiving attention, to date little work has characterized the effects of long-term implantation of ECoG electrodes on underlying cortical tissue. Approach. We implanted and recorded from a high-density ECoG electrode grid subdurally over cortical motor areas of a Rhesus macaque for 666 d. Main results. Histological analysis revealed minimal damage to the cortex underneath the implant, though the grid itself was encapsulated in collagenous tissue. We observed macrophages and foreign body giant cells at the tissue-array interface, indicative of a stereotypical foreign body response. Despite this encapsulation, cortical modulation during reaching movements was observed more than 18 months post-implantation. Significance. These results suggest that ECoG may provide a means by which stable chronic cortical recordings can be obtained with comparatively little tissue damage, facilitating the development of clinically viable BMI systems.

Intact skull chronic windows for mesoscopic wide-field imaging in awake mice

PubMed Central

Silasi, Gergely; Xiao, Dongsheng; Vanni, Matthieu P.; Chen, Andrew C. N.; Murphy, Timothy H.

2016-01-01

Background Craniotomy-based window implants are commonly used for microscopic imaging, in head-fixed rodents, however their field of view is typically small and incompatible with mesoscopic functional mapping of cortex. New Method We describe a reproducible and simple procedure for chronic through-bone wide-field imaging in awake head-fixed mice providing stable optical access for chronic imaging over large areas of the cortex for months. Results The preparation is produced by applying clear-drying dental cement to the intact mouse skull, followed by a glass coverslip to create a partially transparent imaging surface. Surgery time takes about 30 minutes. A single set-screw provides a stable means of attachment for mesoscale assessment without obscuring the cortical field of view. Comparison with Existing Methods We demonstrate the utility of this method by showing seed-pixel functional connectivity maps generated from spontaneous cortical activity of GCAMP6 signals in both awake and anesthetized mice. Conclusions We propose that the intact skull preparation described here may be used for most longitudinal studies that do not require micron scale resolution and where cortical neural or vascular signals are recorded with intrinsic sensors. PMID:27102043

Chronic, long-term social stress can cause decreased microtubule protein network activity and dynamics in cerebral cortex of male Wistar rats.

PubMed

Eskandari Sedighi, Ghazaleh; Riazi, Gholam Hossein; Vaez Mahdavi, Mohammad Reza; Cheraghi, Tayebe; Atarod, Deyhim; Rafiei, Shahrbanoo

2015-03-01

Social stress is viewed as a factor in the etiology of a variety of psychopathologies such as depression and anxiety. Animal models of social stress are well developed and widely used in studying clinical and physiological effects of stress. Stress is known to significantly affect learning and memory, and this effect strongly depends on the type of stress, its intensity, and duration. It has been demonstrated that chronic and acute stress conditions can change neuronal plasticity, characterized by retraction of apical dendrites, reduction in axonogenesis, and decreased neurogenesis. Various behavioral studies have also confirmed a decrease in learning and memory upon exposure of animals to long-term chronic stress. On the other hand, the close relationship between microtubule (MT) protein network and neuroplasticity controlling system suggests the possibility of MT protein alterations in high stressful conditions. In this work, we have studied the kinetics, activity, and dynamicity changes of MT proteins in the cerebral cortex of male Wistar rats that were subjected to social instability for 35 and 100 days. Our results indicate that MT protein network dynamicity and polymerization ability is decreased under long-term (100 days) social stress conditions.

Decoding of motor intentions from epidural ECoG recordings in severely paralyzed chronic stroke patients

NASA Astrophysics Data System (ADS)

Spüler, M.; Walter, A.; Ramos-Murguialday, A.; Naros, G.; Birbaumer, N.; Gharabaghi, A.; Rosenstiel, W.; Bogdan, M.

2014-12-01

Objective. Recently, there have been several approaches to utilize a brain-computer interface (BCI) for rehabilitation with stroke patients or as an assistive device for the paralyzed. In this study we investigated whether up to seven different hand movement intentions can be decoded from epidural electrocorticography (ECoG) in chronic stroke patients. Approach. In a screening session we recorded epidural ECoG data over the ipsilesional motor cortex from four chronic stroke patients who had no residual hand movement. Data was analyzed offline using a support vector machine (SVM) to decode different movement intentions. Main results. We showed that up to seven hand movement intentions can be decoded with an average accuracy of 61% (chance level 15.6%). When reducing the number of classes, average accuracies up to 88% can be achieved for decoding three different movement intentions. Significance. The findings suggest that ipsilesional epidural ECoG can be used as a viable control signal for BCI-driven neuroprosthesis. Although patients showed no sign of residual hand movement, brain activity at the ipsilesional motor cortex still shows enough intention-related activity to decode different movement intentions with sufficient accuracy.

Chronic pain causes a persistent anxiety state leading to increased ethanol intake in CD1 mice.

PubMed

González-Sepúlveda, Marta; Pozo, Oscar J; Marcos, Josep; Valverde, Olga

2016-02-01

Mood disorders and chronic pain are closely linked, but limited progress has been made in understanding the role of chronic and neuropathic pain in the aetiopathogenesis of depression. To explore the pathological mechanisms that mediate the association between pain and depressive-like behaviours, we studied the time-dependent effect of neuropathic pain on the development of anxiety-like and despair behaviours in CD1 mice. We analysed behavioural data, neuroinflammation reactions and changes in neurotransmitter (glutamate and serotonin) levels in the mouse prefrontal cortex. Sciatic-operated mice displayed long-lasting anxiety-like and despair behaviours, starting 5 and 20 days after partial sciatic nerve ligation, respectively. Glutamatergic neurotransmission and IL-1β cytokine expression were enhanced in the prefrontal cortex of mice with neuropathic pain. We found no change in serotonin metabolism, cytokine IL-6 or brain-derived neurotrophic factor levels. While sciatic-operated mice exposed to intermittent ethanol intake (20% v/v) using the drinking in the dark procedure consumed higher amounts of ethanol than sham-operated mice, thermal allodynia and despair behaviour were not attenuated by ethanol consumption. Our findings reveal an association between glutamatergic neurotransmission and pain-induced mood disorders, and indicate that moderate ethanol consumption does not relieve nociceptive and depressive behaviours associated with chronic pain in mice. © The Author(s) 2015.

Effects of the antipsychotic paliperidone on stress-induced changes in the endocannabinoid system in rat prefrontal cortex.

PubMed

MacDowell, Karina S; Sayd, Aline; García-Bueno, Borja; Caso, Javier R; Madrigal, José L M; Leza, Juan Carlos

2017-09-01

Objectives There is a need to explore novel mechanisms of action of existing/new antipsychotics. One potential candidate is the endocannabinoid system (ECS). The present study tried to elucidate the effects of the antipsychotic paliperidone on stress-induced ECS alterations. Methods Wister rats were submitted to acute/chronic restraint stress. Paliperidone (1 mg/kg) was given prior each stress session. Cannabinoid receptors and endocannabinoids (eCBs) synthesis and degradation enzymes were measured in prefrontal cortex (PFC) samples by RT-PCR and Western Blot. Results In the PFC of rats exposed to acute stress, paliperidone increased CB1 receptor (CB1R) expression. Furthermore, paliperidone increased the expression of the eCB synthesis enzymes N-acylphosphatidylethanolamine- hydrolysing phospholipase D and DAGLα, and blocked the stress-induced increased expression of the degrading enzyme fatty acid amide hydrolase. In chronic conditions, paliperidone prevented the chronic stress-induced down-regulation of CB1R, normalised DAGLα expression and reverted stress-induced down-regulation of the 2-AG degrading enzyme monoacylglycerol lipase. ECS was analysed also in periphery. Acute stress decreased DAGLα expression, an effect prevented by paliperidone. Contrarily, chronic stress increased DAGLα and this effect was potentiated by paliperidone. Conclusions The results obtained described a preventive effect of paliperidone on stress-induced alterations in ECS. Considering the diverse alterations on ECS described in psychotic disease, targeting ECS emerges as a new therapeutic possibility.

Role of the primary motor cortex in the maintenance and treatment of pain in fibromyalgia.

PubMed

Castillo Saavedra, Laura; Mendonca, Mariana; Fregni, Felipe

2014-09-01

Fibromyalgia is a highly prevalent, debilitating disease, characterized by chronic widespread pain. The mechanisms underlying pain are not completely understood, but it is believed to be associated with important neuroplastic changes in pain-related neural circuits. Although the involvement of the pain matrix in fibromyalgia is well established, another area that has been found to play a role in the maintenance and treatment of chronic pain is the primary motor cortex (M1). Maladaptive plasticity of M1 is a common finding in patients with chronic pain and many studies in animal models and in human subjects have shown that modulation of the activity of this cortical area induces significant analgesic effects. Furthermore, studies in other chronic pain syndromes have found alterations in baseline characteristics of M1, including an increase in cortical excitability and an abnormally enhanced response to incoming sensory stimuli. Given these findings, we hypothesize that M1 is a major modulator of pain in fibromyalgia and therefore its baseline activity reflects this strong feedback between M1 and pain-related neural areas. However, the feedback loop between M1 and the pain matrix is not enough to decrease pain in fibromyalgia per se, thus increasing its modulatory effect by engaging this network through different behavioral and modulatory techniques is a potentially beneficial treatment for pain in fibromyalgia. Copyright © 2014 Elsevier Ltd. All rights reserved.

Fluoxetine regulates mTOR signalling in a region-dependent manner in depression-like mice

PubMed Central

Liu, Xiao-Long; Luo, Liu; Mu, Rong-Hao; Liu, Bin-Bin; Geng, Di; Liu, Qing; Yi, Li-Tao

2015-01-01

Previous studies have demonstrated that the mammalian target of rapamycin (mTOR) signaling pathway has an important role in ketamine-induced, rapid antidepressant effects despite the acute administration of fluoxetine not affecting mTOR phosphorylation in the brain. However, the effects of long-term fluoxetine treatment on mTOR modulation have not been assessed to date. In the present study, we examined whether fluoxetine, a type of commonly used antidepressant agent, alters mTOR signaling following chronic administration in different brain regions, including the frontal cortex, hippocampus, amygdala and hypothalamus. We also investigated whether fluoxetine enhanced synaptic protein levels in these regions via the activation of the mTOR signaling pathway and its downstream regulators, p70S6K and 4E-BP-1. The results indicated that chronic fluoxetine treatment attenuated the chronic, unpredictable, mild stress (CUMS)-induced mTOR phosphorylation reduction in the hippocampus and amygdala of mice but not in the frontal cortex or the hypothalamus. Moreover, the CUMS-decreased PSD-95 and synapsin I levels were reversed by fluoxetine, and these effects were blocked by rapamycin only in the hippocampus. In conclusion, our findings suggest that chronic treatment with fluoxetine can induce synaptic protein expression by activating the mTOR signaling pathway in a region-dependent manner and mainly in the hippocampus. PMID:26522512

Educators' emotion regulation strategies and their physiological indicators of chronic stress over 1 year.

PubMed

Katz, Deirdre A; Harris, Alexis; Abenavoli, Rachel; Greenberg, Mark T; Jennings, Patricia A

2018-04-01

Studies show teaching is a highly stressful profession and that chronic work stress is associated with adverse health outcomes. This study analysed physiological markers of stress and self-reported emotion regulation strategies in a group of middle school teachers over 1 year. Chronic physiological stress was assessed with diurnal cortisol measures at three time points over 1 year (fall, spring, fall). The aim of this longitudinal study was to investigate the changes in educators' physiological level of stress. Results indicate that compared to those in the fall, cortisol awakening responses were blunted in the spring. Further, this effect was ameliorated by the summer break. Additionally, self-reported use of the emotion regulation strategy reappraisal buffered the observed blunting that occurred in the spring. Copyright © 2017 John Wiley & Sons, Ltd.

Sarcopenia in Patients with Chronic Liver Disease: Can It Be Altered by Diet and Exercise?

PubMed

Kappus, Matthew R; Mendoza, Mardeli Saire; Nguyen, Douglas; Medici, Valentina; McClave, Stephen A

2016-08-01

Sarcopenia, a loss of muscle mass, is being increasingly recognized to have a deleterious effect on outcomes in patients with chronic liver disease. Factors related to diet and the inflammatory nature of chronic liver disease contribute to the occurrence of sarcopenia in these patients. Sarcopenia adversely influences quality of life, performance, morbidity, success of transplantation, and even mortality. Specific deficiencies in macronutrients (protein, polyunsaturated fatty acids) and micronutrients (vitamins C, D, and E, carotenoids, and selenium) have been linked to sarcopenia. Lessons learned from nutritional therapy in geriatric patient populations may provide strategies to manage sarcopenia in patients with liver disease. Combining diet modification and nutrient supplementation with an organized program of exercise may help ameliorate or even reverse the effects of sarcopenia on an already complex disease process.

Effect of chronic usage of tramadol on motor cerebral cortex and testicular tissues of adult male albino rats and the effect of its withdrawal: histological, immunohistochemical and biochemical study.

PubMed

Ghoneim, Fatma M; Khalaf, Hanaa A; Elsamanoudy, Ayman Z; Helaly, Ahmed N

2014-01-01

This study was designed to demonstrate the histopathological and biochemical changes in rat cerebral cortex and testicles due to chronic usage of tramadol and the effect of withdrawal. Thirty adult male rats weighing 180-200 gm were classified into three groups; group I (control group) group II (10 rats received 50 mg/kg/day of tramadol intraperitoneally for 4 weeks) and group III (10 rats received the same dose as group II then kept 4 weeks later to study the effect of withdrawal). Histological and immunohistochemical examination of cerebral cortex and testicular specimens for Bax (apoptotic marker) were carried out. Testicular specimens were examined by electron microscopy. RT-PCR after RNA extraction from both specimens was done for the genes of some antioxidant enzymes .Also, malondialdehyde (MDA) was measured colourimetrically in tissues homogenizate. The results of this study demonstrated histological changes in testicular and brain tissues in group II compared to group I with increased apoptotic index proved by increased Bax expression. Moreover in this group increased MDA level with decreased gene expression of the antioxidant enzymes revealed oxidative stress. Group III showed signs of improvement but not returned completely normal. It could be concluded that administration of tramadol have histological abnormalities on both cerebral cortex and testicular tissues associated with oxidative stress in these organs. Also, there is increased apoptosis in both organs which regresses with withdrawal. These findings may provide a possible explanation for delayed fertility and psychological changes associated with tramadol abuse.

The lateral prefrontal cortex mediates the hyperalgesic effects of negative cognitions in chronic pain patients.

PubMed

Loggia, Marco L; Berna, Chantal; Kim, Jieun; Cahalan, Christine M; Martel, Marc-Olivier; Gollub, Randy L; Wasan, Ajay D; Napadow, Vitaly; Edwards, Robert R

2015-08-01

Although high levels of negative affect and cognitions have been associated with greater pain sensitivity in chronic pain conditions, the neural mechanisms mediating the hyperalgesic effect of psychological factors in patients with pain disorders are largely unknown. In this cross-sectional study, we hypothesized that 1) catastrophizing modulates brain responses to pain anticipation and 2) anticipatory brain activity mediates the hyperalgesic effect of different levels of catastrophizing in fibromyalgia (FM) patients. Using functional magnetic resonance imaging, we scanned the brains of 31 FM patients exposed to visual cues anticipating the onset of moderately intense deep-tissue pain stimuli. Our results indicated the existence of a negative association between catastrophizing and pain-anticipatory brain activity, including in the right lateral prefrontal cortex. A bootstrapped mediation analysis revealed that pain-anticipatory activity in the lateral prefrontal cortex mediates the association between catastrophizing and pain sensitivity. These findings highlight the role of the lateral prefrontal cortex in the pathophysiology of FM-related hyperalgesia and suggest that deficits in the recruitment of pain-inhibitory brain circuitry during pain-anticipatory periods may play an important contributory role in the association between various degrees of widespread hyperalgesia in FM and levels of catastrophizing, a well-validated measure of negative cognitions and psychological distress. This article highlights the presence of alterations in pain-anticipatory brain activity in FM. These findings provide the rationale for the development of psychological or neurofeedback-based techniques aimed at modifying patients' negative affect and cognitions toward pain. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

Social isolation stress and chronic glutathione deficiency have a common effect on the glutamine-to-glutamate ratio and myo-inositol concentration in the mouse frontal cortex.

PubMed

Corcoba, Alberto; Gruetter, Rolf; Do, Kim Q; Duarte, João M N

2017-09-01

Environmental stress can interact with genetic predisposition to increase the risk of developing psychopathology. In this work, we tested the hypothesis that social isolation stress interacts with impaired glutathione synthesis and have cumulative effects on the neurochemical profile of the frontal cortex. A mouse model with chronic glutathione deficit induced by knockout (-/-) of the glutamate-cysteine ligase modulatory subunit (Gclm) was exposed to social isolation stress from weaning to post-natal day 65. Using magnetic resonance methods at high-field (14.1 T), we analysed the neurochemical profile in the frontal cortex, brain size and ventricular volume of adult animals. Glutathione deficit was accompanied by elevated concentrations of N-acetylaspartate, alanine, and glutamine, as well as the ratio of glutamine-to-glutamate (Gln/Glu), and by a reduction in levels of myo-inositol and choline-containing compounds in the frontal cortex of -/- animals with respect to wild-type littermates. Although there was no significant interaction between social isolation stress and glutathione deficiency, mice reared in isolation displayed lower myo-inositol concentration (-8.4%, p < 0.05) and larger Gln/Glu (+7.6%, p < 0.05), relative to those in group housing. Furthermore, glutathione deficiency caused a reduction in whole brain volume and enlargement of ventricles, but social isolation had no effect on these parameters. We conclude that social isolation caused neurochemical alterations that may add to those associated to impaired glutathione synthesis. © 2017 International Society for Neurochemistry.

Evidence for a modulatory effect of sulbutiamine on glutamatergic and dopaminergic cortical transmissions in the rat brain.

PubMed

Trovero, F; Gobbi, M; Weil-Fuggaza, J; Besson, M J; Brochet, D; Pirot, S

2000-09-29

Chronic treatment of rats by sulbutiamine induced no change in density of N-methyl-D-aspartate (NMDA) and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in the cingular cortex, but a significant decrease of the kainate binding sites, as measured by quantitative autoradiography. In the same treated animals, an increase of D1 dopaminergic (DA) binding sites was measured both in the prefrontal and the cingular cortex, while no modification of the D2 binding sites was detected. Furthermore, an acute sulbutiamine administration induced a decrease of kainate binding sites but no change of the density of D1 and D2 DA receptors. Acute sulbutiamine injection led to a decrease of the DA levels in the prefrontal cortex and 3,4-dihydroxyphenylacetic acid levels in both the cingular and the prefrontal cortex. These observations are discussed in terms of a modulatory effect of sulbutiamine on both dopaminergic and glutamatergic cortical transmissions.

A key role of the prefrontal cortex in the maintenance of chronic tinnitus: An fMRI study using a Stroop task.

PubMed

Araneda, Rodrigo; Renier, Laurent; Dricot, Laurence; Decat, Monique; Ebner-Karestinos, Daniela; Deggouj, Naïma; De Volder, Anne G

2018-01-01

Since we recently showed in behavioural tasks that the top-down cognitive control was specifically altered in tinnitus sufferers, here we wanted to establish the link between this impaired executive function and brain alterations in the frontal cortex in tinnitus patients. Using functional magnetic resonance imaging (fMRI), we monitored the brain activity changes in sixteen tinnitus patients (TP) and their control subjects (CS) while they were performing a spatial Stroop task, both in audition and vision. We observed that TP differed from CS in their functional recruitment of the dorsolateral prefrontal cortex (dlPFC, BA46), the cingulate gyrus and the ventromedial prefrontal cortex (vmPFC, BA10). This recruitment was higher during interference conditions in tinnitus participants than in controls, whatever the sensory modality. Furthermore, the brain activity level in the right dlPFC and vmPFC correlated with the performance in the Stroop task in TP. Due to the direct link between poor executive functions and prefrontal cortex alterations in TP, we postulate that a lack of inhibitory modulation following an impaired top-down cognitive control may maintain tinnitus by hampering habituation mechanisms. This deficit in executive functions caused by prefrontal cortex alterations would be a key-factor in the generation and persistence of tinnitus.

Walnut phenolic extract inhibits nuclear factor kappaB signaling in intestinal epithelial cells, and ameliorates experimental colitis and colitis-associated colon cancer in mice.

PubMed

Koh, Seong-Joon; Choi, Youn-I; Kim, Yuri; Kim, Yoo-Sun; Choi, Sang Woon; Kim, Ji Won; Kim, Byeong Gwan; Lee, Kook Lae

2018-05-09

Walnuts (Juglans regia) are known to have anti-cancer and immunomodulatory effects. However, little information is available on the effects of walnut phenolic extract (WPE) on intestinal inflammation and colitis-associated colon cancer. COLO205 cells were pretreated with WPE and then stimulated with tumor necrosis factor (TNF)-α. In the acute colitis model, wild type mice (C57BL/6) were administered 4% dextran sulfate sodium (DSS) for 5 days. In the chronic colitis model, interleukin (IL)-10 -/- mice were administered with either the vehicle or WPE (20 mg/kg) by oral gavage daily for 2 weeks. In an inflammation-associated tumor model, wild type mice were administered a single intraperitoneal injection of azoxymethane followed by three cycles of 2% DSS for 5 days and 2 weeks of free water consumption. WPE significantly inhibited IL-8 and IL-1α expression in COLO205 cells. WPE attenuated both the TNF-α-induced IκB phosphorylation/degradation and NF-κB DNA binding activity. The administration of oral WPE significantly reduced the severity of colitis in both acute and chronic colitis models, including the IL-10 -/- mice. In immunohistochemical staining, WPE attenuated NF-κB signaling in the colons of both colitis models. Finally, WPE also significantly reduced tumor development in a murine model of colitis-associated colon cancer (CAC). WPE ameliorates acute and chronic colitis and CAC in mice, suggesting that WPE may have potentials for the treatment of inflammatory bowel disease.

Early application of Met-RANTES ameliorates chronic allograft nephropathy.

PubMed

Song, Erwei; Zou, Hequn; Yao, Yousheng; Proudfoot, Amanda; Antus, Balazs; Liu, Shanying; Jens, Lutz; Heemann, Uwe

2002-02-01

Initial insults to kidney allografts, characterized by infiltration of mononuclear inflammatory cells, contribute to chronic allograft nephropathy. Chemokines such as RANTES (regulated upon activation, normal T cell expressed) are thought to be responsible for the recruitment and activation of infiltrating cells. The present study investigated whether early application of Met-RANTES, a chemokine receptor antagonist that blocks the effects of RANTES, can protect renal allografts from long-term deterioration. Fisher (F344) rat kidneys were orthotopically transplanted into Lewis recipients and treated with cyclosporine A (1.5 mg/kg/day) for the first 10 days following transplantation, together with either Met-RANTES at 40 microg/day, 200 microg/day or vehicle for the first 7 days. Animals were harvested at 2 and 28 weeks after transplantation for histologic, immunohistologic and molecular analysis. Met-RANTES treatment reduced the infiltration of lymphocytes and macrophages in allografts at 2 weeks after transplantation, accompanied by decreased mRNA expression of interleukin (IL)-2, IL-1beta, tumor necrosis factor-alpha (TNF-alpha) and RANTES. At post-transplantation week 28, Met-RANTES treatment at high and low doses reduced urinary protein excretion and significantly ameliorated glomerulosclerosis, interstitial fibrosis, tubular atrophy, intimal proliferation of graft arteries and mononuclear cell infiltration. However, creatinine clearance was not influenced by Met-RANTES. Furthermore, Met-RANTES suppressed the mRNA expression of transforming growth factor-beta (TGF-beta) and platelet-derived growth factor-B (PDGF-B). Blockade of chemokine receptors by Met-RANTES diminishes early infiltration and activation of mononuclear cells in the grafts, and thus reduces the pace of chronic allograft nephropathy.

Can Ocimum basilicum relieve chronic unpredictable mild stress-induced depression in mice?

PubMed

Ayuob, Nasra Naeim; Firgany, Alaa El-Din L; El-Mansy, Ahmed A; Ali, Soad

2017-10-01

Depression is one of the important world-wide health problems. This study aimed to assess the ameliorative effect of Ocimum basilicum (OB) essential oil on the behavioral, biochemical and histopathological changes resulted from exposure to chronic unpredictable mild stress (CUMS). It also aimed to investigate the underlying mechanism in an animal model of depression. Forty male Swiss albino mice were divided into four groups (n=10): control, CUMS (exposed to CUMS for 4weeks), CUMS plus fluoxetine, and CUMS plus OB. At the end of the experiment, behavioral changes, serum corticosterone level, protein and gene expressions of brain derived neurotropic factor (BDNF) and glucocorticoid receptors (GR) in the hippocampus was all assessed. Immunoexpression of surface makers of glial fibrillary acidic protein (GFAP), Ki67, Caspase-3, BDNF and GR in the hippocampus were estimated. Data were analyzed by using the statistical package for the social sciences (SPSS). OB alleviated both behavioral and biochemical changes recorded in mice after exposure to CUMS. It also reduced neuronal atrophy observed in the hippocampal region III cornu ammonis (CA3) and dentate gyrus and restored back astrocyte number. OB decreased apoptosis in both neurons and glial cells and increased neurogenesis in the dentate gyrus in a pattern comparable to that of fluoxetine. Increased BDNF and GR gene and protein expressions seems to be behind the antidepressant-like effect of OB. Ocimum basilicum ameliorates the changes induced after exposure to the chronic stress. Assessing Ocimum basilicum efficacy on human as antidepressant is recommended in further studies. Copyright © 2017. Published by Elsevier Inc.

Effects of preventive versus "on-demand" nutritional support on paid labour productivity, physical exercise and performance status during PEG-interferon-containing treatment for hepatitis C.

PubMed

Huisman, Ellen J; van Meer, Suzanne; van Hoek, Bart; van Soest, Hanneke; van Nieuwkerk, Karin M J; Arends, Joop E; Siersema, Peter D; van Erpecum, Karel J

2016-04-01

Deterioration of nutritional status during PEG-interferon containing therapy for chronic hepatitis C can be ameliorated by preventive nutritional support. We aimed to explore whether such support also affects paid labour productivity, physical exercise and performance status. In this prospective randomized controlled trial (J Hepatol 2012;57:1069-75), 53 patients with chronic hepatitis C had been allocated to "on demand" support (n=26: nutritional intervention if weight loss>5%) or preventive support (n=27: regular dietary advice plus energy- and protein-rich evening snack) during PEG-interferon-containing therapy. Paid labour productivity, physical exercise and performance status were evaluated at baseline, after 24 and (if applicable) after 48 weeks of treatment. At baseline, 46% of patients performed paid labour and 62% performed some kind of physical exercise. Furthermore, most patients were able to carry out normal activity with only minor symptoms of disease (mean Karnofsky performance score: 94). Decreases of paid labour productivity (-21% vs. -70%, P=0.003), physical exercise activity (-43% vs. -87%, P=0.005) and Karnofsky performance scores (-12% vs. -24%, P<0.001) were less in the preventive than in "on demand" group after 24 weeks of treatment. Effects of preventive nutritional support were even more pronounced after 48 weeks. Preventive nutritional support markedly ameliorates decreases of paid labour productivity, physical exercise and performance status during PEG-interferon-containing treatment for chronic hepatitis C. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Too much of a good thing: blocking noradrenergic facilitation in medial prefrontal cortex prevents the detrimental effects of chronic stress on cognition.

PubMed

Jett, Julianne D; Morilak, David A

2013-03-01

Cognitive impairments associated with dysfunction of the medial prefrontal cortex (mPFC) are prominent in stress-related psychiatric disorders. We have shown that enhancing noradrenergic tone acutely in the rat mPFC facilitated extra-dimensional (ED) set-shifting on the attentional set-shifting test (AST), whereas chronic unpredictable stress (CUS) impaired ED. In this study, we tested the hypothesis that the acute facilitatory effect of norepinephrine (NE) in mPFC becomes detrimental when activated repeatedly during CUS. Using microdialysis, we showed that the release of NE evoked in mPFC by acute stress was unchanged at the end of CUS treatment. Thus, to then determine if repeated elicitation of this NE activity in mPFC during CUS may have contributed to the ED deficit, we infused a cocktail of α(1)-, β(1)-, and β(2)-adrenergic receptor antagonists into the mPFC prior to each CUS session, then tested animals drug free on the AST. Antagonist treatment prevented the CUS-induced ED deficit, suggesting that NE signaling during CUS compromised mPFC function. We confirmed that this was not attributable to sensitization of adrenergic receptor function following chronic antagonist treatment, by administering an additional microinjection into the mPFC immediately prior to ED testing. Acute antagonist treatment did not reverse the beneficial effects of chronic drug treatment during CUS, nor have any effect on baseline ED performance in chronic vehicle controls. Thus, we conclude that blockade of noradrenergic receptors in mPFC protected against the detrimental cognitive effects of CUS, and that repeated elicitation of noradrenergic facilitatory activity is one mechanism by which chronic stress may promote mPFC cognitive dysfunction.

Betaine prevents homocysteine-induced memory impairment via matrix metalloproteinase-9 in the frontal cortex.

PubMed

Kunisawa, K; Nakashima, N; Nagao, M; Nomura, T; Kinoshita, S; Hiramatsu, M

2015-10-01

Betaine plays important roles that include acting as a methyl donor and converting homocysteine (Hcy) to methionine. Elevated plasma Hcy levels are known as hyperhomocysteinemia (HHcy) and contribute to impairments of learning and memory. Although it is commonly known that betaine plays an important role in Hcy metabolism, the effects of betaine on Hcy-induced memory impairment have not been investigated. Previously, we demonstrated the beneficial effects of betaine on acute stress and lipopolysaccharide-induced memory impairment. In the present study, we investigated whether betaine ameliorates Hcy-induced memory impairment and the underlying mechanisms of this putative effect. Mice were treated with Hcy (0.162mg/kg, s.c.) twice a day for nine days, and betaine (25mg/kg, s.c.) was administered 30min before the Hcy injections. The memory functions were evaluated using a spontaneous alternation performance test (Y-maze) at seven days and a step-down type passive avoidance test (SD) at nine and ten days after Hcy injection. We found that betaine suppressed the memory impairment induced by repeated Hcy injections. However, the blood concentrations of Hcy were significantly increased in the Hcy-treated mice immediately after the passive avoidance test, and betaine did not prevent this increase. Furthermore, Hcy induces redox stress in part by activating matrix metalloproteinase-9 (MMP-9), which leads to BBB dysfunction. Therefore, we tested whether betaine affected MMP-9 activity. Interestingly, treatment with betaine significantly inhibited Hcy-induced MMP-9 activity in the frontal cortex but not in the hippocampus after acute Hcy injection. These results suggest that the changes in MMP-9 activity after betaine treatment might have been partially responsible for the amelioration of the memory deficits and that MMP-9 might be a candidate therapeutic target for HHcy. Copyright © 2015 Elsevier B.V. All rights reserved.

Neck Collar with Mild Jugular Vein Compression Ameliorates Brain Activation Changes during a Working Memory Task after a Season of High School Football.

PubMed

Yuan, Weihong; Leach, James; Maloney, Thomas; Altaye, Mekibib; Smith, David; Gubanich, Paul J; Barber Foss, Kim D; Thomas, Staci; DiCesare, Christopher A; Kiefer, Adam W; Myer, Gregory D

2017-08-15

Emerging evidence indicates that repetitive head impacts, even at a sub-concussive level, may result in exacerbated or prolonged neurological deficits in athletes. This study aimed to: 1) quantify the effect of repetitive head impacts on the alteration of neuronal activity based on functional magnetic resonance imaging (fMRI) of working memory after a high school football season; and 2) determine whether a neck collar that applies mild jugular vein compression designed to reduce brain energy absorption in head impact through "slosh" mitigation can ameliorate the altered fMRI activation during a working memory task. Participants were recruited from local high school football teams with 27 and 25 athletes assigned to the non-collar and collar group, respectively. A standard N-Back task was used to engage working memory in the fMRI at both pre- and post-season. The two study groups experienced similar head impact frequency and magnitude during the season (all p > 0.05). fMRI blood oxygen level dependent (BOLD) signal response (a reflection of the neuronal activity level) during the working memory task increased significantly from pre- to post-season in the non-collar group (corrected p < 0.05), but not in the collar group. Areas displaying less activation change in the collar group (corrected p < 0.05) included the precuneus, inferior parietal cortex, and dorsal lateral prefrontal cortex. Additionally, BOLD response in the non-collar group increased significantly in direct association with the total number of impacts and total g-force (p < 0.05). Our data provide initial neuroimaging evidence for the effect of repetitive head impacts on the working memory related brain activity, as well as a potential protective effect that resulted from the use of the purported brain slosh reducing neck collar in contact sports.

A novel synthetic phosphodiesterase 5 inhibitor, KJH-1002, ameliorates scopolamine-induced cognitive impairments in mice by activating the cGMP/CREB signaling pathway and attenuating oxidative damage.

PubMed

Zhang, Lijun; Seo, Jae Hong; Li, Huan; Nam, Ghilsoo; Yang, Hyun Ok

2018-05-30

Inhibition of PDE5 has been demonstrated to improve synaptic plasticity and memory via enhancing of cGMP expression, thus activating the cGMP/CREB signaling pathway. This study aimed to investigate the ameliorating effect of PDE5 inhibitor on scopolamine-induced cognitive dysfunction using memory-related behavioral tests and biochemical assays. After the mice were pretreated with PDE5 inhibitor, amnesia was induced by scopolamine administration. The learning and memory abilities of mice were tested using the Morris water maze test, the Y-maze test, the passive avoidance test and the novel object recognition test in sequence. Expression of memory-related bio-molecules and oxidative stress parameters in brain tissue were measured using western blot and spectrophotometry, respectively. KJH-1002, a novel inhibitor of phosphodiesterase 5 (PDE5), was synthesized (IC 50 of 0.059 ±0.04 nmol·L -1 ), and it markedly improved the memory performance impaired by scopolamine in the behavioral tests, indicating a restoration of cognitive function in the mice. Moreover, KJH-1002 increased the cGMP level in the cortex, the scopolamine-reduced expression of phosphorylated cAMP response element binding protein (CREB), extracellular-regulated kinase 1/2 (ERK 1/2), protein kinase B (Akt) and brain-derived neurotrophic factor (BDNF) in the cortex and hippocampus were reversed by KJH-1002 treatment. In addition, KJH-1002 administration increased the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR), and decreased the level of malondialdehyde (MDA). KJH-1002 restored cognitive function in scopolamine-induced amnesia mice by activating the cGMP/CREB signaling pathway and attenuating oxidative stress. The beneficial effect of KJH-1002 on cognition suggests its potential as a therapeutic candidate for Alzheimer's disease. This article is protected by copyright. All rights reserved.

A Vegetable, Launaea taraxacifolia, Mitigated Mercuric Chloride Alteration of the Microanatomy of Rat Brain.

PubMed

Owoeye, Olatunde; Arinola, Ganiyu O

2017-11-02

Mercuric chloride is an environmental pollutant that affects the nervous systems of mammals. Oxidative damage is one of the mechanisms of its toxicity, and antioxidants should mitigate this effect. A vegetable with antioxidant activity is Launaea taraxacifolia, whose ethanolic extract (EELT) was investigated in this experiment to determine its effect against mercuric chloride (MC) intoxication in rat brain. Thirty male Wistar rats were randomly assigned into five groups (n = 6) as follows: control; propylene glycol; EELT (400 mg/kg bwt) for 19 days; MC (HgCl 2 ) (4 mg/bwt) for 5 days from day 15 of the experiment; EELT+ MC, EELT (400 mg/kg bwt) for 14 days + MC (4 mg/bwt) for 5 days from day 15 of the experiment. All treatments were administered orally by gastric gavage. Behavioral tests were conducted on the 20th day, and rats were euthanized the same day. Blood and brain tissue were examined with regard to microanatomical parameters. Data were analyzed using analysis of variance with statistical significance set at p < .05. MC induced significant (19%) reduction of thrombocytes, which was ameliorated by 57% (p < .05) by pretreatment with EELT when compared with the MC group. Behavioral results showed that MC elicited significant reduction in transitions, rearings, forelimb grip strength, and latency of geotaxis. Histologically, MC induced alterations in the microanatomy of cerebral cortex, dentate gyrus, cornu ammonis 3, and cerebellum of rats. Treatment with EELT prior to MC administration significantly reduced the effect of MC on the hematological, behavioral, and ameliorated histological alterations of the brain. These findings may be attributed partially to the antioxidant property of EELT, which demonstrated protective effects against MC-induced behavioral parameters and alteration of microanatomy of rats' cerebral cortex, hippocampus, and cerebellum. In conclusion, EELT may be a valuable agent for further investigation in the prevention of acute neuropathy caused by inorganic mercury intoxication.

Neural Basis for the Ability of Atypical Antipsychotic Drugs to Improve Cognition in Schizophrenia

PubMed Central

Sumiyoshi, Tomiki; Higuchi, Yuko; Uehara, Takashi

2013-01-01

Cognitive impairments are considered to largely affect functional outcome in patients with schizophrenia, other psychotic illnesses, or mood disorders. Specifically, there is much attention to the role of psychotropic compounds acting on serotonin (5-HT) receptors in ameliorating cognitive deficits of schizophrenia. It is noteworthy that atypical antipsychotic drugs (AAPDs), e.g., clozapine, melperone, risperidone, olanzapine, quetiapine, aripiprazole, perospirone, blonanserin, and lurasidone, have variable affinities for these receptors. Among the 5-HT receptor subtypes, the 5-HT1A receptor is attracting particular interests as a potential target for enhancing cognition, based on preclinical and clinical evidence. The neural network underlying the ability of 5-HT1A agonists to treat cognitive impairments of schizophrenia likely includes dopamine, glutamate, and gamma-aminobutyric acid neurons. A novel strategy for cognitive enhancement in psychosis may be benefited by focusing on energy metabolism in the brain. In this context, lactate plays a major role, and has been shown to protect neurons against oxidative and other stressors. In particular, our data indicate chronic treatment with tandospirone, a partial 5-HT1A agonist, recover stress-induced lactate production in the prefrontal cortex of a rat model of schizophrenia. Recent advances of electrophysiological measures, e.g., event-related potentials, and their imaging have provided insights into facilitative effects on cognition of some AAPDs acting directly or indirectly on 5-HT1A receptors. These findings are expected to promote the development of novel therapeutics for the improvement of functional outcome in people with schizophrenia. PMID:24137114

Peripubertal Stress With Social Support Promotes Resilience in the Face of Aging

PubMed Central

Morrison, Kathleen E.; Narasimhan, Sneha; Fein, Ethan

2016-01-01

The peripubertal period of development is a sensitive window, during which adverse experiences can increase the risk for presentation of cognitive and affective dysfunction throughout the lifespan, especially in women. However, such experiences in the context of a supportive social environment can actually ameliorate this risk, suggesting that resilience can be programmed in early life. Affective disorders and cognitive deficits commonly emerge during aging, with many women reporting increased difficulty with prefrontal cortex (PFC)-dependent executive functions. We have developed a mouse model to examine the interaction between peripubertal experience and age-related changes in cognition and stress regulation. Female mice were exposed to peripubertal chronic stress, during which they were either individually housed or housed with social interaction. One year after this stress experience, mice were examined in tasks to access their cognitive ability and flexibility in stress reactive measures. In a test of spatial memory acquisition and reversal learning where aged females normally display a decreased performance, the females that had experienced stress with social interaction a year earlier showed improved performance in reversal learning, a measure of cognitive flexibility. Because peripuberty is a time of major PFC maturation, we performed transcriptomic and biochemical analysis of the aged PFC, in which long-term changes in microRNA expression and in myelin proteins were found. These data suggest that stress in the context of social support experienced over the pubertal window can promote epigenetic reprogramming in the brain to increase the resilience to age-related cognitive decline in females. PMID:26943365

Brain neuroplastic changes accompany anxiety and memory deficits in a model of complex regional pain syndrome.

PubMed

Tajerian, Maral; Leu, David; Zou, Yani; Sahbaie, Peyman; Li, Wenwu; Khan, Hamda; Hsu, Vivian; Kingery, Wade; Huang, Ting Ting; Becerra, Lino; Clark, J David

2014-10-01

Complex regional pain syndrome (CRPS) is a painful condition with approximately 50,000 annual new cases in the United States. It is a major cause of work-related disability, chronic pain after limb fractures, and persistent pain after extremity surgery. Additionally, CRPS patients often experience cognitive changes, anxiety, and depression. The supraspinal mechanisms linked to these CRPS-related comorbidities remain poorly understood. The authors used a previously characterized mouse model of tibia fracture/cast immobilization showing the principal stigmata of CRPS (n = 8 to 20 per group) observed in humans. The central hypothesis was that fracture/cast mice manifest changes in measures of thigmotaxis (indicative of anxiety) and working memory reflected in neuroplastic changes in amygdala, perirhinal cortex, and hippocampus. The authors demonstrate that nociceptive sensitization in these mice is accompanied by altered thigmotactic behaviors in the zero maze but not open field assay, and working memory dysfunction in novel object recognition and social memory but not in novel location recognition. Furthermore, the authors found evidence of structural changes and synaptic plasticity including changes in dendritic architecture and decreased levels of synaptophysin and brain-derived neurotrophic factor in specific brain regions. The study findings provide novel observations regarding behavioral changes and brain plasticity in a mouse model of CRPS. In addition to elucidating some of the supraspinal correlates of the syndrome, this work supports the potential use of therapeutic interventions that not only directly target sensory input and other peripheral mechanisms, but also attempt to ameliorate the broader pain experience by modifying its associated cognitive and emotional comorbidities.

HIV, Vascular and Aging Injuries in the Brain of Clinically Stable HIV-Infected Adults: A 1H MRS Study

PubMed Central

Cysique, Lucette A.; Moffat, Kirsten; Moore, Danielle M.; Lane, Tammy A.; Davies, Nicholas W. S.; Carr, Andrew; Brew, Bruce J.; Rae, Caroline

2013-01-01

Background Cardiovascular disease (CVD) and premature aging have been hypothesized as new risk factors for HIV associated neurocognitive disorders (HAND) in adults with virally-suppressed HIV infection. Moreover, their significance and relation to more classical HAND biomarkers remain unclear. Methods 92 HIV− infected (HIV+) adults stable on combined antiretroviral therapy (cART) and 30 age-comparable HIV-negative (HIV−) subjects underwent 1H Magnetic Resonance Spectroscopy (MRS) of the frontal white matter (targeting HIV, normal aging or CVD-related neurochemical injury), caudate nucleus (targeting HIV neurochemical injury), and posterior cingulate cortex (targeting normal/pathological aging, CVD-related neurochemical changes). All also underwent standard neuropsychological (NP) testing. CVD risk scores were calculated. HIV disease biomarkers were collected and cerebrospinal fluid (CSF) neuroinflammation biomarkers were obtained in 38 HIV+ individuals. Results Relative to HIV− individuals, HIV+ individuals presented mild MRS alterations: in the frontal white matter: lower N-Acetyl-Aspartate (NAA) (p<.04) and higher myo-inositol (mIo) (p<.04); in the caudate: lower NAA (p = .01); and in the posterior cingulate cortex: higher mIo (p<.008– also significant when Holm-Sidak corrected) and higher Choline/NAA (p<.04). Regression models showed that an HIV*age interaction was associated with lower frontal white matter NAA. CVD risk factors were associated with lower posterior cingulate cortex and caudate NAA in both groups. Past acute CVD events in the HIV+ group were associated with increased mIo in the posterior cingulate cortex. HIV duration was associated with lower caudate NAA; greater CNS cART penetration was associated with lower mIo in the posterior cingulate cortex and the degree of immune recovery on cART was associated with higher NAA in the frontal white matter. CSF neopterin was associated with higher mIo in the posterior cingulate cortex and frontal white matter. Conclusions In chronically HIV+ adults with long-term viral suppression, current CVD risk, past CVD and age are independent factors for neuronal injury and inflammation. This suggests a tripartite model of HIV, CVD and age likely driven by chronic inflammation. PMID:23620788

Minocycline ameliorates prenatal valproic acid induced autistic behaviour, biochemistry and blood brain barrier impairments in rats.

PubMed

Kumar, Hariom; Sharma, Bhupesh

2016-01-01

Autism is a neurodevelopment disorder. One percent worldwide population suffers with autism and males suffer more than females. Microglia plays an important role in neurodevelopment, neuropsychiatric and neurodegenerative disorders. The present study has been designed to investigate the role of minocycline in prenatal valproic acid induced autism in rats. Animals with prenatal valproic acid have reduced social interaction (three chamber social behaviour apparatus), spontaneous alteration (Y-Maze), exploratory activity (Hole board test), intestinal motility, serotonin levels (both in prefrontal cortex and ileum) and prefrontal cortex mitochondrial complex activity (complexes I, II, IV). Furthermore, prenatal valproic acid treated animals have shown an increase in locomotion (actophotometer), anxiety (elevated plus maze), brain oxidative stress (thiobarbituric acid reactive species, glutathione, catalase), nitrosative stress (nitrite/nitrate), inflammation (both in brain and ileum myeloperoxidase activity), calcium and blood brain barrier permeability. Treatment with minocycline significantly attenuated prenatal valproic acid induced reduction in social interaction, spontaneous alteration, exploratory activity intestinal motility, serotonin levels and prefrontal cortex mitochondrial complex activity. Furthermore, minocycline has also attenuated prenatal valproic acid induced increase in locomotion, anxiety, brain oxidative and nitrosative stress, inflammation, calcium and blood brain barrier permeability. Thus, it may be concluded that prenatal valproic acid has induced autistic behaviour, biochemistry and blood brain barrier impairment in animals, which were significantly attenuated by minocycline. Minocycline should be explored further for its therapeutic benefits in autism. Copyright © 2015 Elsevier B.V. All rights reserved.

Inhibition of inflammation by astaxanthin alleviates cognition deficits in diabetic mice.

PubMed

Zhou, Xiaoyan; Zhang, Fang; Hu, Xiaotong; Chen, Jing; Wen, Xiangru; Sun, Ying; Liu, Yonghai; Tang, Renxian; Zheng, Kuiyang; Song, Yuanjian

2015-11-01

Neurons in the hippocampal and cortical functional regions are more susceptible to damage induced by hyperglycemia, which can result in severe spatial learning and memory impairment. Neuroprotection ameliorates cognitive impairment induced by hyperglycemia in diabetic encephalopathy (DE). Astaxanthin has been widely studied in diabetes mellitus and diabetic complications due to its hypoglycemic, antioxidant and anti-apoptotic effects. However, whether astaxanthin can alleviate cognition deficits induced by DE and its precise mechanisms remain undetermined. In this study, DE was induced by streptozotocin (STZ, 150 mg/kg) in ICR mice. We observed the effect of astaxanthin on cognition and investigated its potential mechanisms in DE mice. Results showed that astaxanthin treatment significantly decreased the latency and enhanced the distance and time spent in the target quadrant in the Morris water maze test. Furthermore, neuronal survival was significantly increased in the hippocampal CA3 region and the frontal cortex following treatment with astaxanthin. Meanwhile, immunoblotting was used to observe the nuclear translocation of nuclear factor-kappaB (NF-κB) p65 and the expression of tumor necrosis factor-α (TNF-α) in the hippocampus and frontal cortex. The results indicated that astaxanthin could inhibit NF-κB nuclear translocation and downregulate TNF-α expression in the hippocampus and frontal cortex. Overall, the present study implied that astaxanthin could improve cognition by protecting neurons against inflammation injury potentially through inhibiting the nuclear translocation of NF-κB and down-regulating TNF-α. Copyright © 2015. Published by Elsevier Inc.

Enoxacin Elevates MicroRNA Levels in Rat Frontal Cortex and Prevents Learned Helplessness

PubMed Central

Smalheiser, Neil R.; Zhang, Hui; Dwivedi, Yogesh

2014-01-01

Major depressive disorder (MDD) is a major public health concern. Despite tremendous advancement, the pathogenic mechanisms associated with MDD are still unclear. Moreover, a significant number of MDD subjects do not respond to the currently available medication. MicroRNAs (miRNAs) are a class of small non-coding RNAs that control gene expression by modulating translation, mRNA degradation or stability of mRNA targets. The role of miRNAs in disease pathophysiology is emerging rapidly. Recently, we reported that miRNA expression is down-regulated in frontal cortex of depressed suicide subjects, and that rats exposed to repeated inescapable shock show differential miRNA changes depending on whether they exhibited normal adaptive responses or learned helpless (LH) behavior. Enoxacin, a fluoroquinolone used clinically as an anti-bacterial compound, enhances the production of miRNAs in vitro and in peripheral tissues in vivo, but has not yet been tested as an experimental tool to study the relation of miRNA expression to neural functions or behavior. Treatment of rats with 10 or 25 mg/kg enoxacin for 1 week increased the expression of miRNAs in frontal cortex and decreased the proportion of rats exhibiting LH behavior following inescapable shock. Further studies are warranted to learn whether enoxacin may ameliorate depressive behavior in other rodent paradigms and in human clinical situations, and if so whether its mechanism is due to upregulation of miRNAs. PMID:24575053

Use of transcutaneous electrical nerve stimulation for chronic pruritus.

PubMed

Mohammad Ali, Basma Mourad; Hegab, Doaa Salah; El Saadany, Hanan Mohammad

2015-01-01

Pruritus is a distressing symptom in many dermatological as well as systemic conditions, and it is sometimes very chronic and relapsing. Transcutaneous electrical nerve stimulation (TENS) is an inexpensive form of analgesia that could also ameliorate itching. This study aimed to evaluate TENS efficacy in patients with pruritus due to some types of chronic eczema, and in patients with chronic hepatic disease. Ten patients with atopic dermatitis (AD), 20 patients with lichen simplex chronicus (LSC), and 16 patients with chronic liver disease having chronic distressing pruritus received three sessions of TENS weekly for 12 sessions, and the effect on the visual analogue scale (VAS) scores was recorded after 2 weeks of therapy, at treatment end, and after an additional month for follow up. There was a statistically significant decline in the mean VAS score for studied groups at weeks 2 and 4 of therapy compared to baseline, but the improvement was more significant in patients with AD, and LSC (p < 0.001 for both) than in those with chronic liver disease (p < 0.01) who also showed an early re-elevation of VAS score on follow up. TENS therapy holds promise as a palliative, alternative, safe and inexpensive treatment for patients with some chronic pruritic conditions. © 2015 Wiley Periodicals, Inc.

Dietary Anthocyanins against Obesity and Inflammation

PubMed Central

Lee, Yoon-Mi; Yoon, Young; Yoon, Haelim; Park, Hyun-Min; Song, Sooji; Yeum, Kyung-Jin

2017-01-01

Chronic low-grade inflammation plays a pivotal role in the pathogenesis of obesity, due to its associated chronic diseases such as type II diabetes, cardiovascular diseases, pulmonary diseases and cancer. Thus, targeting inflammation is an attractive strategy to counter the burden of obesity-induced health problems. Recently, food-derived bioactive compounds have been spotlighted as a regulator against various chronic diseases due to their low toxicity, as opposed to drugs that induce severe side effects. Here we describe the beneficial effects of dietary anthocyanins on obesity-induced metabolic disorders and inflammation. Red cabbage microgreen, blueberry, blackcurrant, mulberry, cherry, black elderberry, black soybean, chokeberry and jaboticaba peel contain a variety of anthocyanins including cyanidins, delphinidins, malvidins, pelargonidins, peonidins and petunidins, and have been reported to alter both metabolic markers and inflammatory markers in cells, animals, and humans. This review discusses the interplay between inflammation and obesity, and their subsequent regulation via the use of dietary anthocyanins, suggesting an alternative dietary strategy to ameliorate obesity and obesity associated chronic diseases. PMID:28974032

Dietary Anthocyanins against Obesity and Inflammation.

PubMed

Lee, Yoon-Mi; Yoon, Young; Yoon, Haelim; Park, Hyun-Min; Song, Sooji; Yeum, Kyung-Jin

2017-10-01

Chronic low-grade inflammation plays a pivotal role in the pathogenesis of obesity, due to its associated chronic diseases such as type II diabetes, cardiovascular diseases, pulmonary diseases and cancer. Thus, targeting inflammation is an attractive strategy to counter the burden of obesity-induced health problems. Recently, food-derived bioactive compounds have been spotlighted as a regulator against various chronic diseases due to their low toxicity, as opposed to drugs that induce severe side effects. Here we describe the beneficial effects of dietary anthocyanins on obesity-induced metabolic disorders and inflammation. Red cabbage microgreen, blueberry, blackcurrant, mulberry, cherry, black elderberry, black soybean, chokeberry and jaboticaba peel contain a variety of anthocyanins including cyanidins, delphinidins, malvidins, pelargonidins, peonidins and petunidins, and have been reported to alter both metabolic markers and inflammatory markers in cells, animals, and humans. This review discusses the interplay between inflammation and obesity, and their subsequent regulation via the use of dietary anthocyanins, suggesting an alternative dietary strategy to ameliorate obesity and obesity associated chronic diseases.

Pain Neuroscience Education: State of the Art and Application in Pediatrics.

PubMed

Robins, Hannah; Perron, Victoria; Heathcote, Lauren C; Simons, Laura E

2016-12-21

Chronic pain is a widespread problem in the field of pediatrics. Many interventions to ameliorate pain-related dysfunction have a biobehavioral focus. As treatments for chronic pain (e.g., increased movement) often stand in stark contrast to treatments for an acute injury (e.g., rest), providing a solid rationale for treatment is necessary to gain patient and parent buy-in. Most pain treatment interventions incorporate psychoeducation, or pain neuroscience education (PNE), as an essential component, and in some cases, as a stand-alone approach. The current topical review focuses on the state of pain neuroscience education and its application to pediatric chronic pain. As very little research has examined pain neuroscience education in pediatrics, we aim to describe this emerging area and catalyze further work on this important topic. As the present literature has generally focused on adults with chronic pain, pain neuroscience education merits further attention in the realm of pediatric pain in order to be tailored and implemented in this population.

Granulocyte Macrophage Colony-Stimulating Factor-Activated Eosinophils Promote Interleukin-23 Driven Chronic Colitis

PubMed Central

Griseri, Thibault; Arnold, Isabelle C.; Pearson, Claire; Krausgruber, Thomas; Schiering, Chris; Franchini, Fanny; Schulthess, Julie; McKenzie, Brent S.; Crocker, Paul R.; Powrie, Fiona

2015-01-01

Summary The role of intestinal eosinophils in immune homeostasis is enigmatic and the molecular signals that drive them from protective to tissue damaging are unknown. Most commonly associated with Th2 cell-mediated diseases, we describe a role for eosinophils as crucial effectors of the interleukin-23 (IL-23)-granulocyte macrophage colony-stimulating factor (GM-CSF) axis in colitis. Chronic intestinal inflammation was characterized by increased bone marrow eosinopoiesis and accumulation of activated intestinal eosinophils. IL-5 blockade or eosinophil depletion ameliorated colitis, implicating eosinophils in disease pathogenesis. GM-CSF was a potent activator of eosinophil effector functions and intestinal accumulation, and GM-CSF blockade inhibited chronic colitis. By contrast neutrophil accumulation was GM-CSF independent and dispensable for colitis. In addition to TNF secretion, release of eosinophil peroxidase promoted colitis identifying direct tissue-toxic mechanisms. Thus, eosinophils are key perpetrators of chronic inflammation and tissue damage in IL-23-mediated immune diseases and it suggests the GM-CSF-eosinophil axis as an attractive therapeutic target. PMID:26200014

Pain Neuroscience Education: State of the Art and Application in Pediatrics

PubMed Central

Robins, Hannah; Perron, Victoria; Heathcote, Lauren C.; Simons, Laura E.

2016-01-01

Chronic pain is a widespread problem in the field of pediatrics. Many interventions to ameliorate pain-related dysfunction have a biobehavioral focus. As treatments for chronic pain (e.g., increased movement) often stand in stark contrast to treatments for an acute injury (e.g., rest), providing a solid rationale for treatment is necessary to gain patient and parent buy-in. Most pain treatment interventions incorporate psychoeducation, or pain neuroscience education (PNE), as an essential component, and in some cases, as a stand-alone approach. The current topical review focuses on the state of pain neuroscience education and its application to pediatric chronic pain. As very little research has examined pain neuroscience education in pediatrics, we aim to describe this emerging area and catalyze further work on this important topic. As the present literature has generally focused on adults with chronic pain, pain neuroscience education merits further attention in the realm of pediatric pain in order to be tailored and implemented in this population. PMID:28009822

Stevia Prevents Acute and Chronic Liver Injury Induced by Carbon Tetrachloride by Blocking Oxidative Stress through Nrf2 Upregulation

PubMed Central

Ramos-Tovar, Erika; Hernández-Aquino, Erika; Casas-Grajales, Sael; Buendia-Montaño, Laura D.; Tsutsumi, Víctor

2018-01-01

The effect of stevia on liver cirrhosis has not been previously investigated. In the present study, the antioxidant and anti-inflammatory properties of stevia leaves were studied in male Wistar rats with carbon tetrachloride- (CCl4-) induced acute and chronic liver damage. Acute and chronic liver damage induced oxidative stress, necrosis, and cholestasis, which were significantly ameliorated by stevia. Chronic CCl4 treatment resulted in liver cirrhosis, as evidenced by nodules of hepatocytes surrounded by thick bands of collagen and distortion of the hepatic architecture, and stevia significantly prevented these alterations. Subsequently, the underlying mechanism of action of the plant was analyzed. Our study for the first time shows that stevia upregulated Nrf2, thereby counteracting oxidative stress, and prevented necrosis and cholestasis through modulation of the main proinflammatory cytokines via NF-κB inhibition. These multitarget mechanisms led to the prevention of experimental cirrhosis. Given the reasonable safety profile of stevia, our results indicated that it may be useful for the clinical treatment of acute and chronic liver diseases. PMID:29849889

Corticotrigeminal Projections from the Insular Cortex to the Trigeminal Caudal Subnucleus Regulate Orofacial Pain after Nerve Injury via Extracellular Signal-Regulated Kinase Activation in Insular Cortex Neurons.

PubMed

Wang, Jian; Li, Zhi-Hua; Feng, Ban; Zhang, Ting; Zhang, Han; Li, Hui; Chen, Tao; Cui, Jing; Zang, Wei-Dong; Li, Yun-Qing

2015-01-01

Cortical neuroplasticity alterations are implicated in the pathophysiology of chronic orofacial pain. However, the relationship between critical cortex excitability and orofacial pain maintenance has not been fully elucidated. We recently demonstrated a top-down corticospinal descending pain modulation pathway from the anterior cingulate cortex (ACC) to the spinal dorsal horn that could directly regulate nociceptive transmission. Thus, we aimed to investigate possible corticotrigeminal connections that directly influence orofacial nociception in rats. Infraorbital nerve chronic constriction injury (IoN-CCI) induced significant orofacial nociceptive behaviors as well as pain-related negative emotions such as anxiety/depression in rats. By combining retrograde and anterograde tract tracing, we found powerful evidence that the trigeminal caudal subnucleus (Vc), especially the superficial laminae (I/II), received direct descending projections from granular and dysgranular parts of the insular cortex (IC). Extracellular signal-regulated kinase (ERK), an important signaling molecule involved in neuroplasticity, was significantly activated in the IC following IoN-CCI. Moreover, in IC slices from IoN-CCI rats, U0126, an inhibitor of ERK activation, decreased both the amplitude and the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and reduced the paired-pulse ratio (PPR) of Vc-projecting neurons. Additionally, U0126 also reduced the number of action potentials in the Vc-projecting neurons. Finally, intra-IC infusion of U0126 obviously decreased Fos expression in the Vc, accompanied by the alleviation of both nociceptive behavior and negative emotions. Thus, the corticotrigeminal descending pathway from the IC to the Vc could directly regulate orofacial pain, and ERK deactivation in the IC could effectively alleviate neuropathic pain as well as pain-related negative emotions in IoN-CCI rats, probably through this top-down pathway. These findings may help researchers and clinicians to better understand the underlying modulation mechanisms of orofacial neuropathic pain and indicate a novel mechanism of ERK inhibitor-induced analgesia.

Synaptic protein changes after a chronic period of sensorimotor perturbation in adult rats: a potential role of phosphorylation/O-GlcNAcylation interplay.

PubMed

Fourneau, Julie; Canu, Marie-Hélène; Cieniewski-Bernard, Caroline; Bastide, Bruno; Dupont, Erwan

2018-05-28

In human, a chronic sensorimotor perturbation (SMP) through prolonged body immobilization alters motor task performance through a combination of peripheral and central factors. Studies performed on a rat model of SMP have shown biomolecular changes and a reorganization of sensorimotor cortex through events such as morphological modifications of dendritic spines (number, length, functionality). However, underlying mechanisms are still unclear. It is well known that phosphorylation regulates a wide field of synaptic activity leading to neuroplasticity. Another post-translational modification that interplays with phosphorylation is O-GlcNAcylation. This atypical glycosylation, reversible and dynamic, is involved in essential cellular and physiological processes such as synaptic activity, neuronal morphogenesis, learning and memory. We examined potential roles of phosphorylation/O-GlcNAcylation interplay in synaptic plasticity within rat sensorimotor cortex after a SMP period. For this purpose, sensorimotor cortex synaptosomes were separated by sucrose gradient, in order to isolate a subcellular compartment enriched in proteins involved in synaptic functions. A period of SMP induced plastic changes at the pre- and postsynaptic levels, characterized by a reduction of phosphorylation (synapsin1, AMPAR GluA2) and expression (synaptophysin, PSD-95, AMPAR GluA2) of synaptic proteins, as well as a decrease in MAPK/ERK42 activation. Expression levels of OGT/OGA enzymes was unchanged but we observed a specific reduction of synapsin1 O-GlcNAcylation in sensorimotor cortex synaptosomes. The synergistic regulation of synapsin1 phosphorylation/O-GlcNAcylation could affect presynaptic neurotransmitter release. Associated with other pre- and postsynaptic changes, synaptic efficacy could be impaired in somatosensory cortex of SMP rat. Thus, synapsin1 O-GlcNAcylation/phosphorylation interplay also appears to be involved in this synaptic plasticity by finely regulating neural activity. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Prenatal stress decreases glycogen synthase kinase-3 phosphorylation in the rat frontal cortex.

PubMed

Szymańska, Magdalena; Suska, Anna; Budziszewska, Bogusława; Jaworska-Feil, Lucylla; Basta-Kaim, Agnieszka; Leśkiewicz, Monika; Kubera, Marta; Gergont, Aleksandra; Kroczka, Sławomir; Kaciński, Marek; Lasoń, Władysław

2009-01-01

It has been postulated that hyperactive glycogen synthase kinase-3 (GSK-3) is an important factor in the pathogenesis of depression, and that this enzyme also contributes to the mechanism of antidepressant drug action. In the present study, we investigated the effect of prenatal stress (an animal model of depression) and long-term treatment with antidepressant drugs on the concentration of GSK-3beta and its main regulating protein kinase B (PKB, Akt). The concentration of GSK-3beta, its inactive form (phospho-Ser9-GSK-3beta), and the amounts of active (phospho-Akt) and total Akt were determined in the hippocampus and frontal cortex in rats. In order to verify our animal model of depression, immobility time in the forced swim test (Porsolt test) was also determined.We found that prenatally stressed rats display a high level of immobility in the Porsolt test and chronic treatment with imipramine, fluoxetine, mirtazapine and tianeptine normalize this change. Western blot analysis demonstrated that GSK-3beta levels were significantly elevated in the frontal cortex, but not in the hippocampus, of prenatally stressed rats. The concentration of its non-active form (phospho-Ser9-GSK-3beta) was decreased only in the former brain structure. No changes were found in the amounts of active (phospho-Akt) and total Akt in both studied brain structures. Chronic treatment with antidepressant drugs diminished stress-induced alterations in GSK-3beta and phospho-GSK-3beta the frontal cortex, but had no effect on the concentration of these enzymes in the hippocampus. Moreover, levels of Akt and phospho-Akt in all experimental groups remained unchanged. Since our animal model of depression is connected with hyperactivity of the HPA axis, our results suggest that GSK-3beta is an important intracellular target for maladaptive glucocorticoid action on frontal cortex neurons and in antidepressant drug effects. Furthermore, the influence of stress and antidepressant drugs on GSK-3beta does not appear to impact the kinase activity of Akt.

Therapeutic potential of silymarin in chronic unpredictable mild stress induced depressive-like behavior in mice.

PubMed

Thakare, Vishnu N; Patil, Rajesh R; Oswal, Rajesh J; Dhakane, Valmik D; Aswar, Manoj K; Patel, Bhoomika M

2018-02-01

Silymarin, a plant-derived polyphenolic flavonoid of Silybum marianum, elicited significant antidepressant-like activity in an acute restraint stress model of depression. It improved monoamines, mainly 5-hydroxytryptamine (5-HT) levels in the cortex, dopamine (DA) and norepinephrine (NE) in the cerebellum in mice. The present study was undertaken to explore the antidepressant potential of silymarin in chronic unpredictable mild stress (CUMS) induced depressive-like behavior in mice, and to find out its probable mechanism(s) of action, mainly neurogenesis, neuroinflammation, and/or oxidative stress. The mice were subjected to CUMS for 28 days (4 weeks) and administered with silymarin (100 mg/kg and 200 mg/kg), or fluoxetine or vehicle from days 8 to 28 (3 weeks simultaneously). Animals were evaluated for behavioral changes, such as anhedonia by sucrose preference test, behavioral despair by forced swim test, and exploratory behaviors by an open field test. In addition, neurobiochemical alterations, mainly monoamines, 5-HT, NE, DA, neurotrophic factor BDNF, and cytokines, IL-6, TNF-α, oxidant-antioxidant parameters by determining the malondialdehyde formation (an index of lipid peroxidation process), superoxide dismutase (SOD) and catalase (CAT) activity in hippocampus and cerebral cortex along with serum corticosterone were investigated. Our findings reveal that mice subjected to CUMS exhibited lower sucrose preference, increase immobility time without affecting general locomotion of the animals, and reduce BDNF, 5-HT, NE, and DA level, increased serum corticosterone, IL-6 and TNF-α along with an oxidant-antioxidant imbalance in the hippocampus and cerebral cortex. Silymarin significantly reversed the CUMS-induced changes in the hippocampus and cerebral cortex in mice. Thus, the possible mechanism involved in the antidepressant-like activity of silymarin is correlated to the alleviation of monoaminergic, neurogenesis (enhancing 5-HT, NE, and BDNF levels), and attenuation of inflammatory cytokines system and oxidative stress by modulation of corticosterone response, restoration of antioxidant defense system in cerebral cortex and hippocampus.

Bacopa monnieri (Brahmi) improved novel object recognition task and increased cerebral vesicular glutamate transporter type 3 in sub-chronic phencyclidine rat model of schizophrenia.

PubMed

Piyabhan, Pritsana; Wannasiri, Supaporn; Naowaboot, Jarinyaporn

2016-12-01

Reduced vesicular glutamate transporter 1 (VGLUT1) and 2 (VGLUT2) indicate glutamatergic hypofunction leading to cognitive impairment in schizophrenia. However, VGLUT3 involvement in cognitive dysfunction has not been reported in schizophrenia. Brahmi (Bacopa monnieri) might be a new treatment and prevention for cognitive deficits in schizophrenia by acting on cerebral VGLUT3 density. We aimed to study cognitive enhancement- and neuroprotective-effects of Brahmi on novel object recognition and cerebral VGLUT3 immunodensity in sub-chronic (2 mg/kg, Bid, ip) phencyclidine (PCP) rat model of schizophrenia. Rats were assigned to three groups for cognitive enhancement effect study: Group 1, Control; Group 2, PCP administration; Group 3, PCP+Brahmi. A neuroprotective-effect study was also carried out. Rats were again assigned to three groups: Group 1, Control; Group 2, PCP administration; Group 3, Brahmi+PCP. Discrimination ratio (DR) representing cognitive ability was obtained from a novel object recognition task. VGLUT3 immunodensity was measured in the prefrontal cortex, striatum and cornu ammonis fields 1-3 (CA1-3) using immunohistochemistry. We found reduced DR in the PCP group, which occurred alongside VGLUT3 reduction in all brain areas. PCP+Brahmi showed higher DR score with increased VGLUT3 immunodensity in the prefrontal cortex and striatum. Brahmi+PCP group showed a higher DR score with increased VGLUT3 immunodensity in the prefrontal cortex, striatum and CA1-3. We concluded that reduced cerebral VGLUT3 was involved in cognitive deficit in PCP-administrated rats. Receiving Brahmi after PCP restored cognitive deficit by increasing VGLUT3 in the prefrontal cortex and striatum. Receiving Brahmi before PCP prevented cognitive impairment by elevating VGLUT3 in prefrontal cortex, striatum and CA1-3. Therefore, Brahmi could be a new frontier of restoration and prevention of cognitive deficit in schizophrenia. © 2016 John Wiley & Sons Australia, Ltd.

Effects of CPAP-therapy on brain electrical activity in obstructive sleep apneic patients: a combined EEG study using LORETA and Omega complexity : reversible alterations of brain activity in OSAS.

PubMed

Toth, Marton; Faludi, Bela; Kondakor, Istvan

2012-10-01

Effects of initiation of continuous positive airway pressure (CPAP) therapy on EEG background activity were investigated in patients with obstructive sleep apnea syndrome (OSAS, N = 25) to test possible reversibility of alterations of brain electrical activity caused by chronic hypoxia. Normal control group (N = 14) was also examined. Two EEG examinations were done in each groups: at night and in the next morning. Global and regional (left vs. right, anterior vs. posterior) measures of spatial complexity (Omega complexity) were used to characterize the degree of spatial synchrony of EEG. Low resolution electromagnetic tomography (LORETA) was used to localize generators of EEG activity in separate frequency bands. Before CPAP-treatment, a significantly lower Omega complexity was found globally and over the right hemisphere. Due to CPAP-treatment, these significant differences vanished. Significantly decreased Omega complexity was found in the anterior region after treatment. LORETA showed a decreased activity in all of the beta bands after therapy in the right hippocampus, premotor and temporo-parietal cortex, and bilaterally in the precuneus, paracentral and posterior cingulate cortex. No significant changes were seen in control group. Comparing controls and patients before sleep, an increased alpha2 band activity was seen bilaterally in the precuneus, paracentral and posterior cingulate cortex, while in the morning an increased beta3 band activity in the left precentral and bilateral premotor cortex and a decreased delta band activity in the right temporo-parietal cortex and insula were observed. These findings indicate that effect of sleep on EEG background activity is different in OSAS patients and normal controls. In OSAS patients, significant changes lead to a more normal EEG after a night under CPAP-treatment. Compensatory alterations of brain electrical activity in regions associated with influencing sympathetic outflow, visuospatial abilities, long-term memory and motor performances caused by chronic hypoxia could be reversed by CPAP-therapy.

Analysis of Time-Dependent Brain Network on Active and MI Tasks for Chronic Stroke Patients

PubMed Central

Chang, Won Hyuk; Kim, Yun-Hee; Lee, Seong-Whan; Kwon, Gyu Hyun

2015-01-01

Several researchers have analyzed brain activities by investigating brain networks. However, there is a lack of the research on the temporal characteristics of the brain network during a stroke by EEG and the comparative studies between motor execution and imagery, which became known to have similar motor functions and pathways. In this study, we proposed the possibility of temporal characteristics on the brain networks of a stroke. We analyzed the temporal properties of the brain networks for nine chronic stroke patients by the active and motor imagery tasks by EEG. High beta band has a specific role in the brain network during motor tasks. In the high beta band, for the active task, there were significant characteristics of centrality and small-worldness on bilateral primary motor cortices at the initial motor execution. The degree centrality significantly increased on the contralateral primary motor cortex, and local efficiency increased on the ipsilateral primary motor cortex. These results indicate that the ipsilateral primary motor cortex constructed a powerful subnetwork by influencing the linked channels as compensatory effect, although the contralateral primary motor cortex organized an inefficient network by using the connected channels due to lesions. For the MI task, degree centrality and local efficiency significantly decreased on the somatosensory area at the initial motor imagery. Then, there were significant correlations between the properties of brain networks and motor function on the contralateral primary motor cortex and somatosensory area for each motor execution/imagery task. Our results represented that the active and MI tasks have different mechanisms of motor acts. Based on these results, we indicated the possibility of customized rehabilitation according to different motor tasks. We expect these results to help in the construction of the customized rehabilitation system depending on motor tasks by understanding temporal functional characteristics on brain network for a stroke. PMID:26656269

Glutamatergic neurometabolites during early abstinence from chronic methamphetamine abuse.

PubMed

O'Neill, Joseph; Tobias, Marc C; Hudkins, Matthew; London, Edythe D

2014-10-31

The acute phase of abstinence from methamphetamine abuse is critical for rehabilitation success. Proton magnetic resonance spectroscopy has detected below-normal levels of glutamate+glutamine in anterior middle cingulate of chronic methamphetamine abusers during early abstinence, attributed to abstinence-induced downregulation of the glutamatergic systems in the brain. This study further explored this phenomenon. We measured glutamate+glutamine in additional cortical regions (midline posterior cingulate, midline precuneus, and bilateral inferior frontal cortex) putatively affected by methamphetamine. We examined the relationship between glutamate+glutamine in each region with duration of methamphetamine abuse as well as the depressive symptoms of early abstinence. Magnetic resonance spectroscopic imaging was acquired at 1.5 T from a methamphetamine group of 44 adults who had chronically abused methamphetamine and a control group of 23 age-, sex-, and tobacco smoking-matched healthy volunteers. Participants in the methamphetamine group were studied as inpatients during the first week of abstinence from the drug and were not receiving treatment. In the methamphetamine group, small but significant (5-15%, P<.05) decrements (vs control) in glutamate+glutamine were observed in posterior cingulate, precuneus, and right inferior frontal cortex; glutamate+glutamine in posterior cingulate was negatively correlated (P<.05) with years of methamphetamine abuse. The Beck Depression Inventory score was negatively correlated (P<.005) with glutamate+glutamine in right inferior frontal cortex. Our findings support the idea that glutamatergic metabolism is downregulated in early abstinence in multiple cortical regions. The extent of downregulation may vary with length of abuse and may be associated with severity of depressive symptoms emergent in early recovery. © The Author 2015. Published by Oxford University Press on behalf of CINP.

[The Effects of Chronic Alcoholization on the Expression of Brain-Derived Neurotrophic Factor and Its Receptors in the Brains of Mice Genetically Predisposed to Depressive-Like Behavior].

PubMed

Bazovkina, D V; Kondaurova, E M; Tsybko, A S; Kovetskaya, A I; Ilchibaeva, T V; Naumenko, V S

2017-01-01

Brain-derived neurotropic factor (BDNF) plays an important role in mechanisms of depression. Precursor protein of this factor (proBDNF) can initiate apoptosis in the brain, while the mature form of BDNF is involved in neurogenesis. It is known that chronic alcoholization leads to the activation of apoptotic processes, neurodegeneration, brain injury, and cognitive dysfunction. In this work, we have studied the influence of long-term ethanol exposure on the proBDNF and BDNF protein levels, as well as on the expression of genes that encode these proteins in the brain structures of ASC mice with genetic predisposition to depressive-like behavior and in mice from parental nondepressive CBA strain. It was shown that chronic alcoholization results in a reduction of the BDNF level in the hippocampus and an increase in the amount of TrkB and p75 receptors in the frontal cortex of nondepressive CBA mice. At the same time, the long-term alcoholization of depressive ASC mice results in an increase of the proBDNF level in the frontal cortex and a reduction in the p75 protein level in the hippocampus. It has also been shown that, in depressive ASC mice, proBDNF and BDNF levels are significantly lower in the hippocampus and the frontal cortex compared with nondepressive CBA strain. However, no significant differences in the expression of genes encoding the studied proteins were observed. Thus, changes in the expression patterns of proBDNF, BDNF, and their receptors under the influence of alcoholization in the depressive ASC strain and nondepressive CBA strain mice are different.

Acute and chronic changes in brain activity with deep brain stimulation for refractory depression.

PubMed

Conen, Silke; Matthews, Julian C; Patel, Nikunj K; Anton-Rodriguez, José; Talbot, Peter S

2018-04-01

Deep brain stimulation is a potential option for patients with treatment-refractory depression. Deep brain stimulation benefits have been reported when targeting either the subgenual cingulate or ventral anterior capsule/nucleus accumbens. However, not all patients respond and optimum stimulation-site is uncertain. We compared deep brain stimulation of the subgenual cingulate and ventral anterior capsule/nucleus accumbens separately and combined in the same seven treatment-refractory depression patients, and investigated regional cerebral blood flow changes associated with acute and chronic deep brain stimulation. Deep brain stimulation-response was defined as reduction in Montgomery-Asberg Depression Rating Scale score from baseline of ≥50%, and remission as a Montgomery-Asberg Depression Rating Scale score ≤8. Changes in regional cerebral blood flow were assessed using [ 15 O]water positron emission tomography. Remitters had higher relative regional cerebral blood flow in the prefrontal cortex at baseline and all subsequent time-points compared to non-remitters and non-responders, with prefrontal cortex regional cerebral blood flow generally increasing with chronic deep brain stimulation. These effects were consistent regardless of stimulation-site. Overall, no significant regional cerebral blood flow changes were apparent when deep brain stimulation was acutely interrupted. Deep brain stimulation improved treatment-refractory depression severity in the majority of patients, with consistent changes in local and distant brain regions regardless of target stimulation. Remission of depression was reached in patients with higher baseline prefrontal regional cerebral blood flow. Because of the small sample size these results are preliminary and further evaluation is necessary to determine whether prefrontal cortex regional cerebral blood flow could be a predictive biomarker of treatment response.

Prefrontal Structure Varies as a Function of Pain Symptoms in Chronic Fatigue Syndrome.

PubMed

van der Schaaf, Marieke E; De Lange, Floris P; Schmits, Iris C; Geurts, Dirk E M; Roelofs, Karin; van der Meer, Jos W M; Toni, Ivan; Knoop, Hans

2017-02-15

Chronic fatigue syndrome (CFS) is characterized by severe fatigue persisting for ≥6 months and leading to considerable impairment in daily functioning. Neuroimaging studies of patients with CFS have revealed alterations in prefrontal brain morphology. However, it remains to be determined whether these alterations are specific for fatigue or whether they relate to other common CFS symptoms (e.g., chronic pain, lower psychomotor speed, and reduced physical activity). We used magnetic resonance imaging to quantify gray matter volume (GMV) and the N-acetylaspartate and N-acetylaspartylglutamate/creatine ratio (NAA/Cr) in a group of 89 women with CFS. Building on previous reports, we tested whether GMV and NAA/Cr in the dorsolateral prefrontal cortex are associated with fatigue severity, pain, psychomotor speed, and physical activity, while controlling for depressive symptoms. We also considered GMV and NAA/Cr differences between patients with CFS and 26 sex-, age-, and education-matched healthy controls. The presence of pain symptoms was the main predictor of both GMV and NAA/Cr in the left dorsolateral prefrontal cortex of patients with CFS. More pain was associated with reduced GMVs and NAA/Cr, over and above the effects of fatigue, depressive symptoms, physical activity, and psychomotor speed. In contrast to previous reports and despite a large representative sample, global GMV did not differ between the CFS and healthy control groups. CFS, as diagnosed by Centers for Disease Control and Prevention criteria, is not a clinical entity reliably associated with reduced GMV. Individual variation in the presence of pain, rather than fatigue, is associated with neuronal alterations in the dorsolateral prefrontal cortex of patients with CFS. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

1-Hz rTMS in the treatment of tinnitus: A sham-controlled, randomized multicenter trial.

PubMed

Landgrebe, Michael; Hajak, Göran; Wolf, Stefan; Padberg, Frank; Klupp, Philipp; Fallgatter, Andreas J; Polak, Thomas; Höppner, Jacqueline; Haker, Rene; Cordes, Joachim; Klenzner, Thomas; Schönfeldt-Lecuona, Carlos; Kammer, Thomas; Graf, Erika; Koller, Michael; Kleinjung, Tobias; Lehner, Astrid; Schecklmann, Martin; Pöppl, Timm B; Kreuzer, Peter; Frank, Elmar; Langguth, Berthold

Chronic tinnitus is a frequent, difficult to treat disease with high morbidity. This multicenter randomized, sham-controlled trial investigated the efficacy and safety of 1-Hz repetitive transcranial magnetic stimulation (rTMS) applied to the left temporal cortex in patients with chronic tinnitus. Tinnitus patients were randomized to receive 10 sessions of either real or sham 1-Hz-rTMS (2000 stimuli, 110% motor threshold) to the left temporal cortex. The primary outcome was the change in the sum score of the tinnitus questionnaire (TQ) of Goebel and Hiller from baseline to end of treatment. A total of 163 patients were enrolled in the study (real rTMS: 75; sham rTMS: 78). At day 12, the baseline mean of 43.1 TQ points in 71 patients assigned to real rTMS changed by -0.5 points; it changed by 0.5 points from a baseline of 42.1 in 75 patients randomized to sham rTMS (adjusted mean difference between groups: -1.0; 95.19% confidence interval: -3.2 to 1.2; p = 0.36). All secondary outcome measures including measures of depression and quality of life showed no significant differences either (p > 0.11). The number of participants with side-effects or adverse events did not differ between groups. Real 1-Hz-rTMS over the left temporal cortex was well tolerated but not superior compared with sham rTMS in improving tinnitus severity. These findings are in contrast to results from studies with smaller sample sizes and put the efficacy of this rTMS protocol for treatment of chronic tinnitus into question. Controlled Trials: http://www.isrctn.com/ISRCTN89848288. Copyright © 2017 Elsevier Inc. All rights reserved.

High resolution 1H NMR-based metabonomic study of the auditory cortex analogue of developing chick (Gallus gallus domesticus) following prenatal chronic loud music and noise exposure.

PubMed

Kumar, Vivek; Nag, Tapas Chandra; Sharma, Uma; Mewar, Sujeet; Jagannathan, Naranamangalam R; Wadhwa, Shashi

2014-10-01

Proper functional development of the auditory cortex (ACx) critically depends on early relevant sensory experiences. Exposure to high intensity noise (industrial/traffic) and music, a current public health concern, may disrupt the proper development of the ACx and associated behavior. The biochemical mechanisms associated with such activity dependent changes during development are poorly understood. Here we report the effects of prenatal chronic (last 10 days of incubation), 110dB sound pressure level (SPL) music and noise exposure on metabolic profile of the auditory cortex analogue/field L (AuL) in domestic chicks. Perchloric acid extracts of AuL of post hatch day 1 chicks from control, music and noise groups were subjected to high resolution (700MHz) (1)H NMR spectroscopy. Multivariate regression analysis of the concentration data of 18 metabolites revealed a significant class separation between control and loud sound exposed groups, indicating a metabolic perturbation. Comparison of absolute concentration of metabolites showed that overstimulation with loud sound, independent of spectral characteristics (music or noise) led to extensive usage of major energy metabolites, e.g., glucose, β-hydroxybutyrate and ATP. On the other hand, high glutamine levels and sustained levels of neuromodulators and alternate energy sources, e.g., creatine, ascorbate and lactate indicated a systems restorative measure in a condition of neuronal hyperactivity. At the same time, decreased aspartate and taurine levels in the noise group suggested a differential impact of prenatal chronic loud noise over music exposure. Thus prenatal exposure to loud sound especially noise alters the metabolic activity in the AuL which in turn can affect the functional development and later auditory associated behaviour. Copyright © 2014 Elsevier Ltd. All rights reserved.

iPlasticity: induced juvenile-like plasticity in the adult brain as a mechanism of antidepressants.

PubMed

Umemori, Juzoh; Winkel, Frederike; Didio, Giuliano; Llach Pou, Maria; Castrén, Eero

2018-05-26

The network hypothesis of depression proposes that mood disorders reflect problems in information processing within particular neural networks. Antidepressants, including selective serotonin reuptake inhibitors (SSRIs), function by gradually improving information processing within these networks. Antidepressants have been shown to induce a state of juvenile-like plasticity comparable to that observed during developmental critical periods: such critical-period-like plasticity allows brain networks to better adapt to extrinsic and intrinsic signals. We have coined this drug-induced state of juvenile-like plasticity iPlasticity. A combination of iPlasticity induced by chronic SSRI treatment together with training, rehabilitation, or psychotherapy improves symptoms of neuropsychiatric disorders and issues underlying the developmentally- or genetically-malfunctioning networks. We have proposed that iPlasticity might be a critical component of antidepressant action. We have demonstrated that iPlasticity occurs in the visual cortex, fear erasure network, extinction of aggression caused by social isolation, and spatial reversal memory in rodent models. Chronic SSRI treatment is known to promote neurogenesis and to cause dematuration of granule cells in the dentate gyrus and of interneurons, especially parvalbumin interneurons enwrapped by perineuronal nets in the prefrontal cortex, visual cortex, and amygdala. Brain-derived neurotrophic factor (BDNF), via its receptor Tropomyosin kinase receptor B (TrkB), is involved in processes of the synaptic plasticity, including neurogenesis, neuronal differentiation, weight of synapses, and gene regulation of synaptic formation. BDNF can be activated by both chronic SSRI treatment and neuronal activity. Accordingly, the BDNF/TrkB pathway is critical for iPlasticity, but further analyses will be needed to provide mechanical insight into the processes of iPlasticity. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Gene expression in dopamine and GABA systems in an animal model of schizophrenia: effects of antipsychotic drugs.

PubMed

Lipska, Barbara K; Lerman, Daniel N; Khaing, Zin Z; Weickert, Cynthia Shannon; Weinberger, Daniel R

2003-07-01

We used in situ hybridization histochemistry to assess expression of dopamine receptors (D1R, D2R and D3R), neurotensin, proenkephalin and glutamate decarboxylase-67 (GAD67) in the prefrontal cortex, striatum, and/or nucleus accumbens in adult rats with neonatal ventral hippocampal (VH) lesions and in control animals after acute and chronic treatment with antipsychotic drugs clozapine and haloperidol. We also acquired these measures in a separate cohort of treatment-naïve sham and neonatally VH-lesioned rats used as an animal model of schizophrenia. Our results indicate that the neonatal VH lesion did not alter expression of D1R, D3R, neurotensin or proenkephalin expression in any brain region examined. However, D2R mRNA expression was down-regulated in the striatum, GAD67 mRNA was down-regulated in the prefrontal cortex and prodynorphin mRNA was up-regulated in the striatum of the VH-lesioned rats as compared with sham controls. Antipsychotic drugs did not alter expression of D1R, D2R or D3R receptor mRNAs but elevated neurotensin and proenkephalin expression in both groups of rats; patterns of changes were dependent on the duration of treatment and brain area examined. GAD67 mRNA was up-regulated by chronic antispychotics in the nucleus accumbens and the striatum and by chronic haloperidol in the prefrontal cortex in both sham and lesioned rats. These results indicate that the developmental VH lesion changed the striatal expression of D2R and prodynorphin and robustly compromised prefrontal GAD67 expression but did not modify drug-induced expression of any genes examined in this study.

[Effects of intermittent hypoxia on the responses of genioglossus motor cortex to transcranial magnetic stimulation in rats].

PubMed

Li, Ting; Wang, Wei; Kong, De-lei; Su, Jiao; Kang, Jian

2012-04-01

To explore the influence of intermittent hypoxia on the responses of genioglossus motor cortex to transcranial magnetic stimulation. Male Sprague-Dawley rats were randomly divided into a control group and a chronic intermittent hypoxia group. Transcranial magnetic stimulation was applied in genioglossus motor cortex of the 2 groups. The responses of transcranial magnetic stimulation were recorded and analyzed by single factor analysis of variance. The anterolateral area provided an optimal motor evoked potential response to transcranial magnetic stimulation in the genioglossus motor cortex of the rats. Genioglossus motor evoked potential latency and amplitude were significantly modified by intermittent hypoxic exposure, with a significant decrease in latency (F = 3.294, P < 0.01) at the 1st day [(4.90 ± 0.54) ms] and the 14th day [(4.64 ± 1.71) ms], and an increase in amplitude (F = 1.905, P < 0.05) at the 1st day [(2.28 ± 0.57) mV] and the 7th day [(1.89 ± 0.20) mV]. Intermittent hypoxia could increase the transcranial magnetic stimulation response of genioglossus motor cortex in rats.

Two-Photon Functional Imaging of the Auditory Cortex in Behaving Mice: From Neural Networks to Single Spines.

PubMed

Li, Ruijie; Wang, Meng; Yao, Jiwei; Liang, Shanshan; Liao, Xiang; Yang, Mengke; Zhang, Jianxiong; Yan, Junan; Jia, Hongbo; Chen, Xiaowei; Li, Xingyi

2018-01-01

In vivo two-photon Ca 2+ imaging is a powerful tool for recording neuronal activities during perceptual tasks and has been increasingly applied to behaving animals for acute or chronic experiments. However, the auditory cortex is not easily accessible to imaging because of the abundant temporal muscles, arteries around the ears and their lateral locations. Here, we report a protocol for two-photon Ca 2+ imaging in the auditory cortex of head-fixed behaving mice. By using a custom-made head fixation apparatus and a head-rotated fixation procedure, we achieved two-photon imaging and in combination with targeted cell-attached recordings of auditory cortical neurons in behaving mice. Using synthetic Ca 2+ indicators, we recorded the Ca 2+ transients at multiple scales, including neuronal populations, single neurons, dendrites and single spines, in auditory cortex during behavior. Furthermore, using genetically encoded Ca 2+ indicators (GECIs), we monitored the neuronal dynamics over days throughout the process of associative learning. Therefore, we achieved two-photon functional imaging at multiple scales in auditory cortex of behaving mice, which extends the tool box for investigating the neural basis of audition-related behaviors.

Two-Photon Functional Imaging of the Auditory Cortex in Behaving Mice: From Neural Networks to Single Spines

PubMed Central

Li, Ruijie; Wang, Meng; Yao, Jiwei; Liang, Shanshan; Liao, Xiang; Yang, Mengke; Zhang, Jianxiong; Yan, Junan; Jia, Hongbo; Chen, Xiaowei; Li, Xingyi

2018-01-01

In vivo two-photon Ca2+ imaging is a powerful tool for recording neuronal activities during perceptual tasks and has been increasingly applied to behaving animals for acute or chronic experiments. However, the auditory cortex is not easily accessible to imaging because of the abundant temporal muscles, arteries around the ears and their lateral locations. Here, we report a protocol for two-photon Ca2+ imaging in the auditory cortex of head-fixed behaving mice. By using a custom-made head fixation apparatus and a head-rotated fixation procedure, we achieved two-photon imaging and in combination with targeted cell-attached recordings of auditory cortical neurons in behaving mice. Using synthetic Ca2+ indicators, we recorded the Ca2+ transients at multiple scales, including neuronal populations, single neurons, dendrites and single spines, in auditory cortex during behavior. Furthermore, using genetically encoded Ca2+ indicators (GECIs), we monitored the neuronal dynamics over days throughout the process of associative learning. Therefore, we achieved two-photon functional imaging at multiple scales in auditory cortex of behaving mice, which extends the tool box for investigating the neural basis of audition-related behaviors. PMID:29740289

Differential Regulation of Neuropeptide Y In the Amygdala and Prefrontal Cortex During Recovery from Chronic Variable Stress

DTIC Science & Technology

2011-09-01

T., Pabst, R., and Von Horsten, S. (2003). Behav- ioral effects of neuropeptide Y in F344 rat substrains with a reduced dipeptidyl- peptidase IV...studies and pre-clinical animal models supports a role for neuropeptide Y (NPY) in adaptive emotional response following stress. The long-term impact of...stress-related psychopathol- ogy. In these studies, we examined expression of NPY during recovery from a chronic variable stress (CVS) model of

Therapeutic and protective effects of Caesalpinia gilliesii and Cajanus cajan proteins against acetaminophen overdose-induced renal damage.

PubMed

Aly, Hanan F; Rizk, Maha Z; Abo-Elmatty, Dina M; Desoky, M M; Ibrahim, N A; Younis, Eman A

2016-04-01

The present work aims to evaluate the protective and ameliorative effects of two plant-derived proteins obtained from the seeds of Cajanus cajan and Caesalpinia gilliesii(Leguminosae) against the toxic effects of acetaminophen in kidney after chronic dose through determination of certain biochemical markers including total urea, creatinine, and kidney marker enzyme, that is, glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In addition histopathological examination of intoxicated and treated kidney with both proteins was performed. The present results show a significant increase in serum total urea and creatinine, while significant decrease in GAPDH. Improvement in all biochemical parameters studied was demonstrated, which was documented by the amelioration signs in rats kidney architecture. Thus, both plant protein extracts can counteract the nephrotoxic process, minimize damage to the kidney, delay disease progression, and reduce its complications. © The Author(s) 2013.

Chemoproteomics reveals baicalin activates hepatic CPT1 to ameliorate diet-induced obesity and hepatic steatosis.

PubMed

Dai, Jianye; Liang, Kai; Zhao, Shan; Jia, Wentong; Liu, Yuan; Wu, Hongkun; Lv, Jia; Cao, Chen; Chen, Tao; Zhuang, Shentian; Hou, Xiaomeng; Zhou, Shijie; Zhang, Xiannian; Chen, Xiao-Wei; Huang, Yanyi; Xiao, Rui-Ping; Wang, Yan-Ling; Luo, Tuoping; Xiao, Junyu; Wang, Chu

2018-06-11

Obesity and related metabolic diseases are becoming worldwide epidemics that lead to increased death rates and heavy health care costs. Effective treatment options have not been found yet. Here, based on the observation that baicalin, a flavonoid from the herbal medicine Scutellaria baicalensis , has unique antisteatosis activity, we performed quantitative chemoproteomic profiling and identified carnitine palmitoyltransferase 1 (CPT1), the controlling enzyme for fatty acid oxidation, as the key target of baicalin. The flavonoid directly activated hepatic CPT1 with isoform selectivity to accelerate the lipid influx into mitochondria for oxidation. Chronic treatment of baicalin ameliorated diet-induced obesity (DIO) and hepatic steatosis and led to systemic improvement of other metabolic disorders. Disruption of the predicted binding site of baicalin on CPT1 completely abolished the beneficial effect of the flavonoid. Our discovery of baicalin as an allosteric CPT1 activator opens new opportunities for pharmacological treatment of DIO and associated sequelae.

A plastic stabilizer dibutyltin dilaurate induces subchronic neurotoxicity in rats☆

PubMed Central

Jin, Minghua; Song, Peilin; Li, Na; Li, Xuejun; Chen, Jiajun

2012-01-01

Dibutyltin dilaurate functions as a stabilizer for polyvinyl chloride. In this study, experimental rats were intragastrically administered 5, 10, or 20 mg/kg dibutyltin dilaurate to model sub-chronic poisoning. After exposure, our results showed the activities of superoxide dismutase and glutathione peroxidase decreased in rat brain tissue, while the malondialdehyde and nitric oxide content, as well as nitric oxide synthase activity in rat brain tissue increased. The cell cycle in the right parietal cortex was disordered and the rate of apoptosis increased. DNA damage was aggravated in the cerebral cortex, and the ultrastructure of the right parietal cortex tissues was altered. The above changes became more apparent with exposure to increasing doses of dibutyltin dilaurate. Our experimental findings confirmed the neurotoxicity of dibutyltin dilaurate in rat brain tissues, and demonstrated that the poisoning was dose-dependent. PMID:25538742

All-optical mapping of barrel cortex circuits based on simultaneous voltage-sensitive dye imaging and channelrhodopsin-mediated photostimulation

PubMed Central

Lo, Shun Qiang; Koh, Dawn X. P.; Sng, Judy C. G.; Augustine, George J.

2015-01-01

Abstract. We describe an experimental approach that uses light to both control and detect neuronal activity in mouse barrel cortex slices: blue light patterned by a digital micromirror array system allowed us to photostimulate specific layers and columns, while a red-shifted voltage-sensitive dye was used to map out large-scale circuit activity. We demonstrate that such all-optical mapping can interrogate various circuits in somatosensory cortex by sequentially activating different layers and columns. Further, mapping in slices from whisker-deprived mice demonstrated that chronic sensory deprivation did not significantly alter feedforward inhibition driven by layer 5 pyramidal neurons. Further development of voltage-sensitive optical probes should allow this all-optical mapping approach to become an important and high-throughput tool for mapping circuit interactions in the brain. PMID:26158003

What the cerveau isolé preparation tells us nowadays about sleep-wake mechanisms?

PubMed

Gottesmann, C

1988-01-01

The intercollicular transected preparation opened a rich field for investigations of sleep-wake mechanisms. Initial results showed that brain stem ascending influences are essential for maintaining an activated cortex. It was subsequently shown that the forebrain also develops activating influences, since EEG desynchronization of the cortex reappears in the chronic cerveau isolé preparation, and continuous or almost continuous theta rhythm is able to occur in the acute cerveau isolé preparation. A brief "intermediate stage" of sleep occurs during natural sleep just prior to and after paradoxical sleep. It is characterized by cortical spindle bursts, hippocampal low frequency theta activity (two patterns of the acute cerveau isolé preparation) and is accompanied by a very low thalamic transmission level, suggesting a cerveau isolé-like state. The chronic cerveau isolé preparation also demonstrates that the executive processes of paradoxical sleep are located in the lower brain stem, while the occurrence of this sleep stage seems to be modulated by forebrain structures.

Neuropathic Pain Causes Pyramidal Neuronal Hyperactivity in the Anterior Cingulate Cortex.

PubMed

Zhao, Ruohe; Zhou, Hang; Huang, Lianyan; Xie, Zhongcong; Wang, Jing; Gan, Wen-Biao; Yang, Guang

2018-01-01

The anterior cingulate cortex (ACC) is thought to be important for acute pain perception as well as the development of chronic pain after peripheral nerve injury. Nevertheless, how ACC neurons respond to sensory stimulation under chronic pain states is not well understood. Here, we used an in vivo two-photon imaging technique to monitor the activity of individual neurons in the ACC of awake, head restrained mice. Calcium imaging in the dorsal ACC revealed robust somatic activity in layer 5 (L5) pyramidal neurons in response to peripheral noxious stimuli, and the degree of evoked activity was correlated with the intensity of noxious stimulation. Furthermore, the activation of ACC neurons occurred bilaterally upon noxious stimulation to either contralateral or ipsilateral hind paws. Notably, with nerve injury-induced neuropathic pain in one limb, L5 pyramidal neurons in both sides of the ACC showed enhanced activity in the absence or presence of pain stimuli. These results reveal hyperactivity of L5 pyramidal neurons in the bilateral ACC during the development of neuropathic pain.

Personalized, bilateral whole-body somatosensory cortex stimulation to relieve fatigue in multiple sclerosis.

PubMed

Cancelli, Andrea; Cottone, Carlo; Giordani, Alessandro; Migliore, Simone; Lupoi, Domenico; Porcaro, Camillo; Mirabella, Massimiliano; Rossini, Paolo Maria; Filippi, Maria Maddalena; Tecchio, Franca

2017-07-01

The patients suffering from multiple sclerosis (MS) often consider fatigue the most debilitating symptom they experience, but conventional medicine currently offers poorly efficacious therapies. We executed a replication study of an innovative approach for relieving MS fatigue. According to the sample size estimate, we recruited 10 fatigued MS patients who received 5-day transcranial direct current stimulation (tDCS) in a randomized, double-blind, Sham-controlled, crossover study, with modified Fatigue Impact Scale (mFIS) score reduction at the end of the treatment as primary outcome. A personalized anodal electrode, shaped on the magnetic resonance imaging (MRI)-derived individual cortical folding, targeted the bilateral whole-body primary somatosensory cortex (S1) with an occipital cathode. The amelioration of fatigue symptoms after Real stimulation (40% of baseline) was significantly larger than after Sham stimulation (14%, p = 0.012). Anodal whole body S1 induced a significant fatigue reduction in mildly disabled MS patients when the fatigue-related symptoms severely hampered their quality of life. This second result in an independent group of patients supports the idea that neuromodulation interventions that properly select a personalized target might be a suitable non-pharmacological treatment for MS fatigue.

Mangiferin attenuates blast-induced traumatic brain injury via inhibiting NLRP3 inflammasome.

PubMed

Fan, Kaihua; Ma, Jie; Xiao, Wenjing; Chen, Jingmin; Wu, Juan; Ren, Jiandong; Hou, Jun; Hu, Yonghe; Gu, Jianwen; Yu, Botao

2017-06-01

There is growing evidence that Mangiferin possess therapeutic benefit during neuroinflammation on various brain injury models due to its anti-inflammatory properties. It is reported that inflammatory plays a crucial role in the pathogenesis of secondary injury induced by the blast-induced traumatic brain injury (bTBI). However, the role of mangiferin in bTBI is yet to be studied. In our study, the potential effect of mangiferin in the duration of bTBI was examined first. Fortunately, the amelioration of cerebral cortex damage was found in rats suffering bTBI after mangiferin administration. Furthermore, the detail mechanism of mangiferin's beneficial actions in bTBI was also studied. The results revealed that mangiferin might alleviate brain damage in rats with bTBI by inhibiting the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome activation, which was accompanied by mangiferin's inhibition of oxidative stress and pro-inflammatory cytokines production. Therefore, this research allows us to speculate that, for first time, NLRP3 is involved in the anti-inflammatory effect of mangiferin in the cerebral cortex, and mangiferin could be a potential therapy drug for bTBI. Copyright © 2017 Elsevier B.V. All rights reserved.

Vitamin D3 May Ameliorate the Ketoconazole Induced Adrenal Injury: Histological and Immunohistochemical Studies on Albino Rats

PubMed Central

Khalil, Mahmoud Salah

2015-01-01

Ketoconazole (KZ) is used widely for treating the superficial, systemic fungal activities and hyperandrogenemic states. Its uses are limited by its deleterious effect on histological structure and function of the adrenal cortex. This study investigates whether vitamin D3 supplement can ameliorate the morphological changes induced by KZ. Thirty four adult male albino rats were randomized into control group (Group I) which was subdivided into: control 1 (n=7) and control 2 (n=7): In control 1, rats were intraperitoneal (I.P) injected once with 1 ml of polyethylene glycol-400 for 15 consecutive days and control 2 rats were injected I.P with (1 μg/kg) of vitamin D3 for the same period. Group II (n=10): rats were I.P injected with KZ (10 mg/100 g of body weight) once daily for 15 days; Group III (n=10): rats were I.P concomitantly injected with KZ and vitamin D3 similar doses to animals in groups II and control 2 respectively. Blood samples were collected to determine plasma ACTH, corticosterone and aldosterone levels. The right adrenal specimens sections were stained with Haematoxylin & Eosin and Masson Trichrome for histological studies and treated with Bax, Ubiquitin and vitamin D receptors for immunohistochemical studies. KZ induced adrenal cortical morphological changes in forms of disturbed adrenocorticocyte cytological architecture, nuclear changes, and intracellular lipid accumulation. KZ also increased adrenal Bax and Ub but decreased the vitamin D receptors immunopositive staining expression, in addition to increased plasma ACTH as well as decreased corticosterone and aldosterone levels. These changes were ameliorated by supplementing with vitamin D3. PMID:26379312

Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPARγ, and HO-1

PubMed Central

Wu, Qing Qing; Wang, Yanxia; Senitko, Martin; Meyer, Colin; Wigley, W. Christian; Ferguson, Deborah A.; Grossman, Eric; Chen, Jianlin; Zhou, Xin J.; Hartono, John; Winterberg, Pamela; Chen, Bo; Agarwal, Anapam

2011-01-01

Ischemic acute kidney injury (AKI) triggers expression of adaptive (protective) and maladaptive genes. Agents that increase expression of protective genes should provide a therapeutic benefit. We now report that bardoxolone methyl (BARD) ameliorates ischemic murine AKI as assessed by both renal function and pathology. BARD may exert its beneficial effect by increasing expression of genes previously shown to protect against ischemic AKI, NF-E2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor-γ (PPARγ), and heme oxygenase 1 (HO-1). Although we found that BARD alone or ischemia-reperfusion alone increased expression of these genes, the greatest increase occurred after the combination of both ischemia-reperfusion and BARD. BARD had a different mode of action than other agents that regulate PPARγ and Nrf2. Thus we report that BARD regulates PPARγ, not by acting as a ligand but by increasing the amount of PPARγ mRNA and protein. This should increase ligand-independent effects of PPARγ. Similarly, BARD increased Nrf2 mRNA; this increased Nrf2 protein by mechanisms in addition to the prolongation of Nrf2 protein half-life previously reported. Finally, we localized expression of these protective genes after ischemia and BARD treatment. Using double-immunofluorescence staining for CD31 and Nrf2 or PPARγ, we found increased Nrf2 and PPARγ on glomerular endothelia in the cortex; Nrf2 was also present on cortical peritubular capillaries. In contrast, HO-1 was localized to different cells, i.e., tubules and interstitial leukocytes. Although Nrf2-dependent increases in HO-1 have been described, our data suggest that BARD's effects on tubular and leukocyte HO-1 during ischemic AKI may be Nrf2 independent. We also found that BARD ameliorated cisplatin nephrotoxicity. PMID:21289052

Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPARγ, and HO-1.

PubMed

Wu, Qing Qing; Wang, Yanxia; Senitko, Martin; Meyer, Colin; Wigley, W Christian; Ferguson, Deborah A; Grossman, Eric; Chen, Jianlin; Zhou, Xin J; Hartono, John; Winterberg, Pamela; Chen, Bo; Agarwal, Anapam; Lu, Christopher Y

2011-05-01

Ischemic acute kidney injury (AKI) triggers expression of adaptive (protective) and maladaptive genes. Agents that increase expression of protective genes should provide a therapeutic benefit. We now report that bardoxolone methyl (BARD) ameliorates ischemic murine AKI as assessed by both renal function and pathology. BARD may exert its beneficial effect by increasing expression of genes previously shown to protect against ischemic AKI, NF-E2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor-γ (PPARγ), and heme oxygenase 1 (HO-1). Although we found that BARD alone or ischemia-reperfusion alone increased expression of these genes, the greatest increase occurred after the combination of both ischemia-reperfusion and BARD. BARD had a different mode of action than other agents that regulate PPARγ and Nrf2. Thus we report that BARD regulates PPARγ, not by acting as a ligand but by increasing the amount of PPARγ mRNA and protein. This should increase ligand-independent effects of PPARγ. Similarly, BARD increased Nrf2 mRNA; this increased Nrf2 protein by mechanisms in addition to the prolongation of Nrf2 protein half-life previously reported. Finally, we localized expression of these protective genes after ischemia and BARD treatment. Using double-immunofluorescence staining for CD31 and Nrf2 or PPARγ, we found increased Nrf2 and PPARγ on glomerular endothelia in the cortex; Nrf2 was also present on cortical peritubular capillaries. In contrast, HO-1 was localized to different cells, i.e., tubules and interstitial leukocytes. Although Nrf2-dependent increases in HO-1 have been described, our data suggest that BARD's effects on tubular and leukocyte HO-1 during ischemic AKI may be Nrf2 independent. We also found that BARD ameliorated cisplatin nephrotoxicity.

Vitamin D3 May Ameliorate the Ketoconazole Induced Adrenal Injury: Histological and Immunohistochemical Studies on Albino Rats.

PubMed

Khalil, Mahmoud Salah

2015-08-27

Ketoconazole (KZ) is used widely for treating the superficial, systemic fungal activities and hyperandrogenemic states. Its uses are limited by its deleterious effect on histological structure and function of the adrenal cortex. This study investigates whether vitamin D3 supplement can ameliorate the morphological changes induced by KZ. Thirty four adult male albino rats were randomized into control group (Group I) which was subdivided into: control 1 (n=7) and control 2 (n=7): In control 1, rats were intraperitoneal (I.P) injected once with 1 ml of polyethylene glycol-400 for 15 consecutive days and control 2 rats were injected I.P with (1 μg/kg) of vitamin D3 for the same period. Group II (n=10): rats were I.P injected with KZ (10 mg/100 g of body weight) once daily for 15 days; Group III (n=10): rats were I.P concomitantly injected with KZ and vitamin D3 similar doses to animals in groups II and control 2 respectively. Blood samples were collected to determine plasma ACTH, corticosterone and aldosterone levels. The right adrenal specimens sections were stained with Haematoxylin & Eosin and Masson Trichrome for histological studies and treated with Bax, Ubiquitin and vitamin D receptors for immunohistochemical studies. KZ induced adrenal cortical morphological changes in forms of disturbed adrenocorticocyte cytological architecture, nuclear changes, and intracellular lipid accumulation. KZ also increased adrenal Bax and Ub but decreased the vitamin D receptors immunopositive staining expression, in addition to increased plasma ACTH as well as decreased corticosterone and aldosterone levels. These changes were ameliorated by supplementing with vitamin D3.

Mechanism of Cerebralcare Granule® for Improving Cognitive Function in Resting-State Brain Functional Networks of Sub-healthy Subjects.

PubMed

Li, Jing; Guo, Hao; Ge, Ling; Cheng, Long; Wang, Junjie; Li, Hong; Zhang, Kerang; Xiang, Jie; Chen, Junjie; Zhang, Hui; Xu, Yong

2017-01-01

Cerebralcare Granule® (CG), a Chinese herbal medicine, has been used to ameliorate cognitive impairment induced by ischemia or mental disorders. The ability of CG to improve health status and cognitive function has drawn researchers' attention, but the relevant brain circuits that underlie the ameliorative effects of CG remain unclear. The present study aimed to explore the underlying neurobiological mechanisms of CG in ameliorating cognitive function in sub-healthy subjects using resting-state functional magnetic resonance imaging (fMRI). Thirty sub-healthy participants were instructed to take one 2.5-g package of CG three times a day for 3 months. Clinical cognitive functions were assessed with the Chinese Revised Wechsler Adult Intelligence Scale (WAIS-RC) and Wechsler Memory Scale (WMS), and fMRI scans were performed at baseline and the end of intervention. Functional brain network data were analyzed by conventional network metrics (CNM) and frequent subgraph mining (FSM). Then 21 other sub-healthy participants were enrolled as a blank control group of cognitive functional. We found that administrating CG can improve the full scale of intelligence quotient (FIQ) and Memory Quotient (MQ) scores. At the same time, following CG treatment, in CG group, the topological properties of functional brain networks were altered in various frontal, temporal, occipital cortex regions, and several subcortical brain regions, including essential components of the executive attention network, the salience network, and the sensory-motor network. The nodes involved in the FSM results were largely consistent with the CNM findings, and the changes in nodal metrics correlated with improved cognitive function. These findings indicate that CG can improve sub-healthy subjects' cognitive function through altering brain functional networks. These results provide a foundation for future studies of the potential physiological mechanism of CG.

The neurocircuitry of illicit psychostimulant addiction: acute and chronic effects in humans

PubMed Central

Taylor, Sara B; Lewis, Candace R; Olive, M Foster

2013-01-01

Illicit psychostimulant addiction remains a significant problem worldwide, despite decades of research into the neural underpinnings and various treatment approaches. The purpose of this review is to provide a succinct overview of the neurocircuitry involved in drug addiction, as well as the acute and chronic effects of cocaine and amphetamines within this circuitry in humans. Investigational pharmacological treatments for illicit psychostimulant addiction are also reviewed. Our current knowledge base clearly demonstrates that illicit psychostimulants produce lasting adaptive neural and behavioral changes that contribute to the progression and maintenance of addiction. However, attempts at generating pharmacological treatments for psychostimulant addiction have historically focused on intervening at the level of the acute effects of these drugs. The lack of approved pharmacological treatments for psychostimulant addiction highlights the need for new treatment strategies, especially those that prevent or ameliorate the adaptive neural, cognitive, and behavioral changes caused by chronic use of this class of illicit drugs. PMID:24648786

Oral acetate supplementation attenuates N-methyl D-aspartate receptor hypofunction-induced behavioral phenotypes accompanied by restoration of acetyl-histone homeostasis.

PubMed

Singh, Seema; Choudhury, Arnab; Gusain, Priya; Parvez, Suhel; Palit, Gautam; Shukla, Shubha; Ganguly, Surajit

2016-04-01

Aberrations in cellular acetate-utilization processes leading to global histone hypoacetylation have been implicated in the etiology of neuropsychiatric disorders like schizophrenia. Here, we investigated the role of acetate supplementation in the form of glyceryl triacetate (GTA) for the ability to restore the N-methyl D-aspartate (NMDA) receptor-induced histone hypoacetylation and to ameliorate associated behavioral phenotypes in mice. Taking cues from the studies in SH-SY5Y cells, we monitored acetylation status of specific lysine residues of histones H3 and H4 (H3K9 and H4K8) to determine the impact of oral GTA supplementation in vivo. Mice treated chronically with MK-801 (10 days; 0.15 mg/kg daily) induced hypoacetylation of H3K9 and H4K8 in the hippocampus. Daily oral supplementation of GTA (2.9 g/kg) was able to prevent this MK801-induced hypoacetylation significantly. Though MK-801-stimulated decreases in acetyl-H3K9 and acetyl-H4K8 were found to be associated with ERK1/2 activation, GTA seemed to act independent of this pathway. Simultaneously, GTA administration was able to attenuate the chronic MK-801-induced cognitive behavior phenotypes in elevated plus maze and novel object recognition tests. Not only MK-801, GTA also demonstrated protective effects against behavioral phenotypes generated by another NMDA receptor antagonist, ketamine. Acute (single injection) ketamine-mediated hyperactivity phenotype and chronic (10 days treatment) ketamine-induced phenotype of exaggerated immobility in forced swim test were ameliorated by GTA. The signature behavioral phenotypes induced by acute and chronic regimen of NMDA receptor antagonists seemed to be attenuated by GTA. This study thus provides a therapeutic paradigm of using dietary acetate supplement in psychiatric disorders.

Nonselective inhibition of prostaglandin-endoperoxide synthase by naproxen ameliorates hepatic injury in animals with acute or chronic liver injury

PubMed Central

Bahde, Ralf; Kapoor, Sorabh; Gupta, Sanjeev

2014-01-01

The rising prevalence of hepatic injury due to toxins, metabolites, viruses, etc., necessitates development of further mechanisms for protecting the liver and for treating acute or chronic liver diseases. To examine whether inhibition of inflammation directed by cyclo-oxygenase pathways, we performed animal studies with naproxen, which inhibits prostaglandin-endoperoxide synthases 1 and 2 and is in extensive clinical use. We administered carbon tetrachloride to induce acute liver injury and ligated the common bile duct to induce chronic liver injury in adult rats. These experimental manipulations produced abnormalities in liver tests, tissue necrosis, compensatory hepatocyte or biliary proliferation, and onset of fibrosis, particularly after bile duct ligation. After carbon tetrachloride-induced acute injury, naproxen decreased liver test abnormalities, tissue necrosis and compensatory hepatocellular proliferation. After bile duct ligation-induced chronic injury, naproxen decreased liver test abnormalities, tissue injury and compensatory biliary hyperplasia. Moreover, after bile duct ligation, naproxen-treated rats showed more periductular oval liver cells, which have been classified as hepatic progenitor cells. In naproxen-treated rats, we found greater expression in hepatic stellate cells and mononuclear cells of cytoprotective factors, such as vascular endothelial growth factor. The ability of naproxen to induce expression of vascular endothelial growth factor was verified in cell culture studies with CFSC-8B clone of rat hepatic stellate cells. Whereas assays for carbon tetrachloride toxicity using cultured primary hepatocytes established that naproxen was not directly cytoprotective, we found conditioned medium containing vascular endothelial growth factor from naproxen-treated CFSC-8B cells protected hepatocytes from carbon tetrachloride toxicity. Therefore, naproxen was capable of ameliorating toxic liver injury, which involved naproxen-induced release of physiological cytoprotective factors in nonparenchymal liver cells. Such drug-induced release of endogenous cytoprotectants will advance therapeutic development for hepatic injury. PMID:24220607

The traditional drug Gongjin-Dan ameliorates chronic fatigue in a forced-stress mouse exercise model.

PubMed

Hong, Sung-Shin; Lee, Ji-Young; Lee, Jin-Seok; Lee, Hye-Won; Kim, Hyeong-Geug; Lee, Sam-Keun; Park, Bong-Ki; Son, Chang-Gue

2015-06-20

Gongjin-Dan is a representative traditional Oriental medicine herbal drug that has been used to treat chronic fatigue symptoms for several hundred years. We evaluated the anti-fatigue effects of Gongjin-Dan and the underlying mechanisms in a chronic forced exercise mouse model. Balb/C male mice underwent an extreme treadmill-based running stress (1-h, 5 days/week), and daily oral administration of distilled water, Gongjin-Dan (100, 200, or 400 mg/kg), or ascorbic acid (100 mg/kg) for 28 days. The anti-fatigue effects of Gongjin-Dan were evaluated with behavioral tests (exercise tolerance and swimming tests), and the corresponding mechanisms were investigated based on oxidative stress and inflammatory cytokine and stress hormone levels in skeletal muscle, sera, and brain tissue. Gongjin-Dan significantly increased exercise tolerance and latency times but reduced the number of electric shocks and immobilization time on the treadmill running and swimming tests, compared with the control group. Gongjin-Dan also significantly ameliorated alterations in oxidative stress-related biomarkers (reactive oxygen species and malondialdehyde), inflammatory cytokines (tumor necrosis factor-α, interleukin-1 beta, interleukin-6, and interferon-γ) and glycogen and L-lactate levels in skeletal muscle, compared with those in the control group. Moreover, Gongjin-Dan considerably normalized the forced running stress-induced changes in serum corticosterone and adrenaline levels, as well as brain serotonin level. These antioxidant and anti-stress effects of Gongjin-Dan were supported by the results of Western blotting (4-hydroxynonenal and heme oxygenase-1) and the gene expression levels (serotonin receptor and serotonin transporter). These results support the clinical relevance of Gongjin-Dan regarding anti-chronic fatigue properties. The underlying mechanisms involve attenuation of oxidative and inflammatory reactions in muscle and regulation of the stress response through the hypothalmo-pituitary-adrenal axis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Effects of acamprosate on attentional set-shifting and cellular function in the prefrontal cortex of chronic alcohol-exposed mice

NASA Astrophysics Data System (ADS)

Hu, Wei

Background: The medial prefrontal cortex (mPFC) inhibits impulsive and compulsive behaviors that characterize drug abuse and dependence. Acamprosate is the leading medication approved for the maintenance of abstinence, shown to reduce craving and relapse in animal models and human alcoholics. Whether acamprosate can modulate executive functions that are impaired by chronic ethanol exposure is unknown. Here we explored the effects of acamprosate on an attentional set-shifting task, and tested whether these behavioral effects are correlated with modulation of glutamatergic synaptic transmission and intrinsic excitability of mPFC neurons. Methods: We induced alcohol dependence in mice via chronic intermittent ethanol (CIE) exposure in vapor chambers and measured changes in alcohol consumption in a limited access 2-bottle choice paradigm. Impairments of executive function were assessed in an attentional set-shifting task. Acamprosate was applied subchronically for 2 days during withdrawal before the final behavioral test. Alcohol-induced changes in cellular function of layer 5/6 pyramidal neurons, and the potential modulation of these changes by acamprosate, were measured using patch clamp recordings in brain slices. Results: Chronic ethanol exposure impaired cognitive flexibility in the attentional set-shifting task. Acamprosate improved overall performance and reduced perseveration. Recordings of mPFC neurons showed that chronic ethanol exposure increased use-dependent presynaptic transmitter release and enhanced postsynaptic N-methyl-D-aspartate receptor (NMDAR) function. Moreover, CIE-treatment lowered input resistance, and decreased the threshold and the afterhyperpolarization (AHP) of action potentials, suggesting chronic ethanol exposure also impacted membrane excitability of mPFC neurons. However, acamprosate treatment did not reverse these ethanol-induced changes cellular function. Conclusion: Acamprosate improved attentional control of ethanol exposed animals, but did not alter the concurrent changes in synaptic transmission or membrane excitability of mPFC neurons, indicating that these changes are not the pharmacological targets of acamprosate in the recovery of mPFC functions affected by chronic ethanol exposure.

Curcumin reverses the effects of chronic stress on behavior, the HPA axis, BDNF expression and phosphorylation of CREB.

PubMed

Xu, Ying; Ku, Baoshan; Tie, Lu; Yao, Haiyan; Jiang, Wengao; Ma, Xing; Li, Xuejun

2006-11-29

Curcuma longa is a major constituent of the traditional Chinese medicine Xiaoyao-san, which has been used to effectively manage stress and depression-related disorders in China. Curcumin is the active component of curcuma longa, and its antidepressant effects were described in our prior studies in mouse models of behavioral despair. We hypothesized that curcumin may also alleviate stress-induced depressive-like behaviors and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. Thus in present study we assessed whether curcumin treatment (2.5, 5 and 10 mg/kg, p.o.) affects behavior in a chronic unpredictable stress model of depression in rats and examined what its molecular targets may be. We found that subjecting animals to the chronic stress protocol for 20days resulted in performance deficits in the shuttle-box task and several physiological effects, such as an abnormal adrenal gland weight to body weight (AG/B) ratio and increased thickness of the adrenal cortex as well as elevated serum corticosterone levels and reduced glucocorticoid receptor (GR) mRNA expression. These changes were reversed by chronic curcumin administration (5 or 10 mg/kg, p.o.). In addition, we also found that the chronic stress procedure induced a down-regulation of brain-derived neurotrophic factor (BDNF) protein levels and reduced the ratio of phosphorylated cAMP response element-binding protein (pCREB) to CREB levels (pCREB/CREB) in the hippocampus and frontal cortex of stressed rats. Furthermore, these stress-induced decreases in BDNF and pCREB/CREB were also blocked by chronic curcumin administration (5 or 10 mg/kg, p.o.). These results provide compelling evidence that the behavioral effects of curcumin in chronically stressed animals, and by extension humans, may be related to their modulating effects on the HPA axis and neurotrophin factor expressions.

Brain region differences in regulation of Akt and GSK3 by chronic stimulant administration in mice.

PubMed

Mines, Marjelo A; Jope, Richard S

2012-07-01

Acute amphetamine administration activates glycogen synthase kinase-3 (GSK3) by reducing its inhibitory serine-phosphorylation in mouse striatum and cerebral cortex. This results from Akt inactivation and is required for certain behavioral effects of amphetamine, such as increased locomotor activity. Here we tested if regulation of Akt and GSK3 was similarly affected by longer-term administration of amphetamine, as well as of methylphenidate, since each of these is administered chronically in patients with attention deficit hyperactivity disorder (ADHD). Akt is activated by post-translational phosphorylation on Thr308, and modulated by Ser473 phosphorylation, whereas phosphorylation on Ser21/9 inhibits the two GSK3 isoforms, GSK3α and GSK3β. After eight days of amphetamine or methylphenidate treatment, striatal Akt and GSK3 were dephosphorylated similar to reported changes after acute amphetamine treatment. Oppositely, in the cerebral cortex and hippocampus Akt and GSK3 phosphorylation increased after eight days of amphetamine or methylphenidate treatment. These opposite brain region changes in Akt and GSK3 phosphorylation matched opposite changes in the association of Akt with β-arrestin and GSK3, which after eight days of amphetamine treatment were increased in the striatum and decreased in the cerebral cortex. Thus, whereas the acute dephosphorylating effect of stimulants on Akt and GSK3 in the striatum was maintained, the response switched in the cerebral cortex after eight days of amphetamine or methylphenidate treatment to cause increased phosphorylation of Akt and GSK3. These results demonstrate that prolonged administration of stimulants causes brain region-selective differences in the regulation of Akt and GSK3. Copyright © 2012 Elsevier Inc. All rights reserved.

Functional connectivity and information flow of the respiratory neural network in chronic obstructive pulmonary disease.

PubMed

Yu, Lianchun; De Mazancourt, Marine; Hess, Agathe; Ashadi, Fakhrul R; Klein, Isabelle; Mal, Hervé; Courbage, Maurice; Mangin, Laurence

2016-08-01

Breathing involves a complex interplay between the brainstem automatic network and cortical voluntary command. How these brain regions communicate at rest or during inspiratory loading is unknown. This issue is crucial for several reasons: (i) increased respiratory loading is a major feature of several respiratory diseases, (ii) failure of the voluntary motor and cortical sensory processing drives is among the mechanisms that precede acute respiratory failure, (iii) several cerebral structures involved in responding to inspiratory loading participate in the perception of dyspnea, a distressing symptom in many disease. We studied functional connectivity and Granger causality of the respiratory network in controls and patients with chronic obstructive pulmonary disease (COPD), at rest and during inspiratory loading. Compared with those of controls, the motor cortex area of patients exhibited decreased connectivity with their contralateral counterparts and no connectivity with the brainstem. In the patients, the information flow was reversed at rest with the source of the network shifted from the medulla towards the motor cortex. During inspiratory loading, the system was overwhelmed and the motor cortex became the sink of the network. This major finding may help to understand why some patients with COPD are prone to acute respiratory failure. Network connectivity and causality were related to lung function and illness severity. We validated our connectivity and causality results with a mathematical model of neural network. Our findings suggest a new therapeutic strategy involving the modulation of brain activity to increase motor cortex functional connectivity and improve respiratory muscles performance in patients. Hum Brain Mapp 37:2736-2754, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Beta-hydroxy-beta-methylbutyrate (HMB) ameliorates age-related deficits in water maze performance, especially in male rats.

PubMed

Kougias, Daniel G; Hankosky, Emily R; Gulley, Joshua M; Juraska, Janice M

2017-03-01

Beta-hydroxy-beta-methylbutyrate (HMB) is commonly supplemented to maintain muscle in elderly and clinical populations and has potential as a nootropic. Previously, we have shown that in both male and female rats, long-term HMB supplementation prevents age-related dendritic shrinkage within the medial prefrontal cortex (mPFC) and improves cognitive flexibility and working memory performance that are both age- and sex-specific. In this study, we further explore the cognitive effects by assessing visuospatial learning and memory with the Morris water maze. Female rats were ovariectomized at 11months of age to model human menopause. At 12months of age, male and female rats received relatively short- or long-term (1- or 7-month) dietary HMB (450mg/kg/dose) supplementation twice a day prior to testing. Spatial reference learning and memory was assessed across four days in the water maze with four trials daily and a probe trial on the last day. Consistent with previous work, there were age-related deficits in water maze performance in both sexes. However, these deficits were ameliorated in HMB-treated males during training and in both sexes during probe trial performance. Thus, HMB supplementation prevented the age-related decrement in water maze performance, especially in male rats. Copyright © 2016 Elsevier Inc. All rights reserved.

Sensorimotor Modulation of Mood and Depression: In Search of an Optimal Mode of Stimulation

PubMed Central

Canbeyli, Resit

2013-01-01

Depression involves a dysfunction in an affective fronto-limbic circuitry including the prefrontal cortices, several limbic structures including the cingulate cortex, the amygdala, and the hippocampus as well as the basal ganglia. A major emphasis of research on the etiology and treatment of mood disorders has been to assess the impact of centrally generated (top-down) processes impacting the affective fronto-limbic circuitry. The present review shows that peripheral (bottom-up) unipolar stimulation via the visual and the auditory modalities as well as by physical exercise modulates mood and depressive symptoms in humans and animals and activates the same central affective neurocircuitry involved in depression. It is proposed that the amygdala serves as a gateway by articulating the mood regulatory sensorimotor stimulation with the central affective circuitry by emotionally labeling and mediating the storage of such emotional events in long-term memory. Since both amelioration and aggravation of mood is shown to be possible by unipolar stimulation, the review suggests that a psychophysical assessment of mood modulation by multimodal stimulation may uncover mood ameliorative synergisms and serve as adjunctive treatment for depression. Thus, the integrative review not only emphasizes the relevance of investigating the optimal levels of mood regulatory sensorimotor stimulation, but also provides a conceptual springboard for related future research. PMID:23908624

Chronic In Vivo Imaging Shows No Evidence of Dendritic Plasticity or Functional Remapping in the Contralesional Cortex after Stroke

PubMed Central

Johnston, David G.; Denizet, Marie; Mostany, Ricardo

2013-01-01

Most stroke survivors exhibit a partial recovery from their deficits. This presumably occurs because of remapping of lost capabilities to functionally related brain areas. Functional brain imaging studies suggest that remapping in the contralateral uninjured cortex might represent a transient stage of compensatory plasticity. Some postmortem studies have also shown that cortical lesions, including stroke, can trigger dendritic plasticity in the contralateral hemisphere, but the data are controversial. We used longitudinal in vivo two-photon microscopy in the contralateral homotopic cortex to record changes in dendritic spines of layer 5 pyramidal neurons in green fluorescent protein mice. We could not detect de novo growth of dendrites or changes in the density or turnover of spines for up to 4 weeks after stroke. We also used intrinsic optical signal imaging to investigate whether the forepaw (FP) sensory representation is remapped to the spared homotopic cortex after stroke. Stimulation of the contralateral FP reliably produced strong intrinsic signals in the spared hemisphere, but we could never detect a signal with ipsilateral FP stimulation after stroke. This lack of contralateral plasticity at the level of apical dendrites of layer 5 pyramidal neurons and FP sensory maps suggests that the contralesional cortex may not contribute to functional recovery after stroke and that, at least in mice, the peri-infarct cortex plays the dominant role in postischemic plasticity. PMID:22499800

Chronic in vivo imaging shows no evidence of dendritic plasticity or functional remapping in the contralesional cortex after stroke.

PubMed

Johnston, David G; Denizet, Marie; Mostany, Ricardo; Portera-Cailliau, Carlos

2013-04-01

Most stroke survivors exhibit a partial recovery from their deficits. This presumably occurs because of remapping of lost capabilities to functionally related brain areas. Functional brain imaging studies suggest that remapping in the contralateral uninjured cortex might represent a transient stage of compensatory plasticity. Some postmortem studies have also shown that cortical lesions, including stroke, can trigger dendritic plasticity in the contralateral hemisphere, but the data are controversial. We used longitudinal in vivo two-photon microscopy in the contralateral homotopic cortex to record changes in dendritic spines of layer 5 pyramidal neurons in green fluorescent protein mice. We could not detect de novo growth of dendrites or changes in the density or turnover of spines for up to 4 weeks after stroke. We also used intrinsic optical signal imaging to investigate whether the forepaw (FP) sensory representation is remapped to the spared homotopic cortex after stroke. Stimulation of the contralateral FP reliably produced strong intrinsic signals in the spared hemisphere, but we could never detect a signal with ipsilateral FP stimulation after stroke. This lack of contralateral plasticity at the level of apical dendrites of layer 5 pyramidal neurons and FP sensory maps suggests that the contralesional cortex may not contribute to functional recovery after stroke and that, at least in mice, the peri-infarct cortex plays the dominant role in postischemic plasticity.

Curcumin and Curcuma longa L. extract ameliorate lipid accumulation through the regulation of the endoplasmic reticulum redox and ER stress.

PubMed

Lee, Hwa-Young; Kim, Seung-Wook; Lee, Geum-Hwa; Choi, Min-Kyung; Chung, Han-Wool; Lee, Yong-Chul; Kim, Hyung-Ryong; Kwon, Ho Jeong; Chae, Han-Jung

2017-07-26

For this study, we examined the effects of curcumin against acute and chronic stress, paying specific attention to ROS. We also aimed to clarify the differences between acute and chronic stress conditions. We investigated the effects of curcumin against acute stress (once/1 day CCl 4 treatment) and chronic-stress (every other day/4week CCl 4 treatment). Compared with acute stress, in which the antioxidant system functioned properly and aspartate transaminase (AST) and ROS production increased, chronic stress increased AST, alanine aminotransferase (ALT), hepatic enzymes, and ROS more significantly, and the antioxidant system became impaired. We also found that ER-originated ROS accumulated in the chronic model, another difference between the two conditions. ER stress was induced consistently, and oxidative intra-ER protein folding status, representatively PDI, was impaired, especially in chronic stress. The PDI-associated client protein hepatic apoB accumulated with the PDI-binding status in chronic stress, and curcumin recovered the altered ER folding status, regulating ER stress and the resultant hepatic dyslipidemia. Throughout this study, curcumin and curcumin-rich Curcuma longa L. extract promoted recovery from CCl 4 -induced hepatic toxicity in both stress conditions. For both stress-associated hepatic dyslipidemia, curcumin and Curcuma longa L. extract might be recommendable to recover liver activity.

Combined rTMS treatment targeting the Anterior Cingulate and the Temporal Cortex for the Treatment of Chronic Tinnitus

PubMed Central

Kreuzer, Peter M.; Lehner, Astrid; Schlee, Winfried; Vielsmeier, Veronika; Schecklmann, Martin; Poeppl, Timm B.; Landgrebe, Michael; Rupprecht, Rainer; Langguth, Berthold

2015-01-01

Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a tinnitus treatment option. Promising results have been obtained by consecutive stimulation of lateral frontal and auditory brain regions. We investigated a combined stimulation paradigm targeting the anterior cingulate cortex (ACC) with double cone coil rTMS, followed by stimulation of the temporo-parietal junction area with a figure-of-eight coil. The study was conducted as a randomized, double-blind pilot trial in 40 patients suffering from chronic tinnitus. We compared mediofrontal stimulation with double-cone-coil, (2000 stimuli, 10 Hz) followed by left temporo-parietal stimulation with figure-of-eight-coil (2000 stimuli, 1 Hz) to left dorsolateral-prefrontal-cortex stimulation with figure-of-eight-coil (2000 stimuli, 10 Hz) followed by temporo-parietal stimulation with figure-of-eight-coil (2000 stimuli, 1 Hz). The stimulation was feasible with comparable dropout rates in both study arms; no severe adverse events were registered. Responder rates did not differ in both study arms. There was a significant main effect of time for the change in the TQ score, but no significant time x group interaction. This pilot study demonstrated the feasibility of combined mediofrontal/temporoparietal-rTMS-stimulation with double cone coil in tinnitus patients but failed to show better outcome compared to an actively rTMS treated control group. PMID:26667790

Chronic treatment with rivastigmine in patients with Alzheimer's disease: a study on primary motor cortex excitability tested by 5 Hz-repetitive transcranial magnetic stimulation.

PubMed

Trebbastoni, A; Gilio, F; D'Antonio, F; Cambieri, C; Ceccanti, M; de Lena, C; Inghilleri, M

2012-05-01

To investigate changes in cortical excitability and short-term synaptic plasticity we delivered 5 Hz repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex in 11 patients with mild-to-moderate Alzheimer's disease (AD) before and after chronic therapy with rivastigmine. Resting motor threshold (RMT), motor evoked potential (MEP), cortical silent period (CSP) after single stimulus and MEP facilitation during rTMS trains were tested three times during treatment. All patients underwent neuropsychological tests before and after receiving rivastigmine. rTMS data in patients were compared with those from age-matched healthy controls. At baseline, RMT was significantly lower in patients than in controls whereas CSP duration and single MEP amplitude were similar in both groups. In patients, rTMS failed to induce the normal MEP facilitation during the trains. Chronic rivastigmine intake significantly increased MEP amplitude after a single stimulus, whereas it left the other neurophysiological variables studied unchanged. No significant correlation was found between patients' neuropsychological test scores and TMS measures. Chronic treatment with rivastigmine has no influence on altered cortical excitability and short-term synaptic plasticity as tested by 5 Hz-rTMS. The limited clinical benefits related to cholinesterase inhibitor therapy in patients with AD depend on factors other than improved plasticity within the cortical glutamatergic circuits. Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Primed Physical Therapy Enhances Recovery of Upper Limb Function in Chronic Stroke Patients.

PubMed

Ackerley, Suzanne J; Byblow, Winston D; Barber, P Alan; MacDonald, Hayley; McIntyre-Robinson, Andrew; Stinear, Cathy M

2016-05-01

Recovery of upper limb function is important for regaining independence after stroke. To test the effects of priming upper limb physical therapy with intermittent theta burst stimulation (iTBS), a form of noninvasive brain stimulation. Eighteen adults with first-ever chronic monohemispheric subcortical stroke participated in this randomized, controlled, triple-blinded trial. Intervention consisted of priming with real or sham iTBS to the ipsilesional primary motor cortex immediately before 45 minutes of upper limb physical therapy, daily for 10 days. Changes in upper limb function (Action Research Arm Test [ARAT]), upper limb impairment (Fugl-Meyer Scale), and corticomotor excitability, were assessed before, during, and immediately, 1 month and 3 months after the intervention. Functional magnetic resonance images were acquired before and at one month after the intervention. Improvements in ARAT were observed after the intervention period when therapy was primed with real iTBS, but not sham, and were maintained at 1 month. These improvements were not apparent halfway through the intervention, indicating a dose effect. Improvements in ARAT at 1 month were related to balancing of corticomotor excitability and an increase in ipsilesional premotor cortex activation during paretic hand grip. Two weeks of iTBS-primed therapy improves upper limb function at the chronic stage of stroke, for at least 1 month postintervention, whereas therapy alone may not be sufficient to alter function. This indicates a potential role for iTBS as an adjuvant to therapy delivered at the chronic stage. © The Author(s) 2015.

Down-regulation of MAO-B activity and imidazoline receptors in rat brain following chronic treatment of morphine.

PubMed

Su, R B; Li, J; Li, X; Qin, B Y

2001-07-01

To study the regulation of monoamine oxidase-B (MAO-B) activity and imidazoline receptors (I-R) during long term treatment of morphine. MAO-B activity was detected by high performance liquid chromatography; I-R was detected by [3H]idazoxan binding test. Idazoxan and morphine inhibited whole brain homogenate MAO-B activity in a dose-dependent manner, while agmatine, an endogenous imidazoline ligand, didn't affect the activity of MAO-B, and it had no effect on the inhibition of MAO-B activity by idazoxan or morphine. MAO-B activity of rats decreased markedly in all five brain regions detected (cerebral cortex, hippocampus, thalamus, cerebellum, and striatum) after chronic administration of morphine for 16 d (P < 0.01). Acute challenge with naloxone or idazoxan did not influence MAO-B activity in morphine chronically treated rats. Although agmatine itself did not affect MAO-B activity, co-administration of agmatine with morphine could reverse the effect of morphine on MAO-B activity. Chronic administration of morphine significantly decreased the density of [3H]idazoxan binding sites and increased the binding affinity in cerebral cortex and cerebellum (P < 0.05 or P < 0.01). MAO-B activity was relevant to the abstinent syndrome of morphine dependent rats, but not related to the effect of agmatine on morphine analgesia; influence of agmatine on the pharmacological effects of morphine was based on its activation of imidazoline receptors.

Transcranial magnetic stimulation for the treatment of tinnitus: a new coil positioning method and first results.

PubMed

Langguth, Berthold; Zowe, Marc; Landgrebe, Michael; Sand, Philipp; Kleinjung, Tobias; Binder, Harald; Hajak, Göran; Eichhammer, Peter

2006-01-01

Auditory phantom perceptions are associated with hyperactivity of the central auditory system. Neuronavigation guided repetitive transcranial magnetic stimulation (rTMS) of the area of increased activity was demonstrated to reduce tinnitus perception. The study aimed at developing an easy applicable standard procedure for transcranial magnetic stimulation of the primary auditory cortex and to investigate this coil positioning strategy for the treatment of chronic tinnitus in clinical practice. The left gyrus of Heschl was targeted in 25 healthy subjects using a frameless stereotactical system. Based on individual scalp coordinates of the coil, a positioning strategy with reference to the 10--20-EEG system was developed. Using this coil positioning approach we started an open treatment trial. 28 patients with chronic tinnitus received 10 sessions of rTMS (intensity 110% of motor threshold, 1 Hz, 2000 Stimuli/day). Being within a range of about 20 mm diameter, the scalp coordinates for stimulating the primary auditory cortex allowed to determine a standard procedure for coil positioning. Clinical validation of this coil positioning method resulted in a significant improvement of tinnitus complaints (p<0.001). The newly developed coil positioning strategy may have the potential to offer a more easy-to-use stimulation approach for treating chronic tinnitus as compared with highly sophisticated, imaging guided treatment methods.

Orofacial Neuropathic Pain Leads to a Hyporesponsive Barrel Cortex with Enhanced Structural Synaptic Plasticity.

PubMed

Thibault, Karine; Rivière, Sébastien; Lenkei, Zsolt; Férézou, Isabelle; Pezet, Sophie

2016-01-01

Chronic pain is a long-lasting debilitating condition that is particularly difficult to treat due to the lack of identified underlying mechanisms. Although several key contributing processes have been described at the level of the spinal cord, very few studies have investigated the supraspinal mechanisms underlying chronic pain. Using a combination of approaches (cortical intrinsic imaging, immunohistochemical and behavioural analysis), our study aimed to decipher the nature of functional and structural changes in a mouse model of orofacial neuropathic pain, focusing on cortical areas involved in various pain components. Our results show that chronic neuropathic orofacial pain is associated with decreased haemodynamic responsiveness to whisker stimulation in the barrel field cortex. This reduced functional activation is likely due to the increased basal neuronal activity (measured indirectly using cFos and phospho-ERK immunoreactivity) observed in several cortical areas, including the contralateral barrel field, motor and cingulate cortices. In the same animals, immunohistochemical analysis of markers for active pre- or postsynaptic elements (Piccolo and phospho-Cofilin, respectively) revealed an increased immunofluorescence in deep cortical layers of the contralateral barrel field, motor and cingulate cortices. These results suggest that long-lasting orofacial neuropathic pain is associated with exacerbated neuronal activity and synaptic plasticity at the cortical level.

Region-specific changes in gene expression in rat brain after chronic treatment with levetiracetam or phenytoin

PubMed Central

Hassel, Bjørnar; Taubøll, Erik; Shaw, Renee; Gjerstad, Leif; Dingledine, Ray

2014-01-01

Summary Purpose It is commonly assumed that antiepileptic drugs (AEDs) act similarly in the various parts of the brain as long as their molecular targets are present. A few experimental studies on metabolic effects of vigabatrin, levetiracetam, valproate, and lamotrigine have shown that these drugs may act differently in different brain regions. We examined effects of chronic treatment with levetiracetam or phenytoin on mRNA levels to detect regional drug effects in a broad, nonbiased manner. Methods mRNA levels were monitored in three brain regions with oligonucleotide-based microarrays. Results Levetiracetam (150 mg/kg for 90 days) changed the expression of 65 genes in pons/medulla oblongata, two in hippocampus, and one in frontal cortex. Phenytoin (75 mg/kg), in contrast, changed the expression of only three genes in pons/medulla oblongata, but 64 genes in hippocampus, and 327 genes in frontal cortex. Very little overlap between regions or drug treatments was observed with respect to effects on gene expression. Discussion We conclude that chronic treatment with levetiracetam or phenytoin causes region-specific and highly differential effects on gene expression in the brain. Regional effects on gene expression could reflect regional differences in molecular targets of AEDs, and they could influence the clinical profiles of AEDs. PMID:20345932

Long-Term Occupational Stress Is Associated with Regional Reductions in Brain Tissue Volumes

PubMed Central

Blix, Eva; Perski, Aleksander; Berglund, Hans; Savic, Ivanka

2013-01-01

There are increasing reports of cognitive and psychological declines related to occupational stress in subjects without psychiatric premorbidity or major life trauma. The underlying neurobiology is unknown, and many question the notion that the described disabilities represent a medical condition. Using PET we recently found that persons suffering from chronic occupational stress had limbic reductions in the 5-HT1A receptor binding potential. Here we examine whether chronic work-related stress is also associated with changes in brain structure. We performed MRI-based voxel-based morphometry and structural volumetry in stressed subjects and unstressed controls focusing on gray (GM) and white matter (WM) volumes, and the volumes of hippocampus, caudate, and putamen – structures known to be susceptible to neurotoxic changes. Stressed subjects exhibited significant reductions in the GM volumes of the anterior cingulate cortex and the dorsolateral prefrontal cortex. Furthermore, their caudate and putamen volumes were reduced, and the volumes correlated inversely to the degree of perceived stress. Our results add to previous data on chronic psychosocial stress, and indicate a morphological involvement of the frontostriatal circuits. The present findings of morphological changes in these regions confirm our previous conclusion that symptoms from occupational stress merit careful investigations and targeted treatment. PMID:23776438

Inducing Negative Affect Increases the Reward Value of Appetizing Foods in Dieters

PubMed Central

Wagner, Dylan D.; Boswell, Rebecca G.; Kelley, William M.; Heatherton, Todd F.

2013-01-01

Experiencing negative affect frequently precedes lapses in self-control for dieters, smokers, and drug addicts. Laboratory research has similarly shown that inducing negative emotional distress increases the consumption of food or drugs. One hypothesis for this finding is that emotional distress sensitizes the brain’s reward system to appetitive stimuli. Using functional neuroimaging, we demonstrate that inducing negative affect in chronic dieters increases activity in brain regions representing the reward value of appetitive stimuli when viewing appetizing food cues. Thirty female chronic dieters were randomly assigned to receive either a negative (n = 15) or neutral mood induction (n = 15) immediately followed by exposure to images of appetizing foods and natural scenes during functional magnetic resonance imaging (fMRI). Compared to chronic dieters in a neutral mood, those receiving a negative mood induction showed increased activity in the orbitofrontal cortex to appetizing food images. In addition, activity to food images in the orbitofrontal cortex and ventral striatum was correlated with individual differences in the degree to which the negative mood induction decreased participants’ self-esteem. These findings suggest that distress sensitizes the brain’s reward system to appetitive cues thereby offering a mechanism for the oft-observed relationship between negative affect and disinhibited eating. PMID:22524295

ELEVATED GAMMA-AMINOBUTYRIC ACID LEVELS IN CHRONIC SCHIZOPHRENIA

PubMed Central

Öngür, Dost; Prescot, Andrew P.; McCarthy, Julie; Cohen, Bruce M.; Renshaw, Perry F.

2010-01-01

Background Despite widely-replicated abnormalities of gamma-aminobutyric acid (GABA) neurons in schizophrenia postmortem, few studies have measured tissue GABA levels in vivo. We used proton magnetic resonance spectroscopy to measure tissue GABA levels in participants with schizophrenia and healthy controls in the anterior cingulate cortex (ACC) and parieto-occipital cortex (POC). Methods 21 schizophrenia participants effectively treated on a stable medication regimen (mean age 39.0, 14 male) and 19 healthy controls (mean age 36.3, 12 male) underwent a proton magnetic resonance spectroscopy scan using GABA-selective editing at 4 Tesla after providing informed consent. Data were collected from two 16.7cc voxels and analyzed using LCModel. Results We found elevations in GABA/Cr in the schizophrenia group compared with controls (F(1,65)=4.149, p=0.046) in both brain areas (15.5% elevation in ACC, 11.9% in POC). We also found a positive correlation between GABA/Cr and Glu/Cr which was not accounted for by %GM or brain region. Conclusions We found elevated GABA/Cr in participants with chronically treated schizophrenia. Postmortem studies report evidence for dysfunctional GABAergic neurotransmission in schizophrenia. Elevated GABA levels, whether primary to illness or compensatory to another process, may be associated with dysfunctional GABAergic neurotransmission in chronic schizophrenia. PMID:20598290

Disease-specific molecular events in cortical multiple sclerosis lesions

PubMed Central

Wimmer, Isabella; Höftberger, Romana; Gerlach, Susanna; Haider, Lukas; Zrzavy, Tobias; Hametner, Simon; Mahad, Don; Binder, Christoph J.; Krumbholz, Markus; Bauer, Jan; Bradl, Monika

2013-01-01

Cortical lesions constitute an important part of multiple sclerosis pathology. Although inflammation appears to play a role in their formation, the mechanisms leading to demyelination and neurodegeneration are poorly understood. We aimed to identify some of these mechanisms by combining gene expression studies with neuropathological analysis. In our study, we showed that the combination of inflammation, plaque-like primary demyelination and neurodegeneration in the cortex is specific for multiple sclerosis and is not seen in other chronic inflammatory diseases mediated by CD8-positive T cells (Rasmussen’s encephalitis), B cells (B cell lymphoma) or complex chronic inflammation (tuberculous meningitis, luetic meningitis or chronic purulent meningitis). In addition, we performed genome-wide microarray analysis comparing micro-dissected active cortical multiple sclerosis lesions with those of tuberculous meningitis (inflammatory control), Alzheimer’s disease (neurodegenerative control) and with cortices of age-matched controls. More than 80% of the identified multiple sclerosis-specific genes were related to T cell-mediated inflammation, microglia activation, oxidative injury, DNA damage and repair, remyelination and regenerative processes. Finally, we confirmed by immunohistochemistry that oxidative damage in cortical multiple sclerosis lesions is associated with oligodendrocyte and neuronal injury, the latter also affecting axons and dendrites. Our study provides new insights into the complex mechanisms of neurodegeneration and regeneration in the cortex of patients with multiple sclerosis. PMID:23687122

Antidiabetic effect of Sida cordata in alloxan induced diabetic rats.

PubMed

Shah, Naseer Ali; Khan, Muhammad Rashid

2014-01-01

Medicinal plants are efficient ameliorator of oxidative stress associated with diabetes mellitus. In this study, ethyl acetate fraction (SCEE) of Sida cordata was investigated for scientific validation of its folk use in diabetes. Antidiabetic effect of SCEE was confirmed by antihyperglycemic activity in normal glucose loaded and diabetic glucose loaded animals as well as normal off feed animals. Confirmation of antidiabetic activity and toxicity ameliorative role of S. cordata was investigated in a chronic multiple dose treatment study of fifteen days. A single dose of alloxan (120 mg/kg) produced a decrease in insulin level, hyperglycemia, elevated total lipids, triglycerides, and cholesterol and decreased the high-density lipoproteins. Concurrent with these changes, there was an increase in the concentration of lipid peroxidation (TBARS), H2O2, and nitrite in pancreas, liver, and testis. This oxidative stress was related to a decrease in glutathione content (GSH) and antioxidant enzymes. Administration of SCEE for 15 days after diabetes induction ameliorated hyperglycemia, restored lipid profile, blunted the increase in TBARS, H2O2, and nitrite content, and stimulated the GSH production in the organs of alloxan-treated rats. We suggested that SCEE could be used as antidiabetic component in case of diabetes mellitus. This may be related to its antioxidative properties.

Febuxostat ameliorates secondary progressive experimental autoimmune encephalomyelitis by restoring mitochondrial energy production in a GOT2-dependent manner

PubMed Central

Kinoshita, Makoto; Sumi-Akamaru, Hisae; Sasaki, Tsutomu; Takata, Kazushiro; Koda, Toru; Namba, Akiko; Yamashita, Kazuya; Sanda, Eri; Sakaguchi, Manabu; Kumanogoh, Atsushi; Shirakura, Takashi; Tamura, Mizuho; Sakoda, Saburo; Mochizuki, Hideki

2017-01-01

Oxidative stress and mitochondrial dysfunction are important determinants of neurodegeneration in secondary progressive multiple sclerosis (SPMS). We previously showed that febuxostat, a xanthine oxidase inhibitor, ameliorated both relapsing-remitting and secondary progressive experimental autoimmune encephalomyelitis (EAE) by preventing neurodegeneration in mice. In this study, we investigated how febuxostat protects neuron in secondary progressive EAE. A DNA microarray analysis revealed that febuxostat treatment increased the CNS expression of several mitochondria-related genes in EAE mice, most notably including GOT2, which encodes glutamate oxaloacetate transaminase 2 (GOT2). GOT2 is a mitochondrial enzyme that oxidizes glutamate to produce α-ketoglutarate for the Krebs cycle, eventually leading to the production of adenosine triphosphate (ATP). Whereas GOT2 expression was decreased in the spinal cord during the chronic progressive phase of EAE, febuxostat-treated EAE mice showed increased GOT2 expression. Moreover, febuxostat treatment of Neuro2a cells in vitro ameliorated ATP exhaustion induced by rotenone application. The ability of febuxostat to preserve ATP production in the presence of rotenone was significantly reduced by GOT2 siRNA. GOT2-mediated ATP synthesis may be a pivotal mechanism underlying the protective effect of febuxostat against neurodegeneration in EAE. Accordingly, febuxostat may also have clinical utility as a disease-modifying drug in SPMS. PMID:29107957

Febuxostat ameliorates secondary progressive experimental autoimmune encephalomyelitis by restoring mitochondrial energy production in a GOT2-dependent manner.

PubMed

Honorat, Josephe A; Nakatsuji, Yuji; Shimizu, Mikito; Kinoshita, Makoto; Sumi-Akamaru, Hisae; Sasaki, Tsutomu; Takata, Kazushiro; Koda, Toru; Namba, Akiko; Yamashita, Kazuya; Sanda, Eri; Sakaguchi, Manabu; Kumanogoh, Atsushi; Shirakura, Takashi; Tamura, Mizuho; Sakoda, Saburo; Mochizuki, Hideki; Okuno, Tatsusada

2017-01-01

Oxidative stress and mitochondrial dysfunction are important determinants of neurodegeneration in secondary progressive multiple sclerosis (SPMS). We previously showed that febuxostat, a xanthine oxidase inhibitor, ameliorated both relapsing-remitting and secondary progressive experimental autoimmune encephalomyelitis (EAE) by preventing neurodegeneration in mice. In this study, we investigated how febuxostat protects neuron in secondary progressive EAE. A DNA microarray analysis revealed that febuxostat treatment increased the CNS expression of several mitochondria-related genes in EAE mice, most notably including GOT2, which encodes glutamate oxaloacetate transaminase 2 (GOT2). GOT2 is a mitochondrial enzyme that oxidizes glutamate to produce α-ketoglutarate for the Krebs cycle, eventually leading to the production of adenosine triphosphate (ATP). Whereas GOT2 expression was decreased in the spinal cord during the chronic progressive phase of EAE, febuxostat-treated EAE mice showed increased GOT2 expression. Moreover, febuxostat treatment of Neuro2a cells in vitro ameliorated ATP exhaustion induced by rotenone application. The ability of febuxostat to preserve ATP production in the presence of rotenone was significantly reduced by GOT2 siRNA. GOT2-mediated ATP synthesis may be a pivotal mechanism underlying the protective effect of febuxostat against neurodegeneration in EAE. Accordingly, febuxostat may also have clinical utility as a disease-modifying drug in SPMS.

Bilateral Renal Denervation Ameliorates Isoproterenol-Induced Heart Failure through Downregulation of the Brain Renin-Angiotensin System and Inflammation in Rat

PubMed Central

Li, Jian-Dong; Cheng, Ai-Yuan; Huo, Yan-Li; Fan, Jie; Zhang, Yu-Ping; Fang, Zhi-Qin; Sun, Hong-Sheng; Peng, Wei; Zhang, Jin-Shun

2016-01-01

Heart failure (HF) is characterized by cardiac dysfunction along with autonomic unbalance that is associated with increased renin-angiotensin system (RAS) activity and elevated levels of proinflammatory cytokines (PICs). Renal denervation (RD) has been shown to improve cardiac function in HF, but the protective mechanisms remain unclear. The present study tested the hypothesis that RD ameliorates isoproterenol- (ISO-) induced HF through regulation of brain RAS and PICs. Chronic ISO infusion resulted in remarked decrease in blood pressure (BP) and increase in heart rate and cardiac dysfunction, which was accompanied by increased BP variability and decreased baroreflex sensitivity and HR variability. Most of these adverse effects of ISO on cardiac and autonomic function were reversed by RD. Furthermore, ISO upregulated mRNA and protein expressions of several components of the RAS and PICs in the lamina terminalis and hypothalamic paraventricular nucleus, two forebrain nuclei involved in cardiovascular regulations. RD significantly inhibited the upregulation of these genes. Either intracerebroventricular AT1-R antagonist, irbesartan, or TNF-α inhibitor, etanercept, mimicked the beneficial actions of RD in the ISO-induced HF. The results suggest that the RD restores autonomic balance and ameliorates ISO-induced HF and that the downregulated RAS and PICs in the brain contribute to these beneficial effects of RD. PMID:27746855

Ultraviolet A Eye Irradiation Ameliorates Atopic Dermatitis via p53 and Clock Gene Proteins in NC/Nga Mice.

PubMed

Hiramoto, Keiichi; Yamate, Yurika; Yokoyama, Satoshi

2018-03-01

Atopic dermatitis (AD) is a widespread chronic skin condition that severely affects quality of life and can lead to more serious complications. Although ultraviolet (UV)A eye irradiation can exert various effects on the skin, it is unknown whether UVA can affect AD. To investigate potential associations, we used an NC/Nga mouse model of AD to study the effects of UVA eye irradiation. The eyes of mice were irradiated with a UVA dose of 100 kJ m -2 using a FL20SBLB-A lamp. Our histological data demonstrated that AD symptoms could be ameliorated by UVA eye irradiation. We also observed an increase in the levels of adrenocorticotropic hormone (ACTH), p53 and retinoid X receptor α (RXRα) in mice with UVA-irradiated eyes. In contrast, the levels of thymic stromal lymphopoietin (TSLP), period 2 (PER2) and differentiated embryo chondrocytes 1 (DEC1) protein were decreased in mice treated with UVA irradiation. Furthermore, UVA eye-irradiated mice exhibited reduced DEC1 and RXRα colocalization compared with nonirradiated mice. These results suggested that p53 and various clock gene proteins played important roles in the amelioration of AD symptoms observed after UVA eye irradiation; this technique may have therapeutic applications in AD. © 2017 The American Society of Photobiology.

Quercetin ameliorates pulmonary fibrosis by inhibiting SphK1/S1P signaling.

PubMed

Zhang, Xingcai; Cai, Yuli; Zhang, Wei; Chen, Xianhai

2018-06-25

Idiopathic pulmonary fibrosis (IPF) is an agnogenic chronic disorder with high morbidity and low survival rate. Quercetin is a flavonoid found in a variety of herbs with anti-fibrosis function. In this study, bleomycin was employed to induce a pulmonary fibrosis mouse model. The quercetin administration ameliorated bleomycin-induced pulmonary fibrosis, evidenced by the expression level changes of hydroxyproline, fibronectin, α-smooth muscle actin, Collagen I and Collagen III. The similar results were observed in transforming growth factor (TGF)-β-treated human embryonic lung fibroblast (HELF). The bleomycin or TGF-β administration caused the increase of sphingosine-1-phosphate (S1P) level in pulmonary tissue and HELF cells, as well as its activation-required kinase, sphingosine kinase 1 (SphK1), and its degradation enzyme, sphinogosine-1-phosphate lyase (S1PL). However, the increase of S1P, SphK1 and S1PL was attenuated by application of quercetin. In addition, the effect of quercetin on fibrosis was abolished by the ectopic expression of SphK1. The colocalization of SphK1/S1PL and fibroblast specific protein 1 (FSP1) suggested the roles of fibroblasts in pulmonary fibrosis. In summary, we demonstrated that quercetin ameliorated pulmonary fibrosis in vivo and in vitro by inhibiting SphK1/S1P signaling.

Functional Magnetic Resonance Imaging of Rats with Experimental Autoimmune Encephalomyelitis Reveals Brain Cortex Remodeling

PubMed Central

Tambalo, Stefano; Peruzzotti-Jametti, Luca; Rigolio, Roberta; Fiorini, Silvia; Bontempi, Pietro; Mallucci, Giulia; Balzarotti, Beatrice; Marmiroli, Paola; Sbarbati, Andrea; Cavaletti, Guido

2015-01-01

Cortical reorganization occurring in multiple sclerosis (MS) patients is thought to play a key role in limiting the effect of structural tissue damage. Conversely, its exhaustion may contribute to the irreversible disability that accumulates with disease progression. Several aspects of MS-related cortical reorganization, including the overall functional effect and likely modulation by therapies, still remain to be elucidated. The aim of this work was to assess the extent of functional cortical reorganization and its brain structural/pathological correlates in Dark Agouti rats with experimental autoimmune encephalomyelitis (EAE), a widely accepted preclinical model of chronic MS. Morphological and functional MRI (fMRI) were performed before disease induction and during the relapsing and chronic phases of EAE. During somatosensory stimulation of the right forepaw, fMRI demonstrated that cortical reorganization occurs in both relapsing and chronic phases of EAE with increased activated volume and decreased laterality index versus baseline values. Voxel-based morphometry demonstrated gray matter (GM) atrophy in the cerebral cortex, and both GM and white matter atrophy were assessed by ex vivo pathology of the sensorimotor cortex and corpus callosum. Neuroinflammation persisted in the relapsing and chronic phases, with dendritic spine density in the layer IV sensory neurons inversely correlating with the number of cluster of differentiation 45-positive inflammatory lesions. Our work provides an innovative experimental platform that may be pivotal for the comprehension of key mechanisms responsible for the accumulation of irreversible brain damage and for the development of innovative therapies to reduce disability in EAE/MS. SIGNIFICANCE STATEMENT Since the early 2000s, functional MRI (fMRI) has demonstrated profound modifications in the recruitment of cortical areas during motor, cognitive, and sensory tasks in multiple sclerosis (MS) patients. Experimental autoimmune encephalomyelitis (EAE) represents a reliable model of the chronic-progressive variant of MS. fMRI studies in EAE have not been performed extensively up to now. This paper reports fMRI studies in a rat model of MS with somatosensory stimulation of the forepaw. We demonstrated modifications in the recruitment of cortical areas consistent with data from MS patients. To the best of our knowledge, this is the first report of cortical remodeling in a preclinical in vivo model of MS. PMID:26157006

Chronic stress effects on working memory: association with prefrontal cortical tyrosine hydroxylase.

PubMed

Lee, Young-A; Goto, Yukiori

2015-06-01

Chronic stress causes deficits in cognitive function including working memory, for which transmission of such catecholamines as dopamine and noradrenaline transmission in the prefrontal cortex (PFC) are crucial. Since catecholamine synthesis depends on the rate-limiting enzyme, tyrosine hydroxylase (TH), TH is thought to play an important role in PFC function. In this study, we found that two distinct population existed in Sprague-Dawley rats in terms of working memory capacity, one with higher working memory capacity, and the other with low capacity. This distinction of working memory capacity became apparent after rats were exposed to chronic stress. In addition, such working memory capacity and alterations of working memory function by chronic stress were associated with TH expression in the PFC. Copyright © 2015 Elsevier B.V. All rights reserved.

Zhen-wu-tang ameliorates adenine-induced chronic renal failure in rats: regulation of the canonical Wnt4/beta-catenin signaling in the kidneys.

PubMed

La, Lei; Wang, Lili; Qin, Fei; Jiang, Jian; He, Songqi; Wang, Chunxia; Li, Yuhao

2018-06-12

Zhen-wu-tang (ZWT), composed of Radix Aconiti lateralis, Rhizoma Atractylodis macrocephalae, Poria, Radix Paeoniae alba and ginger, is a classic Chinese herbal formula for the treatment of chronic kidney diseases that may cause chronic renal failure (CRF). To better understand its clinical use, this study investigated the effects and underlying mechanisms of action of ZWT on CRF. CRF was induced by adenine. ZWT was given via an oral gavage method. The serum biochemical parameters were measured enzymatically or by ELISA. The kidneys were examined pathohistologically. The gene expression was analyzed by real time PCR and Western blot. Similar to the positive control losartan, ZWT extract inhibited adenine-induced increase in serum concentrations of creatinine, BUN and advanced oxidation protein products in rats. These effects were accompanied by attenuation of proteinuria and renal pathological changes and suppression of renal mRNA and protein overexpression of Collagen IV and fibronectin, two of the key components of fibrosis. Mechanistically, renal mRNA and protein expression of Wnt4, a Wnt signaling ligand, was increased in the adenine-treated group, compared to the vehicle-treated control. Consistently, Wnt4 downstream genes beta-catenin and Axin were also overexpressed. Treatment with ZWT extract and losartan suppressed adenine-stimulated overexpression of these mRNAs and proteins. The present results demonstrate that ZWT extract ameliorates adenine-induced CRF in rats by regulation of the canonical Wnt4/beta-catenin signaling in the kidneys. Our findings provide new insight into the underlying renoprotective mechanisms of the ancient formula. Copyright © 2017. Published by Elsevier B.V.

ALCOHOL AND THE PREFRONTAL CORTEX

PubMed Central

Abernathy, Kenneth; Chandler, L. Judson; Woodward, John J.

2013-01-01

The prefrontal cortex occupies the anterior portion of the frontal lobes and is thought to be one of the most complex anatomical and functional structures of the mammalian brain. Its major role is to integrate and interpret inputs from cortical and sub-cortical structures and use this information to develop purposeful responses that reflect both present and future circumstances. This includes both action-oriented sequences involved in obtaining rewards and inhibition of behaviors that pose undue risk or harm to the individual. Given the central role in initiating and regulating these often complex cognitive and behavioral responses, it is no surprise that alcohol has profound effects on the function of the prefrontal cortex. In this chapter, we review the basic anatomy and physiology of the prefrontal cortex and discuss what is known about the actions of alcohol on the function of this brain region. This includes a review of both the human and animal literature including information on the electrophysiological and behavioral effects that follow acute and chronic exposure to alcohol. The chapter concludes with a discussion of unanswered questions and areas needing further investigation. PMID:20813246

Pathology of Minamata disease.

PubMed

Eto, K

1997-01-01

Minamata disease, or methylmercury poisoning, was first discovered in 1956 around Minamata Bay, Kumamoto Prefecture, Japan. A similar epidemic occurred in 1965 along the Agano River, Niigata Prefecture, Japan. The neuropathology of Minamata disease has been well studied; this review focuses on human cases of Minamata disease in Kumamoto Prefecture. Nervous system lesions associated with Minamata disease have a characteristic distribution. In the cerebral cortex, the calcarine cortex was found to be involved in all cases of Minamata disease, particularly along the calcarine fissure. The destruction of nerve tissue was prominent in the anterior portions of the calcarine cortex. Occasionally, the centrifugal route from the visual and visual association areas (internal sagittal stratum) showed secondary degeneration in prolonged cases after acute onset. Postcentral, precentral, and temporal transverse cortices showed similar changes, though they were less severe. Intense lesions in the precentral cortex caused the development of secondary bilateral degeneration of the pyramidal tracts. In the cerebellum, the lesions occurred deeper in the hemisphere. The granule cell population was most affected. In the peripheral nerves, sensory nerves were more affected than motor nerves. Secondary degeneration of Goll's tracts was occasionally seen in prolonged or chronic cases.

A water extract of Mucuna pruriens provides long-term amelioration of parkinsonism with reduced risk for dyskinesias.

PubMed

Lieu, Christopher A; Kunselman, Allen R; Manyam, Bala V; Venkiteswaran, Kala; Subramanian, Thyagarajan

2010-08-01

Dopaminergic anti-parkinsonian medications, such as levodopa (LD) cause drug-induced dyskinesias (DID) in majority of patients with Parkinson's disease (PD). Mucuna pruriens, a legume extensively used in Ayurveda to treat PD, is reputed to provide anti-parkinsonian benefits without inducing DID. We compared the behavioral effects of chronic parenteral administration of a water extract of M. pruriens seed powder (MPE) alone without any additives, MPE combined with the peripheral dopa-decarboxylase inhibitor (DDCI) benserazide (MPE+BZ), LD+BZ and LD alone without BZ in the hemiparkinsonian rat model of PD. A battery of behavioral tests assessed by blinded investigators served as outcome measures in these randomized trials. In experiment 1, animals that received LD+BZ or MPE+BZ at high (6mg/kg) and medium (4mg/kg) equivalent doses demonstrated significant alleviation of parkinsonism, but, developed severe dose-dependent DID. LD+BZ at low doses (2mg/kg) did not provide significant alleviation of parkinsonism. In contrast, MPE+BZ at an equivalent low dose significantly ameliorated parkinsonism. In experiment 2, MPE without any additives (12mg/kg and 20mg/kg LD equivalent dose) alleviated parkinsonism with significantly less DID compared to LD+BZ or MPE+BZ. In experiment 3, MPE without additives administered chronically provided long-term anti-parkinsonian benefits without causing DID. In experiment 4, MPE alone provided significantly more behavioral benefit when compared to the equivalent dose of synthetic LD alone without BZ. In experiment 5, MPE alone reduced the severity of DID in animals initially primed with LD+BZ. These findings suggest that M. pruriens contains water-soluble ingredients that either have an intrinsic DDCI-like activity or mitigate the need for an add-on DDCI to ameliorate parkinsonism. These unique long-term anti-parkinsonian effects of a parenterally administered water extract of M. pruriens seed powder may provide a platform for future drug discoveries and novel treatment strategies in PD.

A Water Extract of Mucuna pruriens Provides Long-Term Amelioration of Parkinsonism with Reduced Risk for Dyskinesias

PubMed Central

Lieu, Christopher A.; Kunselman, Allen R.; Manyam, Bala V.; Venkiteswaran, Kala; Subramanian, Thyagarajan

2010-01-01

Dopaminergic anti-parkinsonian medications, such as levodopa (LD) cause drug-induced dyskinesias (DID) in majority of patients with Parkinson's disease (PD). Mucuna pruriens, a legume extensively used in Ayurveda to treat PD, is reputed to provide anti-parkinsonian benefits without inducing DID. We compared the behavioral effects of chronic parenteral administration of a water extract of Mucuna pruriens seed powder (MPE) alone without any additives, MPE combined with the peripheral dopa-decarboxylase inhibitor (DDCI) benserazide (MPE+BZ), LD+BZ and LD alone without BZ in the hemiparkinsonian rat model of PD. A battery of behavioral tests assessed by blinded investigators served as outcome measures in these randomized trials. In experiment 1, animals that received LD+BZ or MPE+BZ at high (6mg/Kg) and medium (4mg/Kg) equivalent doses demonstrated significant alleviation of parkinsonism, but, developed severe dose-dependent DID. LD+BZ at low doses (2mg/Kg) did not provide significant alleviation of parkinsonism. In contrast, MPE+BZ at an equivalent low dose significantly ameliorated parkinsonism. In experiment 2, MPE without any additives (12mg/Kg and 20mg/Kg LD equivalent dose) alleviated parkinsonism with significantly less DID compared to LD+BZ or MPE+BZ. In experiment 3, MPE without additives administered chronically provided long-term anti-parkinsonian benefits without causing DID. In experiment 4, MPE alone provided significantly more behavioral benefit when compared to the equivalent dose of synthetic LD alone without BZ. In experiment 5, MPE alone reduced the severity of DID in animals initially primed with LD+BZ. These findings suggest that Mucuna pruriens contains water soluble ingredients that either have an intrinsic DDCI-like activity or mitigate the need for an add-on DDCI to ameliorate parkinsonism. These unique long-term antiparkinsonian effects of a parenterally administered water extract of Mucuna pruriens seed powder may provide a platform for future drug discoveries and novel treatment strategies in PD. PMID:20570206

Imaging and serum biomarkers reflecting the functional efficacy of extended erythropoietin treatment in rats following infantile traumatic brain injury.

PubMed

Robinson, Shenandoah; Winer, Jesse L; Berkner, Justin; Chan, Lindsay A S; Denson, Jesse L; Maxwell, Jessie R; Yang, Yirong; Sillerud, Laurel O; Tasker, Robert C; Meehan, William P; Mannix, Rebekah; Jantzie, Lauren L

2016-06-01

OBJECTIVE Traumatic brain injury (TBI) is a leading cause of death and severe morbidity for otherwise healthy full-term infants around the world. Currently, the primary treatment for infant TBI is supportive, as no targeted therapies exist to actively promote recovery. The developing infant brain, in particular, has a unique response to injury and the potential for repair, both of which vary with maturation. Targeted interventions and objective measures of therapeutic efficacy are needed in this special population. The authors hypothesized that MRI and serum biomarkers can be used to quantify outcomes following infantile TBI in a preclinical rat model and that the potential efficacy of the neuro-reparative agent erythropoietin (EPO) in promoting recovery can be tested using these biomarkers as surrogates for functional outcomes. METHODS With institutional approval, a controlled cortical impact (CCI) was delivered to postnatal Day (P)12 rats of both sexes (76 rats). On postinjury Day (PID)1, the 49 CCI rats designated for chronic studies were randomized to EPO (3000 U/kg/dose, CCI-EPO, 24 rats) or vehicle (CCI-veh, 25 rats) administered intraperitoneally on PID1-4, 6, and 8. Acute injury (PID3) was evaluated with an immunoassay of injured cortex and serum, and chronic injury (PID13-28) was evaluated with digitized gait analyses, MRI, and serum immunoassay. The CCI-veh and CCI-EPO rats were compared with shams (49 rats) primarily using 2-way ANOVA with Bonferroni post hoc correction. RESULTS Following CCI, there was 4.8% mortality and 55% of injured rats exhibited convulsions. Of the injured rats designated for chronic analyses, 8.1% developed leptomeningeal cyst-like lesions verified with MRI and were excluded from further study. On PID3, Western blot showed that EPO receptor expression was increased in the injured cortex (p = 0.008). These Western blots also showed elevated ipsilateral cortex calpain degradation products for αII-spectrin (αII-SDPs; p < 0.001), potassium chloride cotransporter 2 (KCC2-DPs; p = 0.037), and glial fibrillary acidic protein (GFAP-DPs; p = 0.002), as well as serum GFAP (serum GFAP-DPs; p = 0.001). In injured rats multiplex electrochemiluminescence analyses on PID3 revealed elevated serum tumor necrosis factor alpha (TNFα p = 0.01) and chemokine (CXC) ligand 1 (CXCL1). Chronically, that is, in PID13-16 CCI-veh rats, as compared with sham rats, gait deficits were demonstrated (p = 0.033) but then were reversed (p = 0.022) with EPO treatment. Diffusion tensor MRI of the ipsilateral and contralateral cortex and white matter in PID16-23 CCI-veh rats showed widespread injury and significant abnormalities of functional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD); MD, AD, and RD improved after EPO treatment. Chronically, P13-P28 CCI-veh rats also had elevated serum CXCL1 levels, which normalized in CCI-EPO rats. CONCLUSIONS Efficient translation of emerging neuro-reparative interventions dictates the use of age-appropriate preclinical models with human clinical trial-compatible biomarkers. In the present study, the authors showed that CCI produced chronic gait deficits in P12 rats that resolved with EPO treatment and that chronic imaging and serum biomarkers correlated with this improvement.

Cholinergic Overstimulation Attenuates Rule Selectivity in Macaque Prefrontal Cortex.

PubMed

Major, Alex J; Vijayraghavan, Susheel; Everling, Stefan

2018-01-31

Acetylcholine is released in the prefrontal cortex (PFC) and is a key modulator of cognitive performance in primates. Cholinergic stimulation has been shown to have beneficial effects on performance of cognitive tasks, and cholinergic receptors are being actively explored as promising targets for ameliorating cognitive deficits in Alzheimer's disease. We hypothesized that cholinergic stimulation of PFC during performance of a cognitive task would augment neuronal activity and neuronal coding of task attributes. We iontophoretically applied the general cholinergic receptor agonist carbachol onto neurons in dorsolateral PFC (DLPFC) of male rhesus macaques performing rule-guided prosaccades and antisaccades, a well established oculomotor task for testing cognitive control. Carbachol application had heterogeneous effects on neuronal excitability, with both excitation and suppression observed in significant proportions. Contrary to our prediction, neurons with rule-selective activity exhibited a reduction in selectivity during carbachol application. Cholinergic stimulation disrupted rule selectivity regardless of whether it had suppressive or excitatory effects on these neurons. In addition, cholinergic stimulation excited putative pyramidal neurons, whereas the activity of putative interneurons remained unchanged. Moreover, cholinergic stimulation attenuated saccade direction selectivity in putative pyramidal neurons due to nonspecific increases in activity. Our results suggest excessive cholinergic stimulation has detrimental effects on DLPFC representations of task attributes. These findings delineate the complexity and heterogeneity of neuromodulation of cerebral cortex by cholinergic stimulation, an area of active exploration with respect to the development of cognitive enhancers. SIGNIFICANCE STATEMENT The neurotransmitter acetylcholine is known to be important for cognitive processes in the prefrontal cortex. Removal of acetylcholine from prefrontal cortex can disrupt short-term memory performance and is reminiscent of Alzheimer's disease, which is characterized by degeneration of acetylcholine-producing neurons. Stimulation of cholinergic receptors is being explored to create cognitive enhancers for the treatment of Alzheimer's disease and other psychiatric diseases. Here, we stimulated cholinergic receptors in prefrontal cortex and examined its effects on neurons that are engaged in cognitive behavior. Surprisingly, cholinergic stimulation decreased neurons' ability to discriminate between rules. This work suggests that overstimulation of acetylcholine receptors could disrupt neuronal processing during cognition and is relevant to the design of cognitive enhancers based on stimulating the cholinergic system. Copyright © 2018 the authors 0270-6474/18/381137-14$15.00/0.

The cerebellum mediates conflict resolution.

PubMed

Schweizer, Tom A; Oriet, Chris; Meiran, Nachshon; Alexander, Michael P; Cusimano, Michael; Stuss, Donald T

2007-12-01

Regions within the frontal and parietal cortex have been implicated as important neural correlates for cognitive control during conflict resolution. Despite the extensive reciprocal connectivity between the cerebellum and these putatively critical cortical areas, a role for the cerebellum in conflict resolution has never been identified. We used a task-switching paradigm that separates processes related to task-set switching and the management of response conflict independent of motor processing. Eleven patients with chronic, focal lesions to the cerebellum and 11 healthy controls were compared. Patients were slower and less accurate in conditions involving conflict resolution. In the absence of response conflict, however, tasks-witching abilities were not impaired in our patients. The cerebellum may play an important role in coordinating with other areas of cortex to modulate active response states. These results are the first demonstration of impaired conflict resolution following cerebellar lesions in the presence of an intact prefrontal cortex.

[Functional asymmetry of electric processes in the rabbit brain cortex at formation of the hunger dominant].

PubMed

Rusinova, E V

2011-01-01

The motivational condition of hunger and formation of the hunger dominant after daily food deprivation was studied in the conditions of chronic experiments on rabbits. It was shown, that the hunger condition was accompanied by left sided interhemispher asymmetry on indicators of spectral capacity of EEG frontal and right-hand asymmetry sensorimotor areas of the cortex. A hunger dominant was accompanied by falling of spectral capacity of EEG of areas of both hemispheres. The condition of hunger and a hunger dominant were characterized by right-hand asymmetry on average level of EEG coherence of frontal and sensorimotor areas. At transition of a condition of hunger in a hunger dominant there was an average level of EEG coherence decrease in areas of the right hemisphere. Electric processes of the cortex of the brain at a motivational condition of hunger and a hunger dominant were different.

Magnetic resonance evaluation of hydronephrosis in the dog

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thickman, D.; Kundel, H.; Biery, D.

1984-07-01

The ability of magnetic resonance (MR) imaging to detect and distinguish various stages of obstruction in the canine kidney was investigated. MR images were obtained at acute, subacute, and chronic stages of experimentally produced hydronephrosis. The renal cortex was distinguished from the renal medulla in the normal dog and in the acute and subacute stages of hydronephrosis. T1 relaxation times of the renal cortex and medulla were measured in vitro in 14 normal and nine experimental animals. These values were used to compute the amount of tissue contrast between the cortex and medulla and were compared with the degree ofmore » corticomedullary differentiation seen in the image. A relationship was noted between increasing T1 values and increasing water content. Corticomedullary contrast decreased with obstruction. The variation in corticomedullary image contracts may be useful for assessing the duration of hydronephrosis.« less

Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents

PubMed Central

Asshoff, Malte; Petzer, Verena; Warr, Matthew R.; Haschka, David; Tymoszuk, Piotr; Demetz, Egon; Seifert, Markus; Posch, Wilfried; Nairz, Manfred; Maciejewski, Pat; Fowles, Peter; Burns, Christopher J.; Smith, Gregg; Wagner, Kay-Uwe; Weiss, Guenter; Whitney, J. Andrew

2017-01-01

Patients with myelofibrosis (MF) often develop anemia and frequently become dependent on red blood cell transfusions. Results from a phase 2 study for the treatment of MF with the Janus kinase 1/2 (JAK1/2) inhibitor momelotinib (MMB) demonstrated that MMB treatment ameliorated anemia, which was unexpected for a JAK1/2 inhibitor, because erythropoietin-mediated JAK2 signaling is essential for erythropoiesis. Using a rat model of anemia of chronic disease, we demonstrated that MMB treatment can normalize hemoglobin and red blood cell numbers. We found that this positive effect is driven by direct inhibition of the bone morphogenic protein receptor kinase activin A receptor, type I (ACVR1), and the subsequent reduction of hepatocyte hepcidin production. Of note, ruxolitinib, a JAK1/2 inhibitor approved for the treatment of MF, had no inhibitory activity on this pathway. Further, we demonstrated the effect of MMB is not mediated by direct inhibition of JAK2-mediated ferroportin (FPN1) degradation, because neither MMB treatment nor myeloid-specific deletion of JAK2 affected FPN1 expression. Our data support the hypothesis that the improvement of inflammatory anemia by MMB results from inhibition of ACVR1-mediated hepcidin expression in the liver, which leads to increased mobilization of sequestered iron from cellular stores and subsequent stimulation of erythropoiesis. PMID:28188131

Effect of Hedera helix on lung histopathology in chronic asthma.

PubMed

Hocaoglu, Arzu Babayigit; Karaman, Ozkan; Erge, Duygu Olmez; Erbil, Guven; Yilmaz, Osman; Kivcak, Bijen; Bagriyanik, H Alper; Uzuner, Nevin

2012-12-01

Hedera helix is widely used to treat bronchial asthma for many years. However, effects of this herb on lung histopathology is still far from clear. We aimed to determine the effect of oral administration of Hedera helix on lung histopathology in a murine model of chronic asthma.BALB/c mice were divided into four groups; I (Placebo), II (Hedera helix), III (Dexamethasone) and IV (Control). All mice except controls were sensitized and challenged with ovalbumin. Then, mice in group I received saline, group II 100 mg/kg Hedera helix and group III 1 mg/kg dexamethasone via orogastic gavage once daily for one week. Airway histopathology was evaluated by using light and electron microscopy in all groups.Goblet cell numbers and thicknesses of basement membrane were found significantly lower in group II, but there was no statistically significant difference in terms of number of mast cells, thicknesses of epithelium and subepithelial smooth muscle layers between group I and II. When Hedera helix and dexamethasone groups were compared with each other, thickness of epithelium, subepithelial muscle layers, number of mast cells and goblet cells of group III were significantly ameliorated when compared with the group II. Although Hedera helix administration reduced only goblet cell counts and the thicknesses of basement membrane in the asthmatic airways, dexamethasone ameliorated all histopathologic parameters except thickness of basement membrane better than Hedera helix.

Rescue therapy with Tanshinone IIA hinders transition of acute kidney injury to chronic kidney disease via targeting GSK3β

PubMed Central

Jiang, Chunming; Zhu, Wei; Yan, Xiang; Shao, Qiuyuan; Xu, Biao; Zhang, Miao; Gong, Rujun

2016-01-01

Acute kidney injury (AKI) remains challenging for clinical practice and poses a risk of developing progressive chronic kidney disease (CKD) with no definitive treatment available yet. Tanshinone IIA, an active ingredient of Chinese herbal Salvia miltiorrhiza, has been widely used in Asia for the remarkable organoprotective activities. Its effect on established AKI, however, remains unknown. In mice with folic acid-induced AKI, delayed treatment with Tanshinone IIA, commenced early or late after injury, diminished renal expression of kidney injury markers, reduced apoptosis and improved kidney dysfunction, concomitant with mitigated histologic signs of AKI to CKD transition, including interstitial fibrosis and tubular atrophy, and with an ameliorated inflammatory infiltration in tubulointerstitium and a favored M2-skewed macrophage polarization. Mechanistically, Tanshinone IIA blunted glycogen synthase kinase (GSK)3β overactivity and hyperactivation of its downstream mitogen-activated protein kinases that are centrally implicated in renal fibrogenesis and inflammation. Inhibition of GSK3β is likely a key mechanism mediating the therapeutic activity of Tanshinone IIA, because sodium nitroprusside, a GSK3β activator, largely offset its renoprotective effect. In confirmatory studies, rescue treatment with Tanshinone IIA likewise ameliorated ischemia/reperfusion-induced kidney destruction in mice. Our data suggest that Tanshinone IIA represents a valuable treatment that improves post-AKI kidney salvage via targeting GSK3β. PMID:27857162

Effect of Shenxinning decoction on ventricular remodeling in AT1 receptor-knockout mice with chronic renal insufficiency.

PubMed

Yang, Xuejun; Zhou, Hua; Qu, Huiyan; Liu, Weifang; Huang, Xiaojin; Shun, Yating; He, Liqun

2014-01-01

To observe the efficacy of Shenxinning Decoction (SXND) in ventricular remodeling in AT1 receptor-knockout (AT1-KO) mice with chronic renal insufficiency (CRI). AT1-KO mice modeled with subtotal (5/6) nephrectomy were intervened with SXND for 12 weeks. Subsequently, blood urea nitrogen (BUN), serum creatinine (SCr), brain natriuretic peptide (BNP), echocardiography (left ventricular end-diastolic diameter, LVDD; left ventricular end-systolic diameter, LVDS; fractional shortening, FS; and ejection fraction, EF), collagen types I and III in the heart and kidney, myocardial mitochondria, and cardiac transforming growth factor-β1 (TGF-β1) of the AT1-KO mice were compared with the same model with nephrectomy only and untreated with SXND. AT1-KO mice did not affect the process of CRI but it could significantly affect cardiac remodeling process. SXND decreased to some extent the AT1-KO mice's BUN, SCr, BNP, and cardiac LVDD, LVDS, and BNP, improved FS and EF, lowered the expression of collagen type I and III in heart and kidney, increased the quantity of mitochondria and ameliorated their structure, and down-regulated the expression of TGF-β1. SXND may antagonize the renin-angiotensin system (RAS) and decrease uremia toxins, thereby ameliorating ventricular remodeling in CRI. Furthermore, SXND has a mechanism correlated with the improvement of myocardial energy metabolism and the down-regulation of TGF-β1.

The ameliorative effects of exercise on cognitive impairment and white matter injury from blood-brain barrier disruption induced by chronic cerebral hypoperfusion in adolescent rats.

PubMed

Lee, Jae-Min; Park, Jong-Min; Song, Min Kyung; Oh, Yoo Joung; Kim, Chang-Ju; Kim, Youn-Jung

2017-01-18

Vascular dementia is the progressive change in blood vessels that leads to neuronal injuries in vulnerable areas induced by chronic cerebral hypoperfusion (CCH). CCH induces disruption of blood-brain barrier (BBB), and this BBB disruption can initiate the cognitive impairment and white matter injury. In the present study, we evaluated the effect of treadmill exercise on the cognitive impairment, white matter injury, and BBB disruption induced by CCH. Vascular dementia was induced by permanent bilateral common carotid arteries occlusion (BCCAO) in rats. The rats in the exercise group were made to run on a treadmill for 30min once a day for 14 weeks, starting 4 weeks after birth. Our results revealed that treadmill exercise group was alleviated the cognitive impairment and myelin degradation induced by CCH. The disruption of BBB after CCH indicates degradation of occludin, zonula occluden-1 (ZO-1), and up-regulation of matrix metalloproteinases (MMPs). Treadmill exercise may provide protective effects on BBB disruption from degradation of occludin, ZO-1, and overexpression of MMP-9 after CCH. These findings suggest that treadmill exercise ameliorates cognitive impairment and white matter injury from BBB disruption induced by CCH in rats. The present study will be valuable for means of prophylactic and therapeutic intervention for patients with CCH. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Pirfenidone ameliorates murine chronic GVHD through inhibition of macrophage infiltration and TGF-β production

PubMed Central

Du, Jing; Paz, Katelyn; Flynn, Ryan; Vulic, Ante; Robinson, Tara M.; Lineburg, Katie E.; Alexander, Kylie A.; Meng, Jingjing; Roy, Sabita; Panoskaltsis-Mortari, Angela; Loschi, Michael; Hill, Geoffrey R.; Serody, Jonathan S.; Maillard, Ivan; Miklos, David; Koreth, John; Cutler, Corey S.; Antin, Joseph H.; Ritz, Jerome; MacDonald, Kelli P.; Schacker, Timothy W.; Luznik, Leo

2017-01-01

Allogeneic hematopoietic stem cell transplantation is hampered by chronic graft-versus-host disease (cGVHD), resulting in multiorgan fibrosis and diminished function. Fibrosis in lung and skin leads to progressive bronchiolitis obliterans (BO) and scleroderma, respectively, for which new treatments are needed. We evaluated pirfenidone, a Food and Drug Administration (FDA)-approved drug for idiopathic pulmonary fibrosis, for its therapeutic effect in cGVHD mouse models with distinct pathophysiology. In a full major histocompatibility complex (MHC)-mismatched, multiorgan system model with BO, donor T-cell responses that support pathogenic antibody production are required for cGVHD development. Pirfenidone treatment beginning one month post-transplant restored pulmonary function and reversed lung fibrosis, which was associated with reduced macrophage infiltration and transforming growth factor-β production. Pirfenidone dampened splenic germinal center B-cell and T-follicular helper cell frequencies that collaborate to produce antibody. In both a minor histocompatibility antigen–mismatched as well as a MHC-haploidentical model of sclerodermatous cGVHD, pirfenidone significantly reduced macrophages in the skin, although clinical improvement of scleroderma was only seen in one model. In vitro chemotaxis assays demonstrated that pirfenidone impaired macrophage migration to monocyte chemoattractant protein-1 (MCP-1) as well as IL-17A, which has been linked to cGVHD generation. Taken together, our data suggest that pirfenidone is a potential therapeutic agent to ameliorate fibrosis in cGVHD. PMID:28254742

Ibrutinib treatment ameliorates murine chronic graft-versus-host disease

PubMed Central

Dubovsky, Jason A.; Flynn, Ryan; Du, Jing; Harrington, Bonnie K.; Zhong, Yiming; Kaffenberger, Benjamin; Yang, Carrie; Towns, William H.; Lehman, Amy; Johnson, Amy J.; Muthusamy, Natarajan; Devine, Steven M.; Jaglowski, Samantha; Serody, Jonathan S.; Murphy, William J.; Munn, David H.; Luznik, Leo; Hill, Geoffrey R.; Wong, Henry K.; MacDonald, Kelli K.P.; Maillard, Ivan; Koreth, John; Elias, Laurence; Cutler, Corey; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome; Panoskaltsis-Mortari, Angela; Byrd, John C.; Blazar, Bruce R.

2014-01-01

Chronic graft-versus-host disease (cGVHD) is a life-threatening impediment to allogeneic hematopoietic stem cell transplantation, and current therapies do not completely prevent and/or treat cGVHD. CD4+ T cells and B cells mediate cGVHD; therefore, targeting these populations may inhibit cGVHD pathogenesis. Ibrutinib is an FDA-approved irreversible inhibitor of Bruton’s tyrosine kinase (BTK) and IL-2 inducible T cell kinase (ITK) that targets Th2 cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity. Here, we evaluated whether ibrutinib could reverse established cGVHD in 2 complementary murine models, a model interrogating T cell–driven sclerodermatous cGVHD and an alloantibody-driven multiorgan system cGVHD model that induces bronchiolar obliterans (BO). In the T cell–mediated sclerodermatous cGVHD model, ibrutinib treatment delayed progression, improved survival, and ameliorated clinical and pathological manifestations. In the alloantibody-driven cGVHD model, ibrutinib treatment restored pulmonary function and reduced germinal center reactions and tissue immunoglobulin deposition. Animals lacking BTK and ITK did not develop cGVHD, indicating that these molecules are critical to cGVHD development. Furthermore, ibrutinib treatment reduced activation of T and B cells from patients with active cGVHD. Our data demonstrate that B cells and T cells drive cGVHD and suggest that ibrutinib has potential as a therapeutic agent, warranting consideration for cGVHD clinical trials. PMID:25271622

Modulation of brain structure by catechol-O-methyltransferase Val(158) Met polymorphism in chronic cannabis users.

PubMed

Batalla, Albert; Soriano-Mas, Carles; López-Solà, Marina; Torrens, Marta; Crippa, José A; Bhattacharyya, Sagnik; Blanco-Hinojo, Laura; Fagundo, Ana B; Harrison, Ben J; Nogué, Santiago; de la Torre, Rafael; Farré, Magí; Pujol, Jesús; Martín-Santos, Rocío

2014-07-01

Neuroimaging studies have shown that chronic consumption of cannabis may result in alterations in brain morphology. Recent work focusing on the relationship between brain structure and the catechol-O-methyltransferase (COMT) gene polymorphism suggests that functional COMT variants may affect brain volume in healthy individuals and in schizophrenia patients. We measured the influence of COMT genotype on the volume of four key regions: the prefrontal cortex, neostriatum (caudate-putamen), anterior cingulate cortex and hippocampus-amygdala complex, in chronic early-onset cannabis users and healthy control subjects. We selected 29 chronic cannabis users who began using cannabis before 16 years of age and matched them to 28 healthy volunteers in terms of age, educational level and IQ. Participants were male, Caucasians aged between 18 and 30 years. All were assessed by a structured psychiatric interview (PRISM) to exclude any lifetime Axis-I disorder according to Diagnostic and Statistical Manual for Mental Disorders-Fourth Edition. COMT genotyping was performed and structural magnetic resonance imaging data was analyzed by voxel-based morphometry. The results showed that the COMT polymorphism influenced the volume of the bilateral ventral caudate nucleus in both groups, but in an opposite direction: more copies of val allele led to lesser volume in chronic cannabis users and more volume in controls. The opposite pattern was found in left amygdala. There were no effects of COMT genotype on volumes of the whole brain or the other selected regions. Our findings support recent reports of neuroanatomical changes associated with cannabis use and, for the first time, reveal that these changes may be influenced by the COMT genotype. © 2013 The Authors, Addiction Biology © 2013 Society for the Study of Addiction.

Cortical activation following chronic passive implantation of a wide-field suprachoroidal retinal prosthesis

NASA Astrophysics Data System (ADS)

Villalobos, Joel; Fallon, James B.; Nayagam, David A. X.; Shivdasani, Mohit N.; Luu, Chi D.; Allen, Penelope J.; Shepherd, Robert K.; Williams, Chris E.

2014-08-01

Objective. The research goal is to develop a wide-field retinal stimulating array for prosthetic vision. This study aimed at evaluating the efficacy of a suprachoroidal electrode array in evoking visual cortex activity after long term implantation. Approach. A planar silicone based electrode array (8 mm × 19 mm) was implanted into the suprachoroidal space in cats (ntotal = 10). It consisted of 20 platinum stimulating electrodes (600 μm diameter) and a trans-scleral cable terminated in a subcutaneous connector. Three months after implantation (nchronic = 6), or immediately after implantation (nacute = 4), an electrophysiological study was performed. Electrode total impedance was measured from voltage transients using 500 μs, 1 mA pulses. Electrically evoked potentials (EEPs) and multi-unit activity were recorded from the visual cortex in response to monopolar retinal stimulation. Dynamic range and cortical activation spread were calculated from the multi-unit recordings. Main results. The mean electrode total impedance in vivo following 3 months was 12.5 ± 0.3 kΩ. EEPs were recorded for 98% of the electrodes. The median evoked potential threshold was 150 nC (charge density 53 μC cm-2). The lowest stimulation thresholds were found proximal to the area centralis. Mean thresholds from multiunit activity were lower for chronic (181 ± 14 nC) compared to acute (322 ± 20 nC) electrodes (P < 0.001), but there was no difference in dynamic range or cortical activation spread. Significance. Suprachoroidal stimulation threshold was lower in chronic than acute implantation and was within safe charge limits for platinum. Electrode-tissue impedance following chronic implantation was higher, indicating the need for sufficient compliance voltage (e.g. 12.8 V for mean impedance, threshold and dynamic range). The wide-field suprachoroidal array reliably activated the retina after chronic implantation.

Chronic social isolation suppresses proplastic response and promotes proapoptotic signalling in prefrontal cortex of Wistar rats.

PubMed

Djordjevic, Ana; Adzic, Miroslav; Djordjevic, Jelena; Radojcic, Marija B

2010-08-15

Successful adaptation to stress involves synergized actions of glucocorticoids and catecholamines at several levels of the CNS, including the prefrontal cortex (PFC). Inside the PFC, hormonal signals trigger concerted actions of transcriptional factors, such as glucocorticoid receptor (GR) and nuclear factor kappa B (NFkappaB), culminating in a balanced, proadaptive expression of their common genes, such as proplastic NCAM and/or apoptotic Bax and Bcl-2. In the present study, we hypothesized that chronic stress may compromise the balance between GR and NFkappaB signals and lead to an altered/maladaptive expression of their cognate genes in the PFC. Our results obtained with Wistar rats exposed to chronic social isolation indicated alterations of the GR relative to the NFkappaB, in favor of the GR, in both the cytoplasmic and the nuclear compartments of the PFC. Although these alterations did not affect the induction of proplastic NCAM gene, they decreased the NCAM sialylation necessary for plastic response and caused marked relocation of the mitochondrial membrane antiapoptotic Bcl-2 protein to its cytoplasmic form. Moreover, the compromised PSA-NCAM plastic response found under chronic stress was sustained after exposure of animals to the subsequent acute stress, whereas the proapoptotic signals were further emphasized. It is concluded that chronic social isolation of Wistar animals leads to a maladaptive response of the PFC, considering the diminishment of its plastic potential and potentiating of apoptosis. Such conditions in the PFC are likely to compromise its ability to interact with other CNS structures, such as the hippocampus, which is necessary for successful adaptation to stress. (c) 2010 Wiley-Liss, Inc.

Modulation of risk-taking in marijuana users by transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC).

PubMed

Boggio, Paulo S; Zaghi, Soroush; Villani, Ana Beatriz; Fecteau, Shirley; Pascual-Leone, Alvaro; Fregni, Felipe

2010-12-01

Cognitive deficits that are reported in heavy marijuana users (attention, memory, affect perception, decision-making) appear to be completely reversible after a prolonged abstinence period of about 28 days. However, it remains unclear whether the reversibility of these cognitive deficits indicates that (1) chronic marijuana use is not associated with long-lasting changes in cortical networks or (2) that such changes occur but the brain adapts to and compensates for the drug-induced changes. Therefore, we examined whether chronic marijuana smokers would demonstrate a differential pattern of response in comparison to healthy volunteers on a decision-making paradigm (Risk Task) while undergoing sham or active transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC). Twenty-five chronic marijuana users who were abstinent for at least 24h were randomly assigned to receive left anodal/right cathodal tDCS of DLPFC (n=8), right anodal/left cathodal tDCS of DLPFC (n=9), or sham stimulation (n=8); results on Risk Task during sham/active tDCS were compared to healthy volunteers from a previously published dataset. Chronic marijuana users demonstrated more conservative (i.e. less risky) decision-making during sham stimulation. While right anodal stimulation of the DLPFC enhanced conservative decision-making in healthy volunteers, both right anodal and left anodal DLPFC stimulation increased the propensity for risk-taking in marijuana users. These findings reveal alterations in the decision-making neural networks among chronic marijuana users. Finally, we also assessed the effects of tDCS on marijuana craving and observed that right anodal/left cathodal tDCS of DLPFC is significantly associated with a diminished craving for marijuana. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Effects of chronic social isolation on Wistar rat behavior and brain plasticity markers.

PubMed

Djordjevic, Jelena; Djordjevic, Ana; Adzic, Miroslav; Radojcic, Marija B

2012-01-01

Chronic stress is a contributing risk factor in the development of psychiatric illnesses, including depressive disorders. The mechanisms of their psychopathology are multifaceted and include, besides others, alterations in the brain plasticity. Previously, we investigated the effects of chronic social stress in the limbic brain structures of Wistar rats (hippocampus, HIPPO, and prefrontal cortex, PFC) and found multiple characteristics that resembled alterations described in some clinical studies of depression. We extended our investigations and followed the behavior of stressed animals by the open field test (OFT) and forced swimming test (FST), and the expression and polysialylation of synaptic plasticity markers, neural cell adhesion molecule (NCAM) and L1, in the HIPPO and PFC. We also determined the adrenal gland mass and plasma corticosterone (CORT) as a terminal part of the hypothalamic-pituitary-adrenal axis activity. Our data indicated that stressed animals avoided the central zone in the OFT and displayed decreased swimming, but prolonged immobility in the FST. The animals exhibited marked hypertrophy of the adrenal gland cortex, in spite of decreased serum CORT. Simultaneously, the stressed animals exhibited an increase in NCAM mRNA expression in the HIPPO, but not in the PFC. The synaptosomal NCAM of the HIPPO was markedly polysialylated, while cortical PSA-NCAM was significantly decreased. The results showed that chronic social isolation of Wistar rats causes both anxiety-like and depression-like behavior. These alterations are parallel with molecular changes in the limbic brain, including diminished NCAM sialylation in the PFC. Together with our previous results, the current observations suggest that a chronic social isolation model may potentially be used to study molecular mechanisms that underlie depressive symptomatology. Copyright © 2012 S. Karger AG, Basel.

Chronic marijuana smoke exposure in the rhesus monkey. IV: Neurochemical effects and comparison to acute and chronic exposure to delta-9-tetrahydrocannabinol (THC) in rats.

PubMed

Ali, S F; Newport, G D; Scallet, A C; Paule, M G; Bailey, J R; Slikker, W

1991-11-01

THC is the major psychoactive constituent of marijuana and is known to produce psychopharmacological effects in humans. These studies were designed to determine whether acute or chronic exposure to marijuana smoke or THC produces in vitro or in vivo neurochemical alterations in rat or monkey brain. For the in vitro study, THC was added (1-100 nM) to membranes prepared from different regions of the rat brain and muscarinic cholinergic (MCh) receptor binding was measured. For the acute in vivo study, rats were injected IP with vehicle, 1, 3, 10, or 30 mg THC/kg and sacrificed 2 h later. For the chronic study, rats were gavaged with vehicle or 10 or 20 mg THC/kg daily, 5 days/week for 90 days and sacrificed either 24 h or 2 months later. Rhesus monkeys were exposed to the smoke of a single 2.6% THC cigarette once a day, 2 or 7 days a week for 1 year. Approximately 7 months after the last exposure, animals were sacrificed by overdose with pentobarbital for neurochemical analyses. In vitro exposure to THC produced a dose-dependent inhibition of MCh receptor binding in several brain areas. This inhibition of MCh receptor binding, however, was also observed with two other nonpsychoactive derivatives of marijuana, cannabidiol and cannabinol. In the rat in vivo study, we found no significant changes in MCh or other neurotransmitter receptor binding in hippocampus, frontal cortex or caudate nucleus after acute or chronic exposure to THC. In the monkey brain, we found no alterations in the concentration of neurotransmitters in caudate nucleus, frontal cortex, hypothalamus or brain stem.(ABSTRACT TRUNCATED AT 250 WORDS)

Demonstration of a setup for chronic optogenetic stimulation and recording across cortical areas in non-human primates

NASA Astrophysics Data System (ADS)

Yazdan-Shahmorad, Azadeh; Diaz-Botia, Camilo; Hanson, Tim; Ledochowitsch, Peter; Maharabiz, Michel M.; Sabes, Philip N.

2015-03-01

Although several studies have shown the feasibility of using optogenetics in non-human primates (NHP), reliable largescale chronic interfaces have not yet been reported for such studies in NHP. Here we introduce a chronic setup that permits repeated, daily optogenetic stimulation and large-scale recording from the same sites in NHP cortex. The setup combines optogenetics with a transparent artificial dura (AD) and high-density micro-electrocorticography (μECoG). To obtain expression across large areas of cortex, we infused AAV5-CamKIIa-C1V1-EYFP viral vector using an infusion technique based on convection-enhanced delivery (CED) in primary somatosensory (S1) and motor (M1) cortices. By epifluorescent imaging through AD we were able to confirm high levels of expression covering about 110 mm2 of S1 and M1. We then incorporated a 192-channel μECoG array spanning 192 mm2 into the AD for simultaneous electrophysiological recording during optical stimulation. The array consists of patterned Pt-Au-Pt metal traces embedded in ~10 μm Parylene-C insulator. The parylene is sufficiently transparent to allow minimally attenuated optical access for optogenetic stimulation. The array was chronically implanted over the opsin-expressing areas in M1 and S1 for over two weeks. Optical stimulation was delivered via a fiber optic placed on the surface of the AD. With this setup, we recorded reliable evoked activity following light stimulation at several locations. Similar responses were recorded across tens of days, however a decline in the light-evoked signal amplitude was observed during this period due to the growth of dural tissue over the array. These results show the feasibility of a chronic interface for combined largescale optogenetic stimulation and cortical recordings across days.

Effect of acute and chronic MK-801 administration on extracellular glutamate and ascorbic acid release in the prefrontal cortex of freely moving mice on line with open-field behavior.

PubMed

Zuo, Dai-Ying; Zhang, Ya-Hong; Cao, Yue; Wu, Chun-Fu; Tanaka, Masatoshi; Wu, Ying-Liang

2006-04-04

The present study was designed to investigate the effects of acute and chronic administration of MK-801 (0.6 mg/kg), a noncompetitive NMDA-receptor antagonist on extracellular glutamate (Glu) and ascorbic acid (AA) release in the prefrontal cortex (PFC) of freely moving mice using in vivo microdialysis with open-field behavior. In line with earlier studies, acute administration of MK-801 induced an increase of Glu in the PFC. We also observed single MK-801 treatment increased AA release in the PFC. In addition, our results indicated that the basal AA levels in the PFC after MK-801 administration for 7 consecutive days were significantly decreased, and basal Glu levels also had a decreased tendency. After chronic administration (0.6 mg/kg, 7 days), MK-801 (0.6 mg/kg) challenge significantly decreased dialysate levels of AA and Glu. Our study also found that both acute and chronic administration of MK-801 induced hyperactivity in mice, but the intensity of acute administration was more than that of chronic administration. Furthermore, in all acute treatment mice, individual changes in Glu dialysate concentrations and the numbers of locomotion were positively correlated. In conclusion, this study may provide new evidence that a single MK-801 administration induces increases of dialysate AA and Glu concentrations in the PFC of freely moving mice, which are opposite to those induced by repeated MK-801 administration, with an unknown mechanism. Our results suggested that redox-response might play an important role in the model of schizophrenic symptoms induced by MK-801.

Disrupted Brain Functional Network Architecture in Chronic Tinnitus Patients

PubMed Central

Chen, Yu-Chen; Feng, Yuan; Xu, Jin-Jing; Mao, Cun-Nan; Xia, Wenqing; Ren, Jun; Yin, Xindao

2016-01-01

Purpose: Resting-state functional magnetic resonance imaging (fMRI) studies have demonstrated the disruptions of multiple brain networks in tinnitus patients. Nonetheless, several studies found no differences in network processing between tinnitus patients and healthy controls (HCs). Its neural bases are poorly understood. To identify aberrant brain network architecture involved in chronic tinnitus, we compared the resting-state fMRI (rs-fMRI) patterns of tinnitus patients and HCs. Materials and Methods: Chronic tinnitus patients (n = 24) with normal hearing thresholds and age-, sex-, education- and hearing threshold-matched HCs (n = 22) participated in the current study and underwent the rs-fMRI scanning. We used degree centrality (DC) to investigate functional connectivity (FC) strength of the whole-brain network and Granger causality to analyze effective connectivity in order to explore directional aspects involved in tinnitus. Results: Compared to HCs, we found significantly increased network centrality in bilateral superior frontal gyrus (SFG). Unidirectionally, the left SFG revealed increased effective connectivity to the left middle orbitofrontal cortex (OFC), left posterior lobe of cerebellum (PLC), left postcentral gyrus, and right middle occipital gyrus (MOG) while the right SFG exhibited enhanced effective connectivity to the right supplementary motor area (SMA). In addition, the effective connectivity from the bilateral SFG to the OFC and SMA showed positive correlations with tinnitus distress. Conclusions: Rs-fMRI provides a new and novel method for identifying aberrant brain network architecture. Chronic tinnitus patients have disrupted FC strength and causal connectivity mostly in non-auditory regions, especially the prefrontal cortex (PFC). The current findings will provide a new perspective for understanding the neuropathophysiological mechanisms in chronic tinnitus. PMID:27458377

T-cell infiltration into the perilesional cortex is long-lasting and associates with poor somatomotor recovery after experimental traumatic brain injury.

PubMed

Ndode-Ekane, Xavier Ekolle; Matthiesen, Liz; Bañuelos-Cabrera, Ivette; Palminha, Cátia Alexandra Pêgas; Pitkänen, Asla

2018-06-06

T-lymphocyte (T-cell) invasion into the brain parenchyma is a major consequence of traumatic brain injury (TBI). However, the role of T-cells in the post-TBI functional outcome and secondary inflammatory processes is unknown. We explored the dynamics of T-cell infiltration into the cortex after TBI to establish whether the infiltration relates to post-injury functional impairment/recovery and progression of the secondary injury. TBI was induced in rats by lateral fluid-percussion injury, and the acute functional impairment was assessed using the neuroscore. Animals were killed between 1-90 d post-TBI for immunohistochemical analysis of T-cell infiltration (CD3), chronic macrophage/microglial reaction (CD68), blood-brain barrier (BBB) dysfunction (IgG), and endophenotype of the cortical injury. Furthermore, the occurrence of spontaneous seizures and spike-and-wave discharges were assessed using video-electroencephalography. The number of T-cells peaked at 2-d post-TBI, and then dramatically decreased by 7-d post-TBI (5% of 2-d value). Unexpectedly, chronic T-cell infiltration at 1 or 3 months post-TBI did not correlate with the severity of chronic inflammation (p >  0.05) or BBB dysfunction (p >  0.05). Multiple regression analysis indicated that inflammation and BBB dysfunction is associated with 48% of the perilesional T-cell infiltration even at the chronic time-point (r = 0.695, F = 6.54, p <  0.05). The magnitude of T-cell infiltration did not predict the pathologic endophenotype of cortical injury, but the higher the number of T-cells in the cortex, the poorer the recovery index based on the neuroscore (r = - 0.538, p <  0.05). T-cell infiltration was not associated with the number or duration of age-related spike-and-wave discharges (SWD). Nevertheless, the higher the number of SWD, the poorer the recovery index (r = - 0.767, p <  0.5). These findings suggest that acute infiltration of T-cells into the brain parenchyma after TBI is a contributing factor to poor post-injury recovery.