Matrix metalloproteinase-2-mediated occludin degradation and caveolin-1-mediated claudin-5 redistribution contribute to blood-brain barrier damage in early ischemic stroke stage.

PubMed

Liu, Jie; Jin, Xinchun; Liu, Ke J; Liu, Wenlan

2012-02-29

Blood-brain barrier (BBB) disruption occurs early enough to be within the thrombolytic time window, and this early ischemic BBB damage is closely associated with hemorrhagic transformation and thus emerging as a promising target for reducing the hemorrhagic complications of thrombolytic stroke therapy. However, the mechanisms underlying early ischemic BBB damage remain poorly understood. Here, we investigated the early molecular events of ischemic BBB damage using in vitro oxygen-glucose deprivation (OGD) and in vivo rat middle cerebral artery occlusion (MCAO) models. Exposure of bEND3 monolayer to OGD for 2 h significantly increased its permeability to FITC-labeled dextran and promoted the secretion of metalloproteinase-2 and -9 (MMP-2/9) and cytosolic translocation of caveolin-1 (Cav-1). This same OGD treatment also led to rapid degradation of tight junction protein occludin and dissociation of claudin-5 from the cytoskeleton, which contributed to OGD-induced endothelial barrier disruption. Using selective MMP-2/9 inhibitor SB-3CT (2-[[(4-phenoxyphenyl)sulfonyl]methyl]-thiirane) or their neutralizing antibodies or Cav-1 siRNA, we found that MMP-2 was the major enzyme mediating OGD-induced occludin degradation, while Cav-1 was responsible for claudin-5 redistribution. The interaction between Cav-1 and claudin-5 was further confirmed by coimmunoprecipitation. Consistent with these in vitro findings, we observed fluorescence tracer extravasation, increased gelatinolytic activity, and elevated interstitial MMP-2 levels in ischemic subcortical tissue after 2 h MCAO. Moreover, occludin protein loss and claudin-5 redistribution were detected in ischemic cerebromicrovessels. These data indicate that cerebral ischemia initiates two rapid parallel processes, MMP-2-mediated occludin degradation and Cav-1-mediated claudin-5 redistribution, to cause BBB disruption at early stroke stages relevant to acute thrombolysis.

Matrix metalloproteinase-2-mediated occludin degradation and caveolin-1-mediated claudin-5 redistribution contribute to blood brain barrier damage in early ischemic stroke stage

PubMed Central

Liu, Jie; Jin, Xinchun; Liu, Ke J.; Liu, Wenlan

2012-01-01

Blood brain barrier (BBB) disruption occurs early enough to be within the thrombolytic time window, and this early ischemic BBB damage is closely associated with hemorrhagic transformation and thus emerging as a promising target for reducing the hemorrhagic complications of thrombolytic stroke therapy. However, the mechanisms underlying early ischemic BBB damage remain poorly understood. Here we investigated the early molecular events of ischemic BBB damage using in vitro oxygen-glucose deprivation (OGD) and in vivo rat middle cerebral artery occlusion (MCAO) models. Exposure of bEND3 monolayer to OGD for 2 h significantly increased its permeability to FITC-labeled dextran, and promoted the secretion of metalloproteinase-2 and 9 (MMP-2/9) and cytosolic translocation of caveolin-1 (Cav-1). This same OGD treatment also led to rapid degradation of tight junction protein occludin and dissociation of claudin-5 from the cytoskeleton, which contributed to OGD-induced endothelial barrier disruption. Using selective MMP-2/9 inhibitor SB-3CT or their neutralizing antibodies or Cav-1 siRNA, we found that MMP-2 was the major enzyme mediating OGD-induced occludin degradation, while Cav-1 was responsible for claudin-5 redistribution. The interaction between Cav-1 and claudin-5 was further confirmed by coimmunoprecipitation. Consistent with these in vitro findings, we observed fluorescence tracer extravasation, increased gelatinolytic activity and elevated interstitial MMP-2 levels in ischemic subcortical tissue after 2-h MCAO. Moreover, occludin protein loss and claudin-5 redistribution were detected in ischemic cerebromicrovessels. These data indicate that cerebral ischemia initiates two rapid parallel processes, MMP-2-mediated occludin degradation and Cav-1-mediated claudin-5 redistribution, to cause BBB disruption at early stroke stages relevant to acute thrombolysis. PMID:22378877

Clinical Phase IIB Trial of Oxycyte Perflurocarbon in Severe Human Traumatic Brain Injury

DTIC Science & Technology

2013-10-01

TERMS Penetrating ballistic brain injury, ischemia, hypoxia, perfluorocarbon , cell death, perfusion. 16. SECURITY CLASSIFICATION OF: 17. LIMITATION...SUBTITLE The Role of Perfluorocarbons in Mitigating Traumatic Brain Injury 5a. CONTRACT NUMBER W81XWH-08-1-0419 5b. GRANT NUMBER 5c. PROGRAM...damage seems to be mediated by mechanisms that follow the initial injury (secondary mechanisms). Perfluorocarbons (PFCs) are one of the methods by which

Nutrients, Microglia Aging, and Brain Aging.

PubMed

Wu, Zhou; Yu, Janchun; Zhu, Aiqin; Nakanishi, Hiroshi

2016-01-01

As the life expectancy continues to increase, the cognitive decline associated with Alzheimer's disease (AD) becomes a big major issue in the world. After cellular activation upon systemic inflammation, microglia, the resident immune cells in the brain, start to release proinflammatory mediators to trigger neuroinflammation. We have found that chronic systemic inflammatory challenges induce differential age-dependent microglial responses, which are in line with the impairment of learning and memory, even in middle-aged animals. We thus raise the concept of "microglia aging." This concept is based on the fact that microglia are the key contributor to the acceleration of cognitive decline, which is the major sign of brain aging. On the other hand, inflammation induces oxidative stress and DNA damage, which leads to the overproduction of reactive oxygen species by the numerous types of cells, including macrophages and microglia. Oxidative stress-damaged cells successively produce larger amounts of inflammatory mediators to promote microglia aging. Nutrients are necessary for maintaining general health, including the health of brain. The intake of antioxidant nutrients reduces both systemic inflammation and neuroinflammation and thus reduces cognitive decline during aging. We herein review our microglia aging concept and discuss systemic inflammation and microglia aging. We propose that a nutritional approach to controlling microglia aging will open a new window for healthy brain aging.

Nutrients, Microglia Aging, and Brain Aging

PubMed Central

Wu, Zhou; Yu, Janchun; Zhu, Aiqin; Nakanishi, Hiroshi

2016-01-01

As the life expectancy continues to increase, the cognitive decline associated with Alzheimer's disease (AD) becomes a big major issue in the world. After cellular activation upon systemic inflammation, microglia, the resident immune cells in the brain, start to release proinflammatory mediators to trigger neuroinflammation. We have found that chronic systemic inflammatory challenges induce differential age-dependent microglial responses, which are in line with the impairment of learning and memory, even in middle-aged animals. We thus raise the concept of “microglia aging.” This concept is based on the fact that microglia are the key contributor to the acceleration of cognitive decline, which is the major sign of brain aging. On the other hand, inflammation induces oxidative stress and DNA damage, which leads to the overproduction of reactive oxygen species by the numerous types of cells, including macrophages and microglia. Oxidative stress-damaged cells successively produce larger amounts of inflammatory mediators to promote microglia aging. Nutrients are necessary for maintaining general health, including the health of brain. The intake of antioxidant nutrients reduces both systemic inflammation and neuroinflammation and thus reduces cognitive decline during aging. We herein review our microglia aging concept and discuss systemic inflammation and microglia aging. We propose that a nutritional approach to controlling microglia aging will open a new window for healthy brain aging. PMID:26941889

Acetoacetate protects hippocampal neurons against glutamate-mediated neuronal damage during glycolysis inhibition.

PubMed

Massieu, L; Haces, M L; Montiel, T; Hernández-Fonseca, K

2003-01-01

Glucose is the main substrate that fulfills energy brain demands. However, in some circumstances, such as diabetes, starvation, during the suckling period and the ketogenic diet, brain uses the ketone bodies, acetoacetate and beta-hydroxybutyrate, as energy sources. Ketone body utilization in brain depends directly on its blood concentration, which is normally very low, but increases substantially during the conditions mentioned above. Glutamate neurotoxicity has been implicated in neurodegeneration associated with brain ischemia, hypoglycemia and cerebral trauma, conditions related to energy failure, and to elevation of glutamate extracellular levels in brain. In recent years substantial evidence favoring a close relation between glutamate neurotoxic potentiality and cellular energy levels, has been compiled. We have previously demonstrated that accumulation of extracellular glutamate after inhibition of its transporters, induces neuronal death in vivo during energy impairment induced by glycolysis inhibition. In the present study we have assessed the protective potentiality of the ketone body, acetoacetate, against glutamate-mediated neuronal damage in the hippocampus of rats chronically treated with the glycolysis inhibitor, iodoacetate, and in hippocampal cultured neurons exposed to a toxic concentration of iodoacetate. Results show that acetoacetate efficiently protects against glutamate neurotoxicity both in vivo and in vitro probably by a mechanism involving its role as an energy substrate.

Chlorogenic Acid Prevents Alcohol-induced Brain Damage in Neonatal Rat

PubMed Central

Guo, Zikang; Li, Jiang

2017-01-01

Abstract The present investigation evaluates the neuroprotective effect of chlorogenic acid (CA) in alcohol-induced brain damage in neonatal rats. Ethanol (12 % v/v, 5 g/kg) was administered orally in the wistar rat pups on postnatal days (PD) 7-9. Chlorogenic acid (100 and 200 mg/kg, p.o.) was administered continuously from PD 6 to 28. Cognitive function was estimated by Morris water maze (MWM) test. However, activity of acetylcholinesterase, inflammatory mediators, parameters of oxidative stress and activity of caspase-3 enzyme was estimated in the tissue homogenate of cerebral cortex and hippocampus of ethanol-exposed pups. It has been observed that treatment with CA attenuates the altered cognitive function in ethanol-exposed pups. There was a significant decrease in the activity of acetylcholinesterase in the CA treated group compared to the negative control group. However, treatment with CA significantly ameliorates the increased oxidative stress and concentration of inflammatory mediators in the brain tissues of ethanol-exposed pups. Activity of caspase-3 enzyme was also found significantly decreased in the CA treated group compared to the negative control group. The present study concludes that CA attenuates the neuronal damage induced in alcohol exposed neonatal rat by decreasing the apoptosis of neuronal cells. PMID:29318034

Neuroprotective Role of a Brain-Enriched Tyrosine Phosphatase, STEP, in Focal Cerebral Ischemia

PubMed Central

Deb, Ishani; Manhas, Namratta; Poddar, Ranjana; Rajagopal, Sathyanarayanan; Allan, Andrea M.; Lombroso, Paul J.; Rosenberg, Gary A.; Candelario-Jalil, Eduardo

2013-01-01

The striatal-enriched phosphatase (STEP) is a component of the NMDA-receptor-mediated excitotoxic signaling pathway, which plays a key role in ischemic brain injury. Using neuronal cultures and a rat model of ischemic stroke, we show that STEP plays an initial role in neuroprotection, during the insult, by disrupting the p38 MAPK pathway. Degradation of active STEP during reperfusion precedes ischemic brain damage and is associated with secondary activation of p38 MAPK. Application of a cell-permeable STEP-derived peptide that is resistant to degradation and binds to p38 MAPK protects cultured neurons from hypoxia-reoxygenation injury and reduces ischemic brain damage when injected up to 6 h after the insult. Conversely, genetic deletion of STEP in mice leads to sustained p38 MAPK activation and exacerbates brain injury and neurological deficits after ischemia. Administration of the STEP-derived peptide at the onset of reperfusion not only prevents the sustained p38 MAPK activation but also reduces ischemic brain damage in STEP KO mice. The findings indicate a neuroprotective role of STEP and suggest a potential role of the STEP-derived peptide in stroke therapy. PMID:24198371

Alcohol-induced one-carbon metabolism impairment promotes dysfunction of DNA base excision repair in adult brain.

PubMed

Fowler, Anna-Kate; Hewetson, Aveline; Agrawal, Rajiv G; Dagda, Marisela; Dagda, Raul; Moaddel, Ruin; Balbo, Silvia; Sanghvi, Mitesh; Chen, Yukun; Hogue, Ryan J; Bergeson, Susan E; Henderson, George I; Kruman, Inna I

2012-12-21

The brain is one of the major targets of chronic alcohol abuse. Yet the fundamental mechanisms underlying alcohol-mediated brain damage remain unclear. The products of alcohol metabolism cause DNA damage, which in conditions of DNA repair dysfunction leads to genomic instability and neural death. We propose that one-carbon metabolism (OCM) impairment associated with long term chronic ethanol intake is a key factor in ethanol-induced neurotoxicity, because OCM provides cells with DNA precursors for DNA repair and methyl groups for DNA methylation, both critical for genomic stability. Using histological (immunohistochemistry and stereological counting) and biochemical assays, we show that 3-week chronic exposure of adult mice to 5% ethanol (Lieber-Decarli diet) results in increased DNA damage, reduced DNA repair, and neuronal death in the brain. These were concomitant with compromised OCM, as evidenced by elevated homocysteine, a marker of OCM dysfunction. We conclude that OCM dysfunction plays a causal role in alcohol-induced genomic instability in the brain because OCM status determines the alcohol effect on DNA damage/repair and genomic stability. Short ethanol exposure, which did not disturb OCM, also did not affect the response to DNA damage, whereas additional OCM disturbance induced by deficiency in a key OCM enzyme, methylenetetrahydrofolate reductase (MTHFR) in Mthfr(+/-) mice, exaggerated the ethanol effect on DNA repair. Thus, the impact of long term ethanol exposure on DNA repair and genomic stability in the brain results from OCM dysfunction, and MTHFR mutations such as Mthfr 677C→T, common in human population, may exaggerate the adverse effects of ethanol on the brain.

Thiopental Inhibits Global Protein Synthesis by Repression of Eukaryotic Elongation Factor 2 and Protects from Hypoxic Neuronal Cell Death

PubMed Central

Schwer, Christian I.; Lehane, Cornelius; Guelzow, Timo; Zenker, Simone; Strosing, Karl M.; Spassov, Sashko; Erxleben, Anika; Heimrich, Bernd; Buerkle, Hartmut; Humar, Matjaz

2013-01-01

Ischemic and traumatic brain injury is associated with increased risk for death and disability. The inhibition of penumbral tissue damage has been recognized as a target for therapeutic intervention, because cellular injury evolves progressively upon ATP-depletion and loss of ion homeostasis. In patients, thiopental is used to treat refractory intracranial hypertension by reducing intracranial pressure and cerebral metabolic demands; however, therapeutic benefits of thiopental-treatment are controversially discussed. In the present study we identified fundamental neuroprotective molecular mechanisms mediated by thiopental. Here we show that thiopental inhibits global protein synthesis, which preserves the intracellular energy metabolite content in oxygen-deprived human neuronal SK-N-SH cells or primary mouse cortical neurons and thus ameliorates hypoxic cell damage. Sensitivity to hypoxic damage was restored by pharmacologic repression of eukaryotic elongation factor 2 kinase. Translational inhibition was mediated by calcium influx, activation of the AMP-activated protein kinase, and inhibitory phosphorylation of eukaryotic elongation factor 2. Our results explain the reduction of cerebral metabolic demands during thiopental treatment. Cycloheximide also protected neurons from hypoxic cell death, indicating that translational inhibitors may generally reduce secondary brain injury. In conclusion our study demonstrates that therapeutic inhibition of global protein synthesis protects neurons from hypoxic damage by preserving energy balance in oxygen-deprived cells. Molecular evidence for thiopental-mediated neuroprotection favours a positive clinical evaluation of barbiturate treatment. The chemical structure of thiopental could represent a pharmacologically relevant scaffold for the development of new organ-protective compounds to ameliorate tissue damage when oxygen availability is limited. PMID:24167567

Endotoxin-induced lung alveolar cell injury causes brain cell damage.

PubMed

Rodríguez-González, Raquel; Ramos-Nuez, Ángela; Martín-Barrasa, José Luis; López-Aguilar, Josefina; Baluja, Aurora; Álvarez, Julián; Rocco, Patricia R M; Pelosi, Paolo; Villar, Jesús

2015-01-01

Sepsis is the most common cause of acute respiratory distress syndrome, a severe lung inflammatory disorder with an elevated morbidity and mortality. Sepsis and acute respiratory distress syndrome involve the release of inflammatory mediators to the systemic circulation, propagating the cellular and molecular response and affecting distal organs, including the brain. Since it has been reported that sepsis and acute respiratory distress syndrome contribute to brain dysfunction, we investigated the brain-lung crosstalk using a combined experimental in vitro airway epithelial and brain cell injury model. Conditioned medium collected from an in vitro lipopolysaccharide-induced airway epithelial cell injury model using human A549 alveolar cells was subsequently added at increasing concentrations (no conditioned, 2%, 5%, 10%, 15%, 25%, and 50%) to a rat mixed brain cell culture containing both astrocytes and neurons. Samples from culture media and cells from mixed brain cultures were collected before treatment, and at 6 and 24 h for analysis. Conditioned medium at 15% significantly increased apoptosis in brain cell cultures 24 h after treatment, whereas 25% and 50% significantly increased both necrosis and apoptosis. Levels of brain damage markers S100 calcium binding protein B and neuron-specific enolase, interleukin-6, macrophage inflammatory protein-2, as well as matrix metalloproteinase-9 increased significantly after treating brain cells with ≥2% conditioned medium. Our findings demonstrated that human epithelial pulmonary cells stimulated with bacterial lipopolysaccharide release inflammatory mediators that are able to induce a translational clinically relevant and harmful response in brain cells. These results support a brain-lung crosstalk during sepsis and sepsis-induced acute respiratory distress syndrome. © 2014 by the Society for Experimental Biology and Medicine.

Downregulated Brain-Derived Neurotrophic Factor-Induced Oxidative Stress in the Pathophysiology of Diabetic Retinopathy.

PubMed

Behl, Tapan; Kotwani, Anita

2017-04-01

Brain-derived neurotrophic factor (BDNF), a member of neurotrophin growth factor family, physiologically mediates induction of neurogenesis and neuronal differentiation, promotes neuronal growth and survival and maintains synaptic plasticity and neuronal interconnections. Unlike the central nervous system, its secretion in the peripheral nervous system occurs in an activity-dependent manner. BDNF improves neuronal mortality, growth, differentiation and maintenance. It also provides neuroprotection against several noxious stimuli, thereby preventing neuronal damage during pathologic conditions. However, in diabetic retinopathy (a neuromicrovascular disorder involving immense neuronal degeneration), BDNF fails to provide enough neuroprotection against oxidative stress-induced retinal neuronal apoptosis. This review describes the prime reasons for the downregulation of BDNF-mediated neuroprotective actions during hyperglycemia, which renders retinal neurons vulnerable to damaging stimuli, leading to diabetic retinopathy. Copyright © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

Neuroprotective effects of NAP against excitotoxic brain damage in the newborn mice: implications for cerebral palsy.

PubMed

Sokolowska, P; Passemard, S; Mok, A; Schwendimann, L; Gozes, I; Gressens, P

2011-01-26

Activity-dependent neuroprotective protein (ADNP) was shown to be essential for embryogenesis and brain development while NAP, an active motif of ADNP, is neuroprotective in a broad range of neurodegenerative disorders. In the present study, we examined the protective potential of ADNP/NAP in a mouse model of excitotoxic brain lesion mimicking brain damage associated with cerebral palsy. We demonstrated that NAP had a potent neuroprotective effect against ibotenate-induced excitotoxic damage in the cortical plate and the white matter of P5 mice, and moderate against brain lesions of P0 mice. In contrast, endogenous ADNP appears not to be involved in the response to excitotoxic challenge in the studied model. Our findings further show that NAP reduced the number of apoptotic neurons through activation of PI-3K/Akt pathway in the cortical plate or both PI-3K/Akt and MAPK/MEK1 kinases in the white matter. In addition, NAP prevented ibotenate-induced loss of pre-oligodendrocytes without affecting the number of astrocytes or activated microglia around the site of injection. These findings indicate that protective actions of NAP are mediated by triggering transduction pathways that are crucial for neuronal and oligodendroglial survival, thus, NAP might be a promising therapeutic agent for treating developing brain damage. © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Nitric Oxide Protects against Infection-Induced Neuroinflammation by Preserving the Stability of the Blood-Brain Barrier

PubMed Central

Olivera, Gabriela C.; Ren, Xiaoyuan; Vodnala, Suman K.; Lu, Jun; Coppo, Lucia; Leepiyasakulchai, Chaniya; Holmgren, Arne; Kristensson, Krister; Rottenberg, Martin E.

2016-01-01

Nitric oxide (NO) generated by inducible NO synthase (iNOS) is critical for defense against intracellular pathogens but may mediate inflammatory tissue damage. To elucidate the role of iNOS in neuroinflammation, infections with encephalitogenic Trypanosoma brucei parasites were compared in inos -/- and wild-type mice. Inos -/- mice showed enhanced brain invasion by parasites and T cells, and elevated protein permeability of cerebral vessels, but similar parasitemia levels. Trypanosome infection stimulated T cell- and TNF-mediated iNOS expression in perivascular macrophages. NO nitrosylated and inactivated pro-inflammatory molecules such as NF-κΒp65, and reduced TNF expression and signalling. iNOS-derived NO hampered both TNF- and T cell-mediated parasite brain invasion. In inos -/- mice, TNF stimulated MMP, including MMP9 activity that increased cerebral vessel permeability. Thus, iNOS-generated NO by perivascular macrophages, strategically located at sites of leukocyte brain penetration, can serve as a negative feed-back regulator that prevents unlimited influx of inflammatory cells by restoring the integrity of the blood-brain barrier. PMID:26915097

Damage to the ventromedial prefrontal cortex reduces interpersonal disgust.

PubMed

Ciaramelli, Elisa; Sperotto, Rebecca G; Mattioli, Flavia; di Pellegrino, Giuseppe

2013-02-01

Disgust for contaminating objects (core disgust), immoral behaviors (moral disgust) and unsavory others (interpersonal disgust), have been assumed to be closely related. It is not clear, however, whether different forms of disgust are mediated by overlapping or specific neural substrates. We report that 10 patients with damage to the ventromedial prefrontal cortex (vmPFC) avoided behaviors that normally elicit interpersonal disgust (e.g. using the scarf of a busker) less frequently than healthy and brain-damaged controls, whereas they avoided core and moral disgust elicitors at normal rates. These results indicate that different forms of disgust are dissociated neurally. We propose that the vmPFC is causally (and selectively) involved in mediating interpersonal disgust, shaping patterns of social avoidance and approach.

Damage to the ventromedial prefrontal cortex reduces interpersonal disgust

PubMed Central

Ciaramelli, Elisa; Sperotto, Rebecca G.; Mattioli, Flavia

2013-01-01

Disgust for contaminating objects (core disgust), immoral behaviors (moral disgust) and unsavory others (interpersonal disgust), have been assumed to be closely related. It is not clear, however, whether different forms of disgust are mediated by overlapping or specific neural substrates. We report that 10 patients with damage to the ventromedial prefrontal cortex (vmPFC) avoided behaviors that normally elicit interpersonal disgust (e.g. using the scarf of a busker) less frequently than healthy and brain-damaged controls, whereas they avoided core and moral disgust elicitors at normal rates. These results indicate that different forms of disgust are dissociated neurally. We propose that the vmPFC is causally (and selectively) involved in mediating interpersonal disgust, shaping patterns of social avoidance and approach. PMID:22842816

The effect of brain death in rat steatotic and non-steatotic liver transplantation with previous ischemic preconditioning.

PubMed

Jiménez-Castro, Mónica B; Meroño, Noelia; Mendes-Braz, Mariana; Gracia-Sancho, Jordi; Martínez-Carreres, Laia; Cornide-Petronio, Maria Eugenia; Casillas-Ramirez, Araní; Rodés, Juan; Peralta, Carmen

2015-01-01

Most liver grafts undergoing transplantation derive from brain dead donors, which may also show hepatic steatosis, being both characteristic risk factors in liver transplantation. Ischemic preconditioning shows benefits when applied in non-brain dead clinical situations like hepatectomies, whereas it has been less promising in the transplantation from brain dead patients. This study examined how brain death affects preconditioned steatotic and non-steatotic liver grafts undergoing transplantation. Steatotic and non-steatotic grafts from non-brain dead and brain dead-donors were cold stored for 6h and then transplanted. After 2, 4, and 16 h of reperfusion, hepatic damage was analysed. In addition, two therapeutic strategies, ischemic preconditioning and/or acetylcholine pre-treatment, and their underlying mechanisms were characterized. Preconditioning benefits in non-brain dead donors were associated with nitric oxide and acetylcholine generation. In brain dead donors, preconditioning generated nitric oxide but did not promote acetylcholine upregulation, and this resulted in inflammation and damage. Acetylcholine treatment in brain dead donors, through PKC, increased antioxidants and reduced lipid peroxidation, nitrotyrosines and neutrophil accumulation, altogether protecting against damage. The combination of acetylcholine and preconditioning conferred stronger protection against damage, oxidative stress and neutrophil accumulation than acetylcholine treatment alone. These superior beneficial effects were due to a selective preconditioning-mediated generation of nitric oxide and regulation of PPAR and TLR4 pathways, which were not observed when acetylcholine was administered alone. Our findings propose the combination of acetylcholine+preconditioning as a feasible and highly protective strategy to reduce the adverse effects of brain death and to ultimately improve liver graft quality. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

AMPA receptor-induced local brain-derived neurotrophic factor signaling mediates motor recovery after stroke.

PubMed

Clarkson, Andrew N; Overman, Justine J; Zhong, Sheng; Mueller, Rudolf; Lynch, Gary; Carmichael, S Thomas

2011-03-09

Stroke is the leading cause of adult disability. Recovery after stroke shares similar molecular and cellular properties with learning and memory. A main component of learning-induced plasticity involves signaling through AMPA receptors (AMPARs). We systematically tested the role of AMPAR function in motor recovery in a mouse model of focal stroke. AMPAR function controls functional recovery beginning 5 d after the stroke. Positive allosteric modulators of AMPARs enhance recovery of limb control when administered after a delay from the stroke. Conversely, AMPAR antagonists impair motor recovery. The contributions of AMPARs to recovery are mediated by release of brain-derived neurotrophic factor (BDNF) in periinfarct cortex, as blocking local BDNF function in periinfarct cortex blocks AMPAR-mediated recovery and prevents the normal pattern of motor recovery. In contrast to a delayed AMPAR role in motor recovery, early administration of AMPAR agonists after stroke increases stroke damage. These findings indicate that the role of glutamate signaling through the AMPAR changes over time in stroke: early potentiation of AMPAR signaling worsens stroke damage, whereas later potentiation of the same signaling system improves functional recovery.

Neuroprotective properties of epoetin alfa.

PubMed

Cerami, Anthony; Brines, Michael; Ghezzi, Pietro; Cerami, Carla; Itri, Loretta M

2002-01-01

Erythropoietin and its receptor function as primary mediators of the normal physiological response to hypoxia. Erythropoietin is recognized for its central role in erythropoiesis, but studies in which recombinant human erythropoietin (epoetin alfa) is injected directly into ischaemic rodent brain show that erythropoietin also mediates neuroprotection. Abundant expression of the erythropoietin receptor has been observed at brain capillaries, which could provide a route for circulating erythropoietin to enter the brain. In confirmation of this hypothesis, systemic administration of epoetin alfa before or up to 6 h after focal brain ischaemia reduced injury by 50-75%. Epoetin alfa also limited the extent of concussive brain injury, the immune damage in experimental autoimmune encephalomyelitis and excitotoxicity induced by kainate. Thus, systemically administered epoetin alfa in animal models has neuroprotective effects, demonstrating its potential use after brain injury, trauma and multiple sclerosis. It is evident that erythropoietin has biological activities in addition to increasing red cell mass. Given the excellent safety profile of epoetin alfa, clinical trials evaluating systemically administered epoetin alfa as a general neuroprotective treatment are warranted.

Mangiferin decreases inflammation and oxidative damage in rat brain after stress.

PubMed

Márquez, Lucía; García-Bueno, Borja; Madrigal, José L M; Leza, Juan C

2012-09-01

Stress exposure elicits neuroinflammation and oxidative damage in brain, and stress-related neurological and neuropsychiatric diseases have been associated with cell damage and death. Mangiferin (MAG) is a polyphenolic compound abundant in the stem bark of Mangifera indica L. with antioxidant and anti-inflammatory properties in different experimental settings. In this study, the capacity of MAG to prevent neuroinflammation and brain oxidative damage induced by stress exposure was investigated. Young-adult male Wistar rats immobilized during 6 h were administered by oral gavage with increasing doses of MAG (15, 30, and 60 mg/Kg), respectively, 7 days before stress. Prior treatment with MAG prevented all of the following stress-induced effects: (1) increase in glucocorticoids (GCs) and interleukin-1β (IL-1β) plasma levels, (2) loss of redox balance and reduction in catalase brain levels, (3) increase in pro-inflammatory mediators, such as tumor necrosis factor alpha TNF-α and its receptor TNF-R1, nuclear factor-kappa B (NF-κB) and synthesis enzymes, such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), (4) increase in lipid peroxidation. These multifaceted protective effects suggest that MAG administration could be a new therapeutic strategy in neurological/neuropsychiatric pathologies in which hypothalamic/pituitary/adrenal (HPA) stress axis dysregulation, neuroinflammation, and oxidative damage take place in their pathophysiology.

MCP-1 and CCR2 Contribute to Non-Lymphocyte-Mediated Brain Disease Induced by Fr98 Polytropic Retrovirus Infection in Mice: Role for Astrocytes in Retroviral Neuropathogenesis

PubMed Central

Peterson, Karin E.; Errett, John S.; Wei, Tao; Dimcheff, Derek E.; Ransohoff, Richard; Kuziel, William A.; Evans, Leonard; Chesebro, Bruce

2004-01-01

Virus infection of the central nervous system (CNS) often results in chemokine upregulation. Although often associated with lymphocyte recruitment, increased chemokine expression is also associated with non-lymphocyte-mediated CNS disease. In these instances, the effect of chemokine upregulation on neurological disease is unclear. In vitro, several chemokines including monocyte chemotactic protein 1 (MCP-1) protect neurons from apoptosis. Therefore, in vivo, chemokine upregulation may be a protective host response to CNS damage. Alternatively, chemokines may contribute to pathogenesis by stimulating intrinsic brain cells or recruiting macrophages to the brain. To investigate these possibilities, we studied a neurovirulent retrovirus, Fr98, that induces severe non-lymphocyte-mediated neurological disease and causes the upregulation of several chemokines that bind to chemokine receptors CCR2 and CCR5. Knockout mice deficient in CCR2 had reduced susceptibility to Fr98 pathogenesis, with significantly fewer mice developing clinical disease than did wild-type controls. In contrast, no reduction in Fr98-induced disease was observed in CCR5 knockout mice. Thus, signaling through CCR2, but not CCR5, plays an important role in Fr98-mediated pathogenesis. Three ligands for CCR2 (MCP-1, MCP-3, and MCP-5) were upregulated during Fr98 infection of the brain. Antibody-blocking experiments demonstrated that MCP-1 was important for retrovirus-induced neurological disease. In situ hybridization analysis revealed that MCP-1 was expressed by glial fibrillary acidic protein-positive astrocytes. Thus, astrocytes, previously not thought to play an effector role in the disease process were found to contribute to pathogenesis through the production of MCP-1. This study also demonstrates that chemokines can mediate pathogenesis in the CNS in the absence of lymphocytic infiltrate and gives credence to the hypothesis that chemokine upregulation is a mechanism by which retroviruses such as human immunodeficiency virus induce neurological damage. PMID:15163738

Detrimental role of the EP1 prostanoid receptor in blood-brain barrier damage following experimental ischemic stroke

PubMed Central

Frankowski, Jan C.; DeMars, Kelly M.; Ahmad, Abdullah S.; Hawkins, Kimberly E.; Yang, Changjun; Leclerc, Jenna L.; Doré, Sylvain; Candelario-Jalil, Eduardo

2015-01-01

Cyclooxygenase-2 (COX-2) is activated in response to ischemia and significantly contributes to the neuroinflammatory process. Accumulation of COX-2-derived prostaglandin E2 (PGE2) parallels the substantial increase in stroke-mediated blood-brain barrier (BBB) breakdown. Disruption of the BBB is a serious consequence of ischemic stroke, and is mainly mediated by matrix metalloproteinases (MMPs). This study aimed to investigate the role of PGE2 EP1 receptor in neurovascular injury in stroke. We hypothesized that pharmacological blockade or genetic deletion of EP1 protects against BBB damage and hemorrhagic transformation by decreasing the levels and activity of MMP-3 and MMP-9. We found that post-ischemic treatment with the EP1 antagonist, SC-51089, or EP1 genetic deletion results in a significant reduction in BBB disruption and reduced hemorrhagic transformation in an experimental model of transient focal cerebral ischemia. These neurovascular protective effects of EP1 inactivation are associated with a significant reduction in MMP-9/-3, less peripheral neutrophil infiltration, and a preservation of tight junction proteins (ZO-1 and occludin) composing the BBB. Our study identifies the EP1 signaling pathway as an important link between neuroinflammation and MMP-mediated BBB breakdown in ischemic stroke. Targeting the EP1 receptor could represent a novel approach to diminish the devastating consequences of stroke-induced neurovascular damage. PMID:26648273

Blockade and knock-out of CALHM1 channels attenuate ischemic brain damage.

PubMed

Cisneros-Mejorado, Abraham; Gottlieb, Miroslav; Ruiz, Asier; Chara, Juan C; Pérez-Samartín, Alberto; Marambaud, Philippe; Matute, Carlos

2018-06-01

Overactivation of purinergic receptors during cerebral ischemia results in a massive release of neurotransmitters, including adenosine triphosphate (ATP), to the extracellular space which leads to cell death. Some hypothetical pathways of ATP release are large ion channels, such as calcium homeostasis modulator 1 (CALHM1), a membrane ion channel that can permeate ATP. Since this transmitter contributes to postischemic brain damage, we hypothesized that CALHM1 activation may be a relevant target to attenuate stroke injury. Here, we analyzed the contribution of CALHM1 to postanoxic depolarization after ischemia in cultured neurons and in cortical slices. We observed that the onset of postanoxic currents in neurons in those preparations was delayed after its blockade with ruthenium red or silencing of Calhm1 gene by short hairpin RNA, as well as in slices from CALHM1 knockout mice. Subsequently, we used transient middle cerebral artery occlusion and found that ruthenium red, a blocker of CALHM1, or the lack of CALHM1, substantially attenuated the motor symptoms and reduced significantly the infarct volume. These results show that CALHM1 channels mediate postanoxic depolarization in neurons and brain damage after ischemia. Therefore, targeting CALHM1 may have a high therapeutic potential for treating brain damage after ischemia.

DNA Double-Strand Break Repair Genes and Oxidative Damage in Brain Metastasis of Breast Cancer

PubMed Central

Evans, Lynda; Duchnowska, Renata; Reed, L. Tiffany; Palmieri, Diane; Qian, Yongzhen; Badve, Sunil; Sledge, George; Gril, Brunilde; Aladjem, Mirit I.; Fu, Haiqing; Flores, Natasha M.; Gökmen-Polar, Yesim; Biernat, Wojciech; Szutowicz-Zielińska, Ewa; Mandat, Tomasz; Trojanowski, Tomasz; Och, Waldemar; Czartoryska-Arlukowicz, Bogumiła; Jassem, Jacek; Mitchell, James B.

2014-01-01

Background Breast cancer frequently metastasizes to the brain, colonizing a neuro-inflammatory microenvironment. The molecular pathways facilitating this colonization remain poorly understood. Methods Expression profiling of 23 matched sets of human resected brain metastases and primary breast tumors by two-sided paired t test was performed to identify brain metastasis–specific genes. The implicated DNA repair genes BARD1 and RAD51 were modulated in human (MDA-MB-231-BR) and murine (4T1-BR) brain-tropic breast cancer cell lines by lentiviral transduction of cDNA or short hairpin RNA (shRNA) coding sequences. Their functional contribution to brain metastasis development was evaluated in mouse xenograft models (n = 10 mice per group). Results Human brain metastases overexpressed BARD1 and RAD51 compared with either matched primary tumors (1.74-fold, P < .001; 1.46-fold, P < .001, respectively) or unlinked systemic metastases (1.49-fold, P = .01; 1.44-fold, P = .008, respectively). Overexpression of either gene in MDA-MB-231-BR cells increased brain metastases by threefold to fourfold after intracardiac injections, but not lung metastases upon tail-vein injections. In 4T1-BR cells, shRNA-mediated RAD51 knockdown reduced brain metastases by 2.5-fold without affecting lung metastasis development. In vitro, BARD1- and RAD51-overexpressing cells showed reduced genomic instability but only exhibited growth and colonization phenotypes upon DNA damage induction. Reactive oxygen species were present in tumor cells and elevated in the metastatic neuro-inflammatory microenvironment and could provide an endogenous source of genotoxic stress. Tempol, a brain-permeable oxygen radical scavenger suppressed brain metastasis promotion induced by BARD1 and RAD51 overexpression. Conclusions BARD1 and RAD51 are frequently overexpressed in brain metastases from breast cancer and may constitute a mechanism to overcome reactive oxygen species–mediated genotoxic stress in the metastatic brain. PMID:24948741

DNA double-strand break repair genes and oxidative damage in brain metastasis of breast cancer.

PubMed

Woditschka, Stephan; Evans, Lynda; Duchnowska, Renata; Reed, L Tiffany; Palmieri, Diane; Qian, Yongzhen; Badve, Sunil; Sledge, George; Gril, Brunilde; Aladjem, Mirit I; Fu, Haiqing; Flores, Natasha M; Gökmen-Polar, Yesim; Biernat, Wojciech; Szutowicz-Zielińska, Ewa; Mandat, Tomasz; Trojanowski, Tomasz; Och, Waldemar; Czartoryska-Arlukowicz, Bogumiła; Jassem, Jacek; Mitchell, James B; Steeg, Patricia S

2014-07-01

Breast cancer frequently metastasizes to the brain, colonizing a neuro-inflammatory microenvironment. The molecular pathways facilitating this colonization remain poorly understood. Expression profiling of 23 matched sets of human resected brain metastases and primary breast tumors by two-sided paired t test was performed to identify brain metastasis-specific genes. The implicated DNA repair genes BARD1 and RAD51 were modulated in human (MDA-MB-231-BR) and murine (4T1-BR) brain-tropic breast cancer cell lines by lentiviral transduction of cDNA or short hairpin RNA (shRNA) coding sequences. Their functional contribution to brain metastasis development was evaluated in mouse xenograft models (n = 10 mice per group). Human brain metastases overexpressed BARD1 and RAD51 compared with either matched primary tumors (1.74-fold, P < .001; 1.46-fold, P < .001, respectively) or unlinked systemic metastases (1.49-fold, P = .01; 1.44-fold, P = .008, respectively). Overexpression of either gene in MDA-MB-231-BR cells increased brain metastases by threefold to fourfold after intracardiac injections, but not lung metastases upon tail-vein injections. In 4T1-BR cells, shRNA-mediated RAD51 knockdown reduced brain metastases by 2.5-fold without affecting lung metastasis development. In vitro, BARD1- and RAD51-overexpressing cells showed reduced genomic instability but only exhibited growth and colonization phenotypes upon DNA damage induction. Reactive oxygen species were present in tumor cells and elevated in the metastatic neuro-inflammatory microenvironment and could provide an endogenous source of genotoxic stress. Tempol, a brain-permeable oxygen radical scavenger suppressed brain metastasis promotion induced by BARD1 and RAD51 overexpression. BARD1 and RAD51 are frequently overexpressed in brain metastases from breast cancer and may constitute a mechanism to overcome reactive oxygen species-mediated genotoxic stress in the metastatic brain. Published by Oxford University Press 2014.

Escherichia coli K1-induced cytopathogenicity of human brain microvascular endothelial cells.

PubMed

Khan, Naveed Ahmed; Iqbal, Junaid; Siddiqui, Ruqaiyyah

2012-01-01

Pathophysiology of Escherichia coli sepsis is complex involving circulating bacterial products, cytokine release, and sustained bacteremia resulting in the damage of vascular endothelium. Here, it is shown that E. coli K1 produced cytopathogenicity of human brain microvascular endothelial cells (HBMEC), that constitute the blood-brain barrier. Whole bacteria or their conditioned medium produced severe HBMEC damage suggesting E. coli K1-cytopathogenicity is a contact-independent process. Using lipopolysaccharide (LPS) inhibitor, polymyxin B, purified LPS extracted from E. coli K1 as well as LPS mutant derived from E. coli K1, we showed that LPS is not the sole determinant of E. coli K1-mediated HBMEC death. Bacterial product(s) for HBMEC cytopathogenicity was heat-labile suggesting LPS-associated proteins. Several isogenic gene-deletion mutants (ΔompA, ΔibeA, ΔibeB, Δcnf1) exhibited HBMEC cytopathogenicity similar to that produced by wild type E. coli K1. E. coli K1-mediated HBMEC death was independent of phosphatidylinositol 3-kinase (PI3K) but dependent partially on focal adhesion kinase (FAK) using HBMEC expressing dominant negative FAK and PI3K. Copyright © 2012 Elsevier Ltd. All rights reserved.

Oxidative Burst of Circulating Neutrophils Following Traumatic Brain Injury in Human

PubMed Central

Liao, Yiliu; Liu, Peng; Guo, Fangyuan; Zhang, Zhi-Yuan; Zhang, Zhiren

2013-01-01

Besides secondary injury at the lesional site, Traumatic brain injury (TBI) can cause a systemic inflammatory response, which may cause damage to initially unaffected organs and potentially further exacerbate the original injury. Here we investigated plasma levels of important inflammatory mediators, oxidative activity of circulating leukocytes, particularly focusing on neutrophils, from TBI subjects and control subjects with general trauma from 6 hours to 2 weeks following injury, comparing with values from uninjured subjects. We observed increased plasma level of inflammatory cytokines/molecules TNF-α, IL-6 and CRP, dramatically increased circulating leukocyte counts and elevated expression of TNF-α and iNOS in circulating leukocytes from TBI patients, which suggests a systemic inflammatory response following TBI. Our data further showed increased free radical production in leukocyte homogenates and elevated expression of key oxidative enzymes iNOS, COX-2 and NADPH oxidase (gp91phox) in circulating leukocytes, indicating an intense induction of oxidative burst following TBI, which is significantly greater than that in control subjects with general trauma. Furthermore, flow cytometry assay proved neutrophils as the largest population in circulation after TBI and showed significantly up-regulated oxidative activity and suppressed phagocytosis rate for circulating neutrophils following brain trauma. It suggests that the highly activated neutrophils might play an important role in the secondary damage, even outside the injured brain. Taken together, the potent systemic inflammatory response induced by TBI, especially the intensively increase oxidative activity of circulating leukocytes, mainly neutrophils, may lead to a systemic damage, dysfunction/damage of bystander tissues/organs and even further exacerbate secondary local damage. Controlling these pathophysiological processes may be a promising therapeutic strategy and will protect unaffected organs and the injured brain from the secondary damage. PMID:23894384

Neurosurgical patties: adhesion and damage mitigation.

PubMed

Stratton-Powell, Ashley A; Anderson, Ian A; Timothy, Jake; Kapur, Nikil; Culmer, Peter

2015-07-01

Neurosurgical patties are textile pads used during most neurosurgical operations to protect tissues, manage the fluid environment, control hemostasis, and aid tissue manipulation. Recent research has suggested that, contrary to their aim, patties adhere to brain tissue and cause damage during removal. This study aimed to characterize and quantify the degree of and consequences resulting from adhesion between neurosurgical patties and brain tissue. Using a customized peel apparatus, the authors performed 90° peel tests on 5 patty products: Policot, Telfa, Americot, Delicot, and Ray-Cot (n = 247) from American Surgical Company. They tested 4 conditions: wet patty on glass (control), wet patty on wet brain peeled at 5 mm/sec (wet), dry patty on wet brain peeled at 5 mm/sec (dry), and wet patty on wet brain peeled at 20 mm/sec (speed). The interaction between patty and tissue was analyzed using peel-force traces and pre-peel histological analysis. Adhesion strength differed between patty products (p < 0.001) and conditions (p < 0.001). Adhesion strength was greatest for Delicot patties under wet (2.22 mN/mm) and dry (9.88 mN/mm) conditions. For all patties, damage at the patty-tissue interface was proportional to the degree of fiber contact. When patties were irrigated, mechanical adhesion was reduced by up to 550% compared with dry usage. For all patty products, mechanical (destructive) and liquid-mediated (nondestructive) adhesion caused damage to neural tissue. The greatest adhesion occurred with Delicot patties. To mitigate patty adhesion and neural tissue damage, surgeons should consider regular irrigation to be essential during neurosurgical procedures.

Effect of bacoside A on brain antioxidant status in cigarette smoke exposed rats.

PubMed

Anbarasi, K; Vani, G; Balakrishna, K; Devi, C S Shyamala

2006-02-16

Free radicals mediated oxidative stress has been implicated in the pathogenesis of smoking-related diseases and antioxidant nutrients are reported to prevent the oxidative damage induced by smoking. Therefore, the present study was conducted to evaluate the antioxidant role of bacoside A (triterpenoid saponin isolated from Bacopa monniera) against chronic cigarette smoking induced oxidative damage in rat brain. Adult male albino rats were exposed to cigarette smoke for a period of 12 weeks and simultaneously administered with bacoside A (10 mg/kg b.w./day, p.o.). Antioxidant status of the brain was assessed from the levels of reduced glutathione, vitamin C, vitamin E, and vitamin A and the activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. The levels of copper, iron, zinc and selenium in brain and serum ceruloplasmin activity were also measured. Oxidative stress was evident from the diminished levels of both enzymatic and non-enzymatic antioxidants. Alterations in the levels of trace elements with accumulation of copper and iron, and depletion of zinc and selenium were also observed. Bacoside A administration improved the antioxidant status and maintained the levels of trace elements. These results suggest that chronic cigarette smoke exposure enhances oxidative stress, thereby disturbing the tissue defense system and bacoside A protects the brain from the oxidative damage through its antioxidant potential.

BDNF and exercise enhance neuronal DNA repair by stimulating CREB-mediated production of apurinic/apyrimidinic endonuclease 1.

PubMed

Yang, Jenq-Lin; Lin, Yu-Ting; Chuang, Pei-Chin; Bohr, Vilhelm A; Mattson, Mark P

2014-03-01

Brain-derived neurotrophic factor (BDNF) promotes the survival and growth of neurons during brain development and mediates activity-dependent synaptic plasticity and associated learning and memory in the adult. BDNF levels are reduced in brain regions affected in Alzheimer's, Parkinson's, and Huntington's diseases, and elevation of BDNF levels can ameliorate neuronal dysfunction and degeneration in experimental models of these diseases. Because neurons accumulate oxidative lesions in their DNA during normal activity and in neurodegenerative disorders, we determined whether and how BDNF affects the ability of neurons to cope with oxidative DNA damage. We found that BDNF protects cerebral cortical neurons against oxidative DNA damage-induced death by a mechanism involving enhanced DNA repair. BDNF stimulates DNA repair by activating cyclic AMP response element-binding protein (CREB), which, in turn, induces the expression of apurinic/apyrimidinic endonuclease 1 (APE1), a key enzyme in the base excision DNA repair pathway. Suppression of either APE1 or TrkB by RNA interference abolishes the ability of BDNF to protect neurons against oxidized DNA damage-induced death. The ability of BDNF to activate CREB and upregulate APE1 expression is abolished by shRNA of TrkB as well as inhibitors of TrkB, PI3 kinase, and Akt kinase. Voluntary running wheel exercise significantly increases levels of BDNF, activates CREB, and upregulates APE1 in the cerebral cortex and hippocampus of mice, suggesting a novel mechanism whereby exercise may protect neurons from oxidative DNA damage. Our findings reveal a previously unknown ability of BDNF to enhance DNA repair by inducing the expression of the DNA repair enzyme APE1.

Role of pattern recognition receptors of the neurovascular unit in inflamm-aging.

PubMed

Wilhelm, Imola; Nyúl-Tóth, Ádám; Kozma, Mihály; Farkas, Attila E; Krizbai, István A

2017-11-01

Aging is associated with chronic inflammation partly mediated by increased levels of damage-associated molecular patterns, which activate pattern recognition receptors (PRRs) of the innate immune system. Furthermore, many aging-related disorders are associated with inflammation. PRRs, such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptors (NLRs), are expressed not only in cells of the innate immune system but also in other cells, including cells of the neurovascular unit and cerebral vasculature forming the blood-brain barrier. In this review, we summarize our present knowledge about the relationship between activation of PRRs expressed by cells of the neurovascular unit-blood-brain barrier, chronic inflammation, and aging-related pathologies of the brain. The most important damage-associated molecular pattern-sensing PRRs in the brain are TLR2, TLR4, and NLR family pyrin domain-containing protein-1 and pyrin domain-containing protein-3, which are activated during physiological and pathological aging in microglia, neurons, astrocytes, and possibly endothelial cells and pericytes. Copyright © 2017 the American Physiological Society.

Autophagy Constitutes a Protective Mechanism against Ethanol Toxicity in Mouse Astrocytes and Neurons.

PubMed

Pla, Antoni; Pascual, María; Guerri, Consuelo

2016-01-01

Ethanol induces brain damage and neurodegeneration by triggering inflammatory processes in glial cells through activation of Toll-like receptor 4 (TLR4) signaling. Recent evidence indicates the role of protein degradation pathways in neurodegeneration and alcoholic liver disease, but how these processes affect the brain remains elusive. We have demonstrated that chronic ethanol consumption impairs proteolytic pathways in mouse brain, and the immune response mediated by TLR4 receptors participates in these dysfunctions. We evaluate the in vitro effects of an acute ethanol dose on the autophagy-lysosome pathway (ALP) on WT and TLR4-/- mouse astrocytes and neurons in primary culture, and how these changes affect cell survival. Our results show that ethanol induces overexpression of several autophagy markers (ATG12, LC3-II, CTSB), and increases the number of lysosomes in WT astrocytes, effects accompanied by a basification of lysosomal pH and by lowered phosphorylation levels of autophagy inhibitor mTOR, along with activation of complexes beclin-1 and ULK1. Notably, we found only minor changes between control and ethanol-treated TLR4-/- mouse astroglial cells. Ethanol also triggers the expression of the inflammatory mediators iNOS and COX-2, but induces astroglial death only slightly. Blocking autophagy by using specific inhibitors increases both inflammation and cell death. Conversely, in neurons, ethanol down-regulates the autophagy pathway and triggers cell death, which is partially recovered by using autophagy enhancers. These results support the protective role of the ALP against ethanol-induced astroglial cell damage in a TLR4-dependent manner, and provide new insight into the mechanisms that underlie ethanol-induced brain damage and are neuronal sensitive to the ethanol effects.

Delayed increases in microvascular pathology after experimental traumatic brain injury are associated with prolonged inflammation, blood-brain barrier disruption, and progressive white matter damage.

PubMed

Glushakova, Olena Y; Johnson, Danny; Hayes, Ronald L

2014-07-01

Traumatic brain injury (TBI) is a significant risk factor for chronic traumatic encephalopathy (CTE), Alzheimer's disease (AD), and Parkinson's disease (PD). Cerebral microbleeds, focal inflammation, and white matter damage are associated with many neurological and neurodegenerative disorders including CTE, AD, PD, vascular dementia, stroke, and TBI. This study evaluates microvascular abnormalities observed at acute and chronic stages following TBI in rats, and examines pathological processes associated with these abnormalities. TBI in adult rats was induced by controlled cortical impact (CCI) of two magnitudes. Brain pathology was assessed in white matter of the corpus callosum for 24 h to 3 months following injury using immunohistochemistry (IHC). TBI resulted in focal microbleeds that were related to the magnitude of injury. At the lower magnitude of injury, microbleeds gradually increased over the 3 month duration of the study. IHC revealed TBI-induced focal abnormalities including blood-brain barrier (BBB) damage (IgG), endothelial damage (intercellular adhesion molecule 1 [ICAM-1]), activation of reactive microglia (ionized calcium binding adaptor molecule 1 [Iba1]), gliosis (glial fibrillary acidic protein [GFAP]) and macrophage-mediated inflammation (cluster of differentiation 68 [CD68]), all showing different temporal profiles. At chronic stages (up to 3 months), apparent myelin loss (Luxol fast blue) and scattered deposition of microbleeds were observed. Microbleeds were surrounded by glial scars and co-localized with CD68 and IgG puncta stainings, suggesting that localized BBB breakdown and inflammation were associated with vascular damage. Our results indicate that evolving white matter degeneration following experimental TBI is associated with significantly delayed microvascular damage and focal microbleeds that are temporally and regionally associated with development of punctate BBB breakdown and progressive inflammatory responses. Increased understanding of mechanisms underlying delayed microvascular damage following TBI could provide novel insights into chronic pathological responses to TBI and potential common mechanisms underlying TBI and neurodegenerative diseases.

Effect of Ca2EDTA on Zinc Mediated Inflammation and Neuronal Apoptosis in Hippocampus of an In Vivo Mouse Model of Hypobaric Hypoxia

PubMed Central

Malairaman, Udayabanu; Dandapani, Kumaran; Katyal, Anju

2014-01-01

Background Calcium overload has been implicated as a critical event in glutamate excitotoxicity associated neurodegeneration. Recently, zinc accumulation and its neurotoxic role similar to calcium has been proposed. Earlier, we reported that free chelatable zinc released during hypobaric hypoxia mediates neuronal damage and memory impairment. The molecular mechanism behind hypobaric hypoxia mediated neuronal damage is obscure. The role of free zinc in such neuropathological condition has not been elucidated. In the present study, we investigated the underlying role of free chelatable zinc in hypobaric hypoxia-induced neuronal inflammation and apoptosis resulting in hippocampal damage. Methods Adult male Balb/c mice were exposed to hypobaric hypoxia and treated with saline or Ca2EDTA (1.25 mM/kg i.p) daily for four days. The effects of Ca2EDTA on apoptosis (caspases activity and DNA fragmentation), pro-inflammatory markers (iNOS, TNF-α and COX-2), NADPH oxidase activity, poly(ADP ribose) polymerase (PARP) activity and expressions of Bax, Bcl-2, HIF-1α, metallothionein-3, ZnT-1 and ZIP-6 were examined in the hippocampal region of brain. Results Hypobaric hypoxia resulted in increased expression of metallothionein-3 and zinc transporters (ZnT-1 and ZIP-6). Hypobaric hypoxia elicited an oxidative stress and inflammatory response characterized by elevated NADPH oxidase activity and up-regulation of iNOS, COX-2 and TNF-α. Furthermore, hypobaric hypoxia induced HIF-1α protein expression, PARP activation and apoptosis in the hippocampus. Administration of Ca2EDTA significantly attenuated the hypobaric hypoxia induced oxidative stress, inflammation and apoptosis in the hippocampus. Conclusion We propose that hypobaric hypoxia/reperfusion instigates free chelatable zinc imbalance in brain associated with neuroinflammation and neuronal apoptosis. Therefore, zinc chelating strategies which block zinc mediated neuronal damage linked with cerebral hypoxia and other neurodegenerative conditions can be designed in future. PMID:25340757

Effect of Ca2EDTA on zinc mediated inflammation and neuronal apoptosis in hippocampus of an in vivo mouse model of hypobaric hypoxia.

PubMed

Malairaman, Udayabanu; Dandapani, Kumaran; Katyal, Anju

2014-01-01

Calcium overload has been implicated as a critical event in glutamate excitotoxicity associated neurodegeneration. Recently, zinc accumulation and its neurotoxic role similar to calcium has been proposed. Earlier, we reported that free chelatable zinc released during hypobaric hypoxia mediates neuronal damage and memory impairment. The molecular mechanism behind hypobaric hypoxia mediated neuronal damage is obscure. The role of free zinc in such neuropathological condition has not been elucidated. In the present study, we investigated the underlying role of free chelatable zinc in hypobaric hypoxia-induced neuronal inflammation and apoptosis resulting in hippocampal damage. Adult male Balb/c mice were exposed to hypobaric hypoxia and treated with saline or Ca2EDTA (1.25 mM/kg i.p) daily for four days. The effects of Ca2EDTA on apoptosis (caspases activity and DNA fragmentation), pro-inflammatory markers (iNOS, TNF-α and COX-2), NADPH oxidase activity, poly(ADP ribose) polymerase (PARP) activity and expressions of Bax, Bcl-2, HIF-1α, metallothionein-3, ZnT-1 and ZIP-6 were examined in the hippocampal region of brain. Hypobaric hypoxia resulted in increased expression of metallothionein-3 and zinc transporters (ZnT-1 and ZIP-6). Hypobaric hypoxia elicited an oxidative stress and inflammatory response characterized by elevated NADPH oxidase activity and up-regulation of iNOS, COX-2 and TNF-α. Furthermore, hypobaric hypoxia induced HIF-1α protein expression, PARP activation and apoptosis in the hippocampus. Administration of Ca2EDTA significantly attenuated the hypobaric hypoxia induced oxidative stress, inflammation and apoptosis in the hippocampus. We propose that hypobaric hypoxia/reperfusion instigates free chelatable zinc imbalance in brain associated with neuroinflammation and neuronal apoptosis. Therefore, zinc chelating strategies which block zinc mediated neuronal damage linked with cerebral hypoxia and other neurodegenerative conditions can be designed in future.

γδ T cells as early sensors of tissue damage and mediators of secondary neurodegeneration

PubMed Central

Gelderblom, Mathias; Arunachalam, Priyadharshini; Magnus, Tim

2014-01-01

Spontaneous or medically induced reperfusion occurs in up to 70% of patients within 24 h after cerebral ischemia. Reperfusion of ischemic brain tissue can augment the inflammatory response that causes additional injury. Recently, T cells have been shown to be an essential part of the post-ischemic tissue damage, and especially IL-17 secreting T cells have been implicated in the pathogenesis of a variety of inflammatory reactions in the brain. After stroke, it seems that the innate γδ T cells are the main IL-17 producing cells and that the γδ T cell activation constitutes an early and mainly damaging immune response in stroke. Effector mechanism of γδ T cell derived IL-17 in the ischemic brain include the induction of metalloproteinases, proinflammatory cytokines and neutrophil attracting chemokines, leading to a further amplification of the detrimental inflammatory response. In this review, we will give an overview on the concepts of γδ T cells and IL-17 in stroke pathophysiology and on their potential importance for human disease conditions. PMID:25414640

Reciprocal inhibition of p53 and nuclear factor-kappaB transcriptional activities determines cell survival or death in neurons.

PubMed

Culmsee, Carsten; Siewe, Jan; Junker, Vera; Retiounskaia, Marina; Schwarz, Stephanie; Camandola, Simonetta; El-Metainy, Shahira; Behnke, Hagen; Mattson, Mark P; Krieglstein, Josef

2003-09-17

The tumor suppressor and transcription factor p53 is a key modulator of cellular stress responses, and activation of p53 precedes apoptosis in many cell types. Controversial reports exist on the role of the transcription factor nuclear factor-kappaB (NF-kappaB) in p53-mediated apoptosis, depending on the cell type and experimental conditions. Therefore, we sought to elucidate the role of NF-kappaB in p53-mediated neuron death. In cultured neurons DNA damaging compounds induced activation of p53, whereas NF-kappaB activity declined significantly. The p53 inhibitor pifithrin-alpha (PFT) preserved NF-kappaB activity and protected neurons against apoptosis. Immunoprecipitation experiments revealed enhanced p53 binding to the transcriptional cofactor p300 after induction of DNA damage, whereas binding of p300 to NF-kappaB was reduced. In contrast, PFT blocked the interaction of p53 with the cofactor, whereas NF-kappaB binding to p300 was enhanced. Most interestingly, similar results were observed after oxygen glucose deprivation in cultured neurons and in ischemic brain tissue. Ischemia-induced repression of NF-kappaB activity was prevented and brain damage was reduced by the p53 inhibitor PFT in a dose-dependent manner. It is concluded that a balanced competitive interaction of p53 and NF-kappaB with the transcriptional cofactor p300 exists in neurons. Exposure of neurons to lethal stress activates p53 and disrupts NF-kappaB binding to p300, thereby blocking NF-kappaB-mediated survival signaling. Inhibitors of p53 provide pronounced neuroprotective effects because they block p53-mediated induction of cell death and concomitantly enhance NF-kappaB-induced survival signaling.

Role of inter-hemispheric transfer in generating visual evoked potentials in V1-damaged brain hemispheres

PubMed Central

Kavcic, Voyko; Triplett, Regina L.; Das, Anasuya; Martin, Tim; Huxlin, Krystel R.

2015-01-01

Partial cortical blindness is a visual deficit caused by unilateral damage to the primary visual cortex, a condition previously considered beyond hopes of rehabilitation. However, recent data demonstrate that patients may recover both simple and global motion discrimination following intensive training in their blind field. The present experiments characterized motion-induced neural activity of cortically blind (CB) subjects prior to the onset of visual rehabilitation. This was done to provide information about visual processing capabilities available to mediate training-induced visual improvements. Visual Evoked Potentials (VEPs) were recorded from two experimental groups consisting of 9 CB subjects and 9 age-matched, visually-intact controls. VEPs were collected following lateralized stimulus presentation to each of the 4 visual field quadrants. VEP waveforms were examined for both stimulus-onset (SO) and motion-onset (MO) related components in postero-lateral electrodes. While stimulus presentation to intact regions of the visual field elicited normal SO-P1, SO-N1, SO-P2 and MO-N2 amplitudes and latencies in contralateral brain regions of CB subjects, these components were not observed contralateral to stimulus presentation in blind quadrants of the visual field. In damaged brain hemispheres, SO-VEPs were only recorded following stimulus presentation to intact visual field quadrants, via inter-hemispheric transfer. MO-VEPs were only recorded from damaged left brain hemispheres, possibly reflecting a native left/right asymmetry in inter-hemispheric connections. The present findings suggest that damaged brain hemispheres contain areas capable of responding to visual stimulation. However, in the absence of training or rehabilitation, these areas only generate detectable VEPs in response to stimulation of the intact hemifield of vision. PMID:25575450

Zingiber zerumbet L. (Smith) extract alleviates the ethanol-induced brain damage via its antioxidant activity.

PubMed

Hamid, Asmah; Ibrahim, Farah Wahida; Ming, Teoh Hooi; Nasrom, Mohd Nazir; Eusoff, Norelina; Husain, Khairana; Abdul Latif, Mazlyzam

2018-03-20

Zingiber zerumbet (L.) Smith belongs to the Zingiberaceae family that is widely distributed throughout the tropics, particularly in Southeast Asia. It is locally known as 'Lempoyang' and traditionally used to treat fever, constipation and to relieve pain. It is also known to possess antioxidant and anti-inflammatory activities. Based on these antioxidant and anti-inflammatory activities, this study was conducted to investigate the effects of ethyl-acetate extract of Z. zerumbet rhizomes against ethanol-induced brain damage in male Wistar rats. Twenty-four male Wistar rats were divided into four groups which consist of normal, 1.8 g/kg ethanol (40% v/v), 200 mg/kg Z. zerumbet extract plus ethanol and 400 mg/kg Z. zerumbet plus ethanol. The extract of Z. zerumbet was given once daily by oral gavage, 30 min prior to ethanol exposure via intraperitoneal route for 14 consecutive days. The rats were then sacrificed. Blood and brain homogenate were subjected to biochemical tests and part of the brain tissue was sectioned for histological analysis. Treatment with ethyl-acetate Z. zerumbet extract at 200 mg/kg and 400 mg/kg significantly reduced the level of malondialdehyde (MDA) and protein carbonyl (p < 0.05) in the brain homogenate. Both doses of extracts also significantly increased the level of serum superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities as well as glutathione (GSH) level (p < 0.05). However, administration of ethyl-acetate Z. zerumbet extract at 400 mg/kg showed better protective effects on the ethanol-induced brain damage as shown with higher levels of SOD, CAT, GPx and GSH in the brain homogenate as compared to 200 mg/kg dose. Histological observation of the cerebellum and cerebral cortex showed that the extract prevented the loss of Purkinje cells and retained the number and the shape of the cells. Ethyl-acetate extract of Z. zerumbet has protective effects against ethanol-induced brain damage and this is mediated through its antioxidant properties. Z. zerumbet extract protects against ethanol-induced brain damage via its antioxidant properties.

Cyclic AMP response element binding protein and brain-derived neurotrophic factor: Molecules that modulate our mood?

PubMed Central

Nair, A; Vaidya, V A

2008-01-01

Depression is the major psychiatric ailment of our times, afflicting ~20% of the population. Despite its prevalence, the pathophysiology of this complex disorder is not well understood. In addition, although antidepressants have been in existence for the past several decades, the mechanisms that underlie their therapeutic effects remain elusive. Building evidence implicates a role for the plasticity of specific neuro-circuitry in both the pathophysiology and treatment of depression. Damage to limbic regions is thought to contribute to the etiology of depression and antidepressants have been reported to reverse such damage and promote adaptive plasticity. The molecular pathways that contribute to the damage associated with depression and antidepressant-mediated plasticity are a major focus of scientific enquiry. The transcription factor cyclic AMP response element binding protein (CREB) and the neurotrophin brain-derived neurotrophic factor (BDNF) are targets of diverse classes of antidepressants and are known to be regulated in animal models and in patients suffering from depression. Given their role in neuronal plasticity, CREB and BDNF have emerged as molecules that may play an important role in modulating mood. The purpose of this review is to discuss the role of CREB and BDNF in depression and as targets/mediators of antidepressant action. PMID:17006024

Characteristics of taurine release in slices from adult and developing mouse brain stem.

PubMed

Saransaari, P; Oja, S S

2006-07-01

Taurine has been thought to function as a regulator of neuronal activity, neuromodulator and osmoregulator. Moreover, it is essential for the development and survival of neural cells and protects them under cell-damaging conditions. Taurine is also involved in many vital functions regulated by the brain stem, including cardiovascular control and arterial blood pressure. The release of taurine has been studied both in vivo and in vitro in higher brain areas, whereas the mechanisms of release have not been systematically characterized in the brain stem. The properties of release of preloaded [(3)H]taurine were now characterized in slices prepared from the mouse brain stem from developing (7-day-old) and young adult (3-month-old) mice, using a superfusion system. In general, taurine release was found to be similar to that in other brain areas, consisting of both Ca(2+)-dependent and Ca(2+)-independent components. Moreover, the release was mediated by Na(+)-, Cl(-)-dependent transporters operating outwards, as both Na(+)-free and Cl(-) -free conditions greatly enhanced it. Cl(-) channel antagonists and a Cl(-) transport inhibitor reduced the release at both ages, indicating that a part of the release occurs through ion channels. Protein kinases appeared not to be involved in taurine release in the brain stem, since substances affecting the activity of protein kinase C or tyrosine kinase had no significant effects. The release was modulated by cAMP second messenger systems and phospholipases at both ages. Furthermore, the metabotropic glutamate receptor agonists likewise suppressed the K(+)-stimulated release at both ages. In the immature brain stem, the ionotropic glutamate receptor agonists N-methyl-D-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) potentiated taurine release in a receptor-mediated manner. This could constitute an important mechanism against excitotoxicity, protecting the brain stem under cell-damaging conditions.

A cannabinoid receptor 2 agonist reduces blood-brain barrier damage via induction of MKP-1 after intracerebral hemorrhage in rats.

PubMed

Li, Lin; Yun, Debo; Zhang, Yuan; Tao, Yihao; Tan, Qiang; Qiao, Fei; Luo, Bo; Liu, Yi; Fan, Runjin; Xian, Jishu; Yu, Anyong

2018-06-07

The blood-brain barrier (BBB) disruption and the following development of brain edema, is the most life-threatening secondary injury after intracerebral hemorrhage (ICH). This study is to investigate a potential role and mechanism of JWH133, a selected cannabinoid receptor type2 (CB2R) agonist, on protecting blood-brain barrier integrity after ICH. 192 adult male Sprague-Dawley (SD) rats were randomly divided into Sham; ICH+Vehicle; ICH+JWH 1.0mg/kg, ICH+JWH 1.5mg/kg and ICH+JWH 2.0mg/kg; ICH+SR+JWH respectively. Animals were euthanized at 24 hours following western blots and immunofluorescence staining, we also examined the effect of JWH133 on the brain water contents, neurobehavioral deficits and blood brain barrier (BBB) permeability, meanwhile reassessed the inflammatory cytokines concentrations around the hematoma by enzyme-linked immunosorbent assay (ELISA) in each group. JWH133 (1.5mg/kg) administration ameliorated brain edema, neurological deficits and blood-brain barrier damage, as well as microglia activation. The expression of pro-inflammatory mediators interleukin 1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and matrix metallopeptidase-2/9(MMP2/9) were attenuated, but not monocyte chemoattractant protein-1 (MCP-1). Additionally, decreases in zonula occludens-1 (ZO-1) and claudin-5 expression were partially recovered by JWH133. Furthermore, JWH133 upregulated the expression level of MKP-1, which leads to the inhibition of MAPKs signaling pathway activation, especially for ERK and P38. However, these effects were reversed by pretreatment with a selective CB2R antagonist, SR144528. CB2R agonist alleviated neuroinflammation and protected blood-brain barrier permeability in a rat ICH model. Further molecular mechanisms revealed which is probably mediated by enhancing the expression of MKP-1, then inhibited MAPKs signal transduction. Copyright © 2018. Published by Elsevier B.V.

Regulation of endogenous neural stem/progenitor cells for neural repair—factors that promote neurogenesis and gliogenesis in the normal and damaged brain

PubMed Central

Christie, Kimberly J.; Turnley, Ann M.

2012-01-01

Neural stem/precursor cells in the adult brain reside in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus. These cells primarily generate neuroblasts that normally migrate to the olfactory bulb (OB) and the dentate granule cell layer respectively. Following brain damage, such as traumatic brain injury, ischemic stroke or in degenerative disease models, neural precursor cells from the SVZ in particular, can migrate from their normal route along the rostral migratory stream (RMS) to the site of neural damage. This neural precursor cell response to neural damage is mediated by release of endogenous factors, including cytokines and chemokines produced by the inflammatory response at the injury site, and by the production of growth and neurotrophic factors. Endogenous hippocampal neurogenesis is frequently also directly or indirectly affected by neural damage. Administration of a variety of factors that regulate different aspects of neural stem/precursor biology often leads to improved functional motor and/or behavioral outcomes. Such factors can target neural stem/precursor proliferation, survival, migration and differentiation into appropriate neuronal or glial lineages. Newborn cells also need to subsequently survive and functionally integrate into extant neural circuitry, which may be the major bottleneck to the current therapeutic potential of neural stem/precursor cells. This review will cover the effects of a range of intrinsic and extrinsic factors that regulate neural stem/precursor cell functions. In particular it focuses on factors that may be harnessed to enhance the endogenous neural stem/precursor cell response to neural damage, highlighting those that have already shown evidence of preclinical effectiveness and discussing others that warrant further preclinical investigation. PMID:23346046

Vascular and Inflammatory Factors in the Pathophysiology of Blast-Induced Brain Injury

PubMed Central

Elder, Gregory A.; Gama Sosa, Miguel A.; De Gasperi, Rita; Stone, James Radford; Dickstein, Dara L.; Haghighi, Fatemeh; Hof, Patrick R.; Ahlers, Stephen T.

2015-01-01

Blast-related traumatic brain injury (TBI) has received much recent attention because of its frequency in the conflicts in Iraq and Afghanistan. This renewed interest has led to a rapid expansion of clinical and animal studies related to blast. In humans, high-level blast exposure is associated with a prominent hemorrhagic component. In animal models, blast exerts a variety of effects on the nervous system including vascular and inflammatory effects that can be seen with even low-level blast exposures which produce minimal or no neuronal pathology. Acutely, blast exposure in animals causes prominent vasospasm and decreased cerebral blood flow along with blood-brain barrier breakdown and increased vascular permeability. Besides direct effects on the central nervous system, evidence supports a role for a thoracically mediated effect of blast; whereby, pressure waves transmitted through the systemic circulation damage the brain. Chronically, a vascular pathology has been observed that is associated with alterations of the vascular extracellular matrix. Sustained microglial and astroglial reactions occur after blast exposure. Markers of a central and peripheral inflammatory response are found for sustained periods after blast injury and include elevation of inflammatory cytokines and other inflammatory mediators. At low levels of blast exposure, a microvascular pathology has been observed in the presence of an otherwise normal brain parenchyma, suggesting that the vasculature may be selectively vulnerable to blast injury. Chronic immune activation in brain following vascular injury may lead to neurobehavioral changes in the absence of direct neuronal pathology. Strategies aimed at preventing or reversing vascular damage or modulating the immune response may improve the chronic neuropsychiatric symptoms associated with blast-related TBI. PMID:25852632

Targeting RNS/caveolin-1/MMP signaling cascades to protect against cerebral ischemia-reperfusion injuries: potential application for drug discovery.

PubMed

Chen, Han-Sen; Chen, Xi; Li, Wen-Ting; Shen, Jian-Gang

2018-05-01

Reactive nitrogen species (RNS) play important roles in mediating cerebral ischemia-reperfusion injury. RNS activate multiple signaling pathways and participate in different cellular events in cerebral ischemia-reperfusion injury. Recent studies have indicated that caveolin-1 and matrix metalloproteinase (MMP) are important signaling molecules in the pathological process of ischemic brain injury. During cerebral ischemia-reperfusion, the production of nitric oxide (NO) and peroxynitrite (ONOO - ), two representative RNS, down-regulates the expression of caveolin-1 (Cav-1) and, in turn, further activates nitric oxide synthase (NOS) to promote RNS generation. The increased RNS further induce MMP activation and mediate disruption of the blood-brain barrier (BBB), aggravating the brain damage in cerebral ischemia-reperfusion injury. Therefore, the feedback interaction among RNS/Cav-1/MMPs provides an amplified mechanism for aggravating ischemic brain damage during cerebral ischemia-reperfusion injury. Targeting the RNS/Cav-1/MMP pathway could be a promising therapeutic strategy for protecting against cerebral ischemia-reperfusion injury. In this mini-review article, we highlight the important role of the RNS/Cav-1/MMP signaling cascades in ischemic stroke injury and review the current progress of studies seeking therapeutic compounds targeting the RNS/Cav-1/MMP signaling cascades to attenuate cerebral ischemia-reperfusion injury. Several representative natural compounds, including calycosin-7-O-β-D-glucoside, baicalin, Momordica charantia polysaccharide (MCP), chlorogenic acid, lutein and lycopene, have shown potential for targeting the RNS/Cav-1/MMP signaling pathway to protect the brain in ischemic stroke. Therefore, the RNS/Cav-1/MMP pathway is an important therapeutic target in ischemic stroke treatment.

Involvement of brain-gut axis in treatment of cerebral infarction by β-asaron and paeonol.

PubMed

He, Xiaogang; Cai, Qiufang; Li, Jianxiang; Guo, Weifeng

2018-02-14

Cerebral infarction (CI) causes severe brain damage with high incidence. This study aimed to investigate the involvement of brain-gut axis in the treatment of CI by combined administration of β-asaron and paeonol. Rat middle cerebral artery occlusion (MCAO) model was established, the interleukin-1beta (IL-1β) and tumor necrosis factor α (TNF-α) in the rat peripheral blood were determined by ELISA assay, and brain tissue damage was evaluated by TUNNEL assay. The correlation of cholecystokinin (CCK) and nuclear factor-kappaB (NF-κB) signaling components between intestinal mucosa and prefrontal cortex of MCAO rats treated with β-asaron and paeonol were analyzed by quantitative RT-PCR and western blotting. In vitro transwell co-culture was performed to confirm the correlated expression. The expression of CCK and NF-κB signaling components were closely correlated between the intestinal mucosa and prefrontal cortex of MCAO rats treated with β-asaron and paeonol. The combined administration also regulates the IL-1β and TNF-α in the MCAO rat peripheral blood and ameliorate the brain damage in MCAO rats. Elevated expression of related genes was observed in the cortical neurons co-cultured with intestinal mucosal epithelial cells treated by β-asaron and paeonol. The brain-gut axis mediates the therapeutic effect of β-asaron and paeonol for cerebral infarction through CCK and NF-κB signaling. Copyright © 2017 Elsevier B.V. All rights reserved.

Complement C3 and C5 play critical roles in traumatic brain cryoinjury: blocking effects on neutrophil extravasation by C5a receptor antagonist☆

PubMed Central

Sewell, Diane L.; Nacewicz, Brendon; Liu, Frances; Macvilay, Sinarack; Erdei, Anna; Lambris, John D.; Sandor, Matyas; Fabry, Zsuzsa

2016-01-01

The role of complement components in traumatic brain injury is poorly understood. Here we show that secondary damage after acute cryoinjury is significantly reduced in C3−/− or C5−/− mice or in mice treated with C5a receptor antagonist peptides. Injury sizes and neutrophil extravasation were compared. While neutrophil density increased following traumatic brain injury in wild type (C57BL/6) mice, C3-deficient mice demonstrated lower neutrophil extravasation and injury sizes in the brain. RNase protection assay indicated that C3 contributes to the induction of brain inflammatory mediators, MIF, RANTES (CCL5) and MCP-1 (CCL2). Intracranial C3 injection induced neutrophil extravasation in injured brains of C3−/− mice suggesting locally produced C3 is important in brain inflammation. We show that neutrophil extravasation is significantly reduced in both C5−/− mice and C5a receptor antagonist treated cryoinjured mice suggesting that one of the possible mechanisms of C3 effect on neutrophil extravasation is mediated via downstream complement activation products such as C5a. Our data indicates that complement inhibitors may ameliorate traumatic brain injury. PMID:15342196

Persistent Neuroinflammatory Effects of Serial Exposure to Stress and Methamphetamine on the Blood-Brain Barrier

PubMed Central

Northrop, Nicole A.

2013-01-01

Studies of methamphetamine (Meth)-induced neurotoxicity have traditionally focused on monoaminergic terminal damage while more recent studies have found that stress exacerbates these damaging effects of Meth. Similarities that exist between the mechanisms that cause monoaminergic terminal damage in response to stress and Meth and those capable of producing a disruption of the blood-brain barrier (BBB) suggest that the well-known high comorbidity of stress and Meth could produce long-lasting structural and functional BBB disruption. The current studies examined the role of neuroinflammation in mediating the effects of exposure to chronic stress and/or Meth on BBB structure and function. Rats were pre-exposed to chronic unpredictable stress (CUS) and/or challenged with Meth. Twenty-four hours after the treatment of Meth in rats pre-exposed to CUS, occludin and claudin-5 immunoreactivity were decreased while truncation of β-dystroglycan, as well as FITC-dextran and water extravasation was increased. All changes other than β-dystroglycan and edema persisted 7 days later, occurred with increases in GFAP and COX-2, and were blocked by ketoprofen after Meth treatment. In addition, persistent increases in FITC-dextran extravasation were prevented by treatment with an EP1 receptor antagonist after Meth exposure. The results indicate that CUS and Meth synergize to produce long-lasting structural and functional BBB disruptions that are mediated by cyclooxygenase and protracted increases in inflammation. These results suggest that stress and Meth can synergize to produce a long-lasting vulnerability of the brain to subsequent environmental insults resulting from the persistent breach of the BBB. PMID:22833424

Neurotoxic lupus autoantibodies alter brain function through two distinct mechanisms

PubMed Central

Faust, Thomas W.; Chang, Eric H.; Kowal, Czeslawa; Berlin, RoseAnn; Gazaryan, Irina G.; Bertini, Eva; Zhang, Jie; Sanchez-Guerrero, Jorge; Fragoso-Loyo, Hilda E.; Volpe, Bruce T.; Diamond, Betty; Huerta, Patricio T.

2010-01-01

Damaging interactions between antibodies and brain antigenic targets may be responsible for an expanding range of neurological disorders. In the case of systemic lupus erythematosus (SLE), patients generate autoantibodies (AAbs) that frequently bind dsDNA. Although some symptoms of SLE may arise from direct reactivity to dsDNA, much of the AAb-mediated damage originates from cross-reactivity with other antigens. We have studied lupus AAbs that bind dsDNA and cross-react with the NR2A and NR2B subunits of the NMDA receptor (NMDAR). In adult mouse models, when the blood–brain barrier is compromised, these NMDAR-reactive AAbs access the brain and elicit neuronal death with ensuing cognitive dysfunction and emotional disturbance. The cellular mechanisms that underlie these deleterious effects remain incompletely understood. Here, we show that, at low concentration, the NMDAR-reactive AAbs are positive modulators of receptor function that increase the size of NMDAR-mediated excitatory postsynaptic potentials, whereas at high concentration, the AAbs promote excitotoxicity through enhanced mitochondrial permeability transition. Other synaptic receptors are completely unaffected by the AAbs. NMDAR activation is required for producing both the synaptic and the mitochondrial effects. Our study thus reveals the mechanisms by which NMDAR-reactive AAbs trigger graded cellular alterations, which are likely to be responsible for the transient and permanent neuropsychiatric symptoms observed in patients with SLE. Our study also provides a model in which local AAb concentration determines the exact nature of the cellular response. PMID:20921396

Glymphatic system disruption as a mediator of brain trauma and chronic traumatic encephalopathy.

PubMed

Sullan, Molly J; Asken, Breton M; Jaffee, Michael S; DeKosky, Steven T; Bauer, Russell M

2018-01-01

Traumatic brain injury (TBI) is an increasingly important issue among veterans, athletes and the general public. Difficulties with sleep onset and maintenance are among the most commonly reported symptoms following injury, and sleep debt is associated with increased accumulation of beta amyloid (Aβ) and phosphorylated tau (p-tau) in the interstitial space. Recent research into the glymphatic system, a lymphatic-like metabolic clearance mechanism in the central nervous system (CNS) which relies on cerebrospinal fluid (CSF), interstitial fluid (ISF), and astrocytic processes, shows that clearance is potentiated during sleep. This system is damaged in the acute phase following mTBI, in part due to re-localization of aquaporin-4 channels away from astrocytic end feet, resulting in reduced potential for waste removal. Long-term consequences of chronic dysfunction within this system in the context of repetitive brain trauma and insomnia have not been established, but potentially provide one link in the explanatory chain connecting repetitive TBI with later neurodegeneration. Current research has shown p-tau deposition in perivascular spaces and along interstitial pathways in chronic traumatic encephalopathy (CTE), pathways related to glymphatic flow; these are the main channels by which metabolic waste is cleared. This review addresses possible links between mTBI-related damage to glymphatic functioning and physiological changes found in CTE, and proposes a model for the mediating role of sleep disruption in increasing the risk for developing CTE-related pathology and subsequent clinical symptoms following repetitive brain trauma. Copyright © 2017 Elsevier Ltd. All rights reserved.

Taurine and neural cell damage.

PubMed

Saransaari, P; Oja, S S

2000-01-01

The inhibitory amino acid taurine is an osmoregulator and neuromodulator, also exerting neuroprotective actions in neural tissue. We review now the involvement of taurine in neuron-damaging conditions, including hypoxia, hypoglycemia, ischemia, oxidative stress, and the presence of free radicals, metabolic poisons and an excess of ammonia. The brain concentration of taurine is increased in several models of ischemic injury in vivo. Cell-damaging conditions which perturb the oxidative metabolism needed for active transport across cell membranes generally reduce taurine uptake in vitro, immature brain tissue being more tolerant to the lack of oxygen. In ischemia nonsaturable diffusion increases considerably. Both basal and K+-stimulated release of taurine in the hippocampus in vitro is markedly enhanced under cell-damaging conditions, ischemia, free radicals and metabolic poisons being the most potent. Hypoxia, hypoglycemia, ischemia, free radicals and oxidative stress also increase the initial basal release of taurine in cerebellar granule neurons, while the release is only moderately enhanced in hypoxia and ischemia in cerebral cortical astrocytes. The taurine release induced by ischemia is for the most part Ca2+-independent, a Ca2+-dependent mechanism being discernible only in hippocampal slices from developing mice. Moreover, a considerable portion of hippocampal taurine release in ischemia is mediated by the reversal of Na+-dependent transporters. The enhanced release in adults may comprise a swelling-induced component through Cl- channels, which is not discernible in developing mice. Excitotoxic concentrations of glutamate also potentiate taurine release in mouse hippocampal slices. The ability of ionotropic glutamate receptor agonists to evoke taurine release varies under different cell-damaging conditions, the N-methyl-D-aspartate-evoked release being clearly receptor-mediated in ischemia. Neurotoxic ammonia has been shown to provoke taurine release from different brain preparations, indicating that the ammonia-induced release may modify neuronal excitability in hyperammonic conditions. Taurine released simultane ously with an excess of excitatory amino acids in the hippocampus under ischemic and other neuron-damaging conditions may constitute an important protective mechanism against excitotoxicity, counteracting the harmful effects which lead to neuronal death. The release of taurine may prevent excitation from reaching neurotoxic levels.

Innate defense regulator peptide 1018 protects against perinatal brain injury.

PubMed

Bolouri, Hayde; Sävman, Karin; Wang, Wei; Thomas, Anitha; Maurer, Norbert; Dullaghan, Edie; Fjell, Christopher D; Ek, C Joakim; Hagberg, Henrik; Hancock, Robert E W; Brown, Kelly L; Mallard, Carina

2014-03-01

There is currently no pharmacological treatment that provides protection against brain injury in neonates. It is known that activation of an innate immune response is a key, contributing factor in perinatal brain injury; therefore, the neuroprotective therapeutic potential of innate defense regulator peptides (IDRs) was investigated. The anti-inflammatory effects of 3 IDRs was measured in lipopolysaccharide (LPS)-activated murine microglia. IDRs were then assessed for their ability to confer neuroprotection in vivo when given 3 hours after neonatal brain injury in a clinically relevant model that combines an inflammatory challenge (LPS) with hypoxia-ischemia (HI). To gain insight into peptide-mediated effects on LPS-induced inflammation and neuroprotective mechanisms, global cerebral gene expression patterns were analyzed in pups that were treated with IDR-1018 either 4 hours before LPS or 3 hours after LPS+HI. IDR-1018 reduced inflammatory mediators produced by LPS-stimulated microglia cells in vitro and modulated LPS-induced neuroinflammation in vivo. When administered 3 hours after LPS+HI, IDR-1018 exerted effects on regulatory molecules of apoptotic (for, eg, Fadd and Tnfsf9) and inflammatory (for, eg, interleukin 1, tumor necrosis factor α, chemokines, and cell adhesion molecules) pathways and showed marked protection of both white and gray brain matter. IDR-1018 suppresses proinflammatory mediators and cell injurious mechanisms in the developing brain, and postinsult treatment is efficacious in reducing LPS-induced hypoxic-ischemic brain damage. IDR-1018 is effective in the brain when given systemically, confers neuroprotection of both gray and white matter, and lacks significant effects on the brain under normal conditions. Thus, this peptide provides the features of a promising neuroprotective agent in newborns with brain injury. © 2014 Child Neurology Society/American Neurological Association.

Cisplatin-tethered gold nanospheres for multimodal chemo-radiotherapy of glioblastoma

NASA Astrophysics Data System (ADS)

Setua, Sonali; Ouberai, Myriam; Piccirillo, Sara G.; Watts, Colin; Welland, Mark

2014-08-01

Glioblastoma multiforme (GBM) remains the most aggressive and challenging brain tumour to treat. We report the first successful chemo-radiotherapy on patient derived treatment resistant GBM cells using a cisplatin-tethered gold nanosphere. After intracellular uptake, the nanosphere effects DNA damage which initiates caspase-mediated apoptosis in those cells. In the presence of radiation, both gold and platinum of cisplatin, serve as high atomic number radiosensitizers leading to the emission of ionizing photoelectrons and Auger electrons. This resulted in enhanced synergy between cisplatin and radiotherapy mediated cytotoxicity, and photo/Auger electron mediated radiosensitisation leading to complete ablation of the tumour cells in an in vitro model system. This study demonstrates the potential of designed nanoparticles to target aggressive cancers in the patient derived cell lines providing a platform to move towards treatment strategies.Glioblastoma multiforme (GBM) remains the most aggressive and challenging brain tumour to treat. We report the first successful chemo-radiotherapy on patient derived treatment resistant GBM cells using a cisplatin-tethered gold nanosphere. After intracellular uptake, the nanosphere effects DNA damage which initiates caspase-mediated apoptosis in those cells. In the presence of radiation, both gold and platinum of cisplatin, serve as high atomic number radiosensitizers leading to the emission of ionizing photoelectrons and Auger electrons. This resulted in enhanced synergy between cisplatin and radiotherapy mediated cytotoxicity, and photo/Auger electron mediated radiosensitisation leading to complete ablation of the tumour cells in an in vitro model system. This study demonstrates the potential of designed nanoparticles to target aggressive cancers in the patient derived cell lines providing a platform to move towards treatment strategies. Electronic supplementary information (ESI) available: Additional figures. See DOI: 10.1039/c4nr03693j

N-acetyl-L-cysteine protects against cadmium-induced neuronal apoptosis by inhibiting ROS-dependent activation of Akt/mTOR pathway in mouse brain

PubMed Central

Chen, Sujuan; Ren, Qian; Zhang, Jinfei; Ye, Yangjing; Zhang, Zhen; Xu, Yijiao; Guo, Min; Ji, Haiyan; Xu, Chong; Gu, Chenjian; Gao, Wei; Huang, Shile; Chen, Long

2014-01-01

Aims This study explores the neuroprotective effects and mechanisms of N-acetyl-L-cysteine (NAC) in mice exposed to cadmium (Cd). Methods NAC (150 mg/kg) was intraperitoneally administered to mice exposed to Cd (10-50 mg/L) in drinking water for 6 weeks. The changes of cell damage and death, reactive oxygen species (ROS), antioxidant enzymes, as well as Akt/mammalian target of rapamycin (mTOR) signaling pathway in brain neurons were assessed. To verify the role of mTOR activation in Cd-induced neurotoxicity, mice also received a subacute regimen of intraperitoneally administered Cd (1 mg/kg) with/without rapamycin (7.5 mg/kg) for 11 days. Results Chronic exposure of mice to Cd induced brain damage or neuronal cell death, due to ROS induction. Co-administration of NAC significantly reduced Cd levels in the plasma and brain of the animals. NAC prevented Cd-induced ROS and significantly attenuated Cd-induced brain damage or neuronal cell death. The protective effect of NAC was mediated, at least partially, by elevating the activities of Cu/Zn-superoxide dismutase, catalase and glutathione peroxidase, as well as the level of glutathione in the brain. Furthermore, Cd-induced activation of Akt/mTOR pathway in the brain was also inhibited by NAC. Rapamycin in vitro and in vivo protected against Cd-induced neurotoxicity. Conclusions NAC protects against Cd-induced neuronal apoptosis in mouse brain partially by inhibiting ROS-dependent activation of Akt/mTOR pathway. The findings highlight that NAC may be exploited for prevention and treatment of Cd-induced neurodegenerative diseases. PMID:24299490

Rapid Link of Innate Immune Signal to Adaptive Immunity by Brain–Fat Axis

PubMed Central

Kim, Min Soo; Yan, Jingqi; Wu, Wenhe; Zhang, Guo; Zhang, Yalin; Cai, Dongsheng

2015-01-01

Innate immunity signals induced by pathogen/damage-associated molecular patterns are essential for adaptive immune responses, but it is unclear if the brain plays a role in this process. Here we show that while tumor necrosis factor (TNF) quickly increased in the brain of mice following bacterial infection, intra-brain TNF delivery mimicked bacterial infection to rapidly increase peripheral lymphocytes, especially in the spleen and fat. Multiple mouse models revealed that hypothalamic responses to TNF were accountable for this increase of peripheral lymphocytes in response to bacterial infection. Finally, hypothalamic induction of lipolysis was found to mediate the brain's action in promoting this increase in peripheral adaptive immune response. Thus, the brain-fat axis is important for rapidly linking innate immunity to adaptive immunity. PMID:25848866

Strategies for enhancing catecholamine-mediated neurotransmission

NASA Technical Reports Server (NTRS)

Wurtman, Richard J.

1992-01-01

Major findings made during this project period included the following observations: changes in tyrosine availability do affect brain dopamine release, as assessed by in vivo microdialysis, but that neuronal feedback mechanisms limit the durations of this effect except when dopaminergic neurotransmission has been deficient; the circulating hormone TRH markedly stimulates brain dopamine release, an effect probably mediated by its diketopiperazine metabolite; the amount of circulating L-dopa which enters the brain is both enhanced by carbohydrate consumption and suppressed by protein intake (both nutritional effects can be damaging, inasmuch as a sudden rush of L-dopa into the brain can facilitate dyskinesias, while the inhibition of brain L-dopa uptake by proteins suppresses its conversion to brain dopamine; an appropriate mixture of dietary proteins and carbohydrates can obviate both effects); serotonin release from superfused hypothalamic slices is a linear function of available tryptophan levels throughout the normal dynamic range; the daily rhythm in plasma melatonin levels is abnormal both in the sudden infant death syndrome and in women with secondary amenorrhea; tyrosine can potentiate the anorectic effects of widely-used sympathomimetic drugs; newly-described COMT inhibitors can enhance brain dopamine release in vivo; and a cell culture system, based on Y-79 (retinoblast) cells, exists in which melatonin reliably suppresses dopamine release.

Endocannabinoids and traumatic brain injury.

PubMed

Shohami, Esther; Cohen-Yeshurun, Ayelet; Magid, Lital; Algali, Merav; Mechoulam, Raphael

2011-08-01

Traumatic brain injury (TBI) represents the leading cause of death in young individuals. It triggers the accumulation of harmful mediators, leading to secondary damage, yet protective mechanisms are also set in motion. The endocannabinoid (eCB) system consists of ligands, such as anandamide and 2-arachidonoyl-glycerol (2-AG), receptors (e.g. CB1, CB2), transporters and enzymes, which are responsible for the 'on-demand' synthesis and degradation of these lipid mediators. There is a large body of evidence showing that eCB are markedly increased in response to pathogenic events. This fact, as well as numerous studies on experimental models of brain toxicity, neuroinflammation and trauma supports the notion that the eCB are part of the brain's compensatory or repair mechanisms. These are mediated via CB receptors signalling pathways that are linked to neuronal survival and repair. The levels of 2-AG, the most highly abundant eCB, are significantly elevated after TBI and when administered to TBI mice, 2-AG decreases brain oedema, inflammation and infarct volume and improves clinical recovery. The role of CB1 in mediating these effects was demonstrated using selective antagonists or CB1 knockout mice. CB2 were shown in other models of brain insults to reduce white blood cell rolling and adhesion, to reduce infarct size and to improve motor function. This review is focused on the role the eCB system plays as a self-neuroprotective mechanism and its potential as a basis for the development of novel therapeutic modality for the treatment of CNS pathologies with special emphasis on TBI. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Endocannabinoids and traumatic brain injury

PubMed Central

Shohami, Esther; Cohen-Yeshurun, Ayelet; Magid, Lital; Algali, Merav; Mechoulam, Raphael

2011-01-01

Traumatic brain injury (TBI) represents the leading cause of death in young individuals. It triggers the accumulation of harmful mediators, leading to secondary damage, yet protective mechanisms are also set in motion. The endocannabinoid (eCB) system consists of ligands, such as anandamide and 2-arachidonoyl-glycerol (2-AG), receptors (e.g. CB1, CB2), transporters and enzymes, which are responsible for the ‘on-demand’ synthesis and degradation of these lipid mediators. There is a large body of evidence showing that eCB are markedly increased in response to pathogenic events. This fact, as well as numerous studies on experimental models of brain toxicity, neuroinflammation and trauma supports the notion that the eCB are part of the brain's compensatory or repair mechanisms. These are mediated via CB receptors signalling pathways that are linked to neuronal survival and repair. The levels of 2-AG, the most highly abundant eCB, are significantly elevated after TBI and when administered to TBI mice, 2-AG decreases brain oedema, inflammation and infarct volume and improves clinical recovery. The role of CB1 in mediating these effects was demonstrated using selective antagonists or CB1 knockout mice. CB2 were shown in other models of brain insults to reduce white blood cell rolling and adhesion, to reduce infarct size and to improve motor function. This review is focused on the role the eCB system plays as a self-neuroprotective mechanism and its potential as a basis for the development of novel therapeutic modality for the treatment of CNS pathologies with special emphasis on TBI. LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-7 PMID:21418185

The role of the immune system in central nervous system plasticity after acute injury.

PubMed

Peruzzotti-Jametti, Luca; Donegá, Matteo; Giusto, Elena; Mallucci, Giulia; Marchetti, Bianca; Pluchino, Stefano

2014-12-26

Acute brain injuries cause rapid cell death that activates bidirectional crosstalk between the injured brain and the immune system. In the acute phase, the damaged CNS activates resident and circulating immune cells via the local and systemic release of soluble mediators. This early immune activation is necessary to confine the injured tissue and foster the clearance of cellular debris, thus bringing the inflammatory reaction to a close. In the chronic phase, a sustained immune activation has been described in many CNS disorders, and the degree of this prolonged response has variable effects on spontaneous brain regenerative processes. The challenge for treating acute CNS damage is to understand how to optimally engage and modify these immune responses, thus providing new strategies that will compensate for tissue lost to injury. Herein we have reviewed the available information regarding the role and function of the innate and adaptive immune responses in influencing CNS plasticity during the acute and chronic phases of after injury. We have examined how CNS damage evolves along the activation of main cellular and molecular pathways that are associated with intrinsic repair, neuronal functional plasticity and facilitation of tissue reorganization. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Soluble TNF receptor 1-secreting ex vivo-derived dendritic cells reduce injury after stroke.

PubMed

Works, Melissa G; Koenig, Jenny B; Sapolsky, Robert M

2013-09-01

Inflammation is a major factor in the progression of damage after stroke and in the clinic, current therapies treat the clot, not the resulting damage. We have developed a novel method of protein delivery that exploits the migration ability of leukocytes after ischemic stroke (transient middle cerebral artery occlusion; tMCAO). In our studies, ex vivo-derived dendritic cells (exDCs) migrate to the inflamed rat brain soon after tMCAO onset and the number of cells that remain in the brain after injection is significantly correlated with the amount of local inflammation at the injury site. In addition, exDCs transduced to overexpress soluble tumor necrosis factor (TNF) receptor1 (sTNFR1) produce functional cargo that is secreted and that blocks TNF-α bioavailability in vitro. When delivered at 6 hours post-tMCAO reperfusion, sTNFR1-exDC-treated rats show significantly smaller infarct size and decreased inflammation compared with animals treated with exDCs transduced with GFP lentivirus. These studies indicate that cell-mediated delivery of proteins may be a promising new approach to reduce brain damage after acute neurologic insult.

Use of EPO as an adjuvant in PDT of brain tumors to reduce damage to normal brain

NASA Astrophysics Data System (ADS)

Rendon, Cesar A.; Lilge, Lothar

2004-10-01

In order to reduce damage to surrounding normal brain in the treatment of brain tumors with photodynamic therapy (PDT), we have investigated the use of the cytokine erythropoietin (EPO) to exploit its well-established role as a neuroprotective agent. In vitro experiments demonstrated that EPO does not confer protection from PDT to rat glioma cells. In vivo testing of the possibility of EPO protecting normal brain tissue was carried out. The normal brains of Lewis rats were treated with Photofrin mediated PDT (6.25 mg/Kg B.W. 22 hours pre irradiation) and the outcome of the treatment compared between animals that received EPO (5000 U/Kg B.W. 22 hours pre irradiation) and controls. This comparison was made based on the volume of necrosis, as measured with the viability stain 2,3,5- Triphenyl tetrazoium chloride (TTC), and incidence of apoptosis, as measured with in situ end labeling assay (ISEL). Western blotting showed that EPO reaches the normal brain and activates the anti-apoptotic protein PKB/AKT1 within the brain cortex. The comparison based on volume of necrosis showed no statistical significance between the two groups. No clear difference was observed in the ISEL staining between the groups. A possible lack of responsivity in the assays that give rise to these results is discussed and future corrections are described.

Mechanisms of Endogenous Neuroprotective Effects of Astrocytes in Brain Injury

PubMed Central

2018-01-01

Astrocytes, once believed to serve only as “glue” for the structural support of neurons, have been demonstrated to serve critical functions for the maintenance and protection of neurons, especially under conditions of acute or chronic injury. There are at least seven distinct mechanisms by which astrocytes protect neurons from damage; these are (1) protection against glutamate toxicity, (2) protection against redox stress, (3) mediation of mitochondrial repair mechanisms, (4) protection against glucose-induced metabolic stress, (5) protection against iron toxicity, (6) modulation of the immune response in the brain, and (7) maintenance of tissue homeostasis in the presence of DNA damage. Astrocytes support these critical functions through specialized responses to stress or toxic conditions. The detoxifying activities of astrocytes are essential for maintenance of the microenvironment surrounding neurons and in whole tissue homeostasis. Improved understanding of the mechanisms by which astrocytes protect the brain could lead to the development of novel targets for the development of neuroprotective strategies.

High-mobility group box 1 from reactive astrocytes enhances the accumulation of endothelial progenitor cells in damaged white matter.

PubMed

Hayakawa, Kazuhide; Miyamoto, Nobukazu; Seo, Ji Hae; Pham, Loc-Duyen D; Kim, Kyu-Won; Lo, Eng H; Arai, Ken

2013-04-01

High-mobility group box 1 (HMGB1) was initially described as a damage-associated-molecular-pattern (DAMP) mediator that worsens acute brain injury after stroke. But, recent findings suggest that HMGB1 can play a surprisingly beneficial role during stroke recovery by promoting endothelial progenitor cell (EPC) function and vascular remodeling in cortical gray matter. Here, we ask whether HMGB1 may also influence EPC responses in white matter injury. The standard lysophosphatidylcholine (LPC) injection model was used to induce focal demyelination in the corpus callosum of mice. Immunostaining showed that within the focal white matter lesions, HMGB1 was up-regulated in GFAP-positive reactive astrocytes, along with the accumulation of Flk1/CD34-double-positive EPCs that expressed pro-recovery mediators such as brain-derived neurotrophic factor and basic fibroblast growth factor. Astrocyte-EPC signaling required the HMGB1 receptor RAGE as treatment with RAGE-neutralizing antibody significantly decreased EPC accumulation. Moreover, suppression of HMGB1 with siRNA in vivo significantly decreased EPC numbers in damaged white matter as well as proliferated endothelial cell numbers. Finally, in vitro cell culture systems confirmed that HMGB1 directly affected EPC function such as migration and tube formation. Taken together, our findings suggest that HMGB1 from reactive astrocytes may attract EPCs to promote recovery after white matter injury. © 2012 International Society for Neurochemistry.

Prophylactic neuroprotective efficiency of co-administration of Ginkgo biloba and Trifolium pretense against sodium arsenite-induced neurotoxicity and dementia in different regions of brain and spinal cord of rats.

PubMed

Abdou, Heba M; Yousef, Mokhtar I; El Mekkawy, Desouki A; Al-Shami, Ahmed S

2016-08-01

The present study was carried out to evaluate the potential protective role of co-administration of Ginkgo biloba, Trifolium pretenseagainst sodium arsenite-induced neurotoxicity in different parts of brain (Cerebral cortex, Hippocampus, striatum and Hind brain) and in the spinal cord of rats. Sodium arsenite caused impairment in the acquisition and learning in all the behavioral tasks and caused significant increase in tumor necrosis factor-α,thiobarbituric acid-reactive substances andlipid profile, while caused significant decrease in glutathione, total thiol content, total antioxidant capacity, acetylcholinesterase, monoamine oxidase and ATPases activities. These results were confirmed by histopathological, fluorescence and scanning electron microscopy examination of different regions of brain. From these results sodium arsenite-induced neurodegenerative disorder in different regions of brain and spinal cord and this could be mediated through modifying the intracellular brain ions homeostasis, cholinergic dysfunction and oxidative damage. The presence of Ginkgo biloba and/orTrifolium pretense with sodium arsenite minimized its neurological damages. It was pronounced that using Ginkgo biloba and Trifolium pretense in combination was more effective as protective agents compared to use eachone of them alone. Copyright © 2016 Elsevier Ltd. All rights reserved.

Biological Signatures of Brain Damage Associated with High Serum Ferritin Levels in Patients with Acute Ischemic Stroke and Thrombolytic Treatment

PubMed Central

Millán, Mónica; Sobrino, Tomás; Arenillas, Juan Francisco; Rodríguez-Yáñez, Manuel; García, María; Nombela, Florentino; Castellanos, Mar; de la Ossa, Natalia Pérez; Cuadras, Patricia; Serena, Joaquín; Castillo, José; Dávalos, Antoni

2008-01-01

Background and purpose: Increased body iron stores have been related to greater oxidative stress and brain injury in clinical and experimental cerebral ischemia and reperfusion. We aimed to investigate the biological signatures of excitotoxicity, inflammation and blood brain barrier disruption potentially associated with high serum ferritin levels-related damage in acute stroke patients treated with i.v. t-PA. Methods: Serum levels of ferritin (as index of increased cellular iron stores), glutamate, interleukin-6, matrix metalloproteinase-9 and cellular fibronectin were determined in 134 patients treated with i.v. t-PA within 3 hours from stroke onset in blood samples obtained before t-PA treatment, at 24 and 72 hours. Results: Serum ferritin levels before t-PA infusion correlated to glutamate (r = 0.59, p < 0.001) and interleukin-6 (r = 0.55, p <0.001) levels at baseline, and with glutamate (r = 0.57,p <0.001), interleukin-6 (r = 0.49,p <0.001), metalloproteinase-9 (r = 0.23, p = 0.007) and cellular fibronectin (r = 0.27, p = 0.002) levels measured at 24 hours and glutamate (r = 0.415, p < 0.001), interleukin-6 (r = 0.359, p < 0.001) and metalloproteinase-9 (r = 0.261, p = 0.004) at 72 hours. The association between ferritin and glutamate levels remained after adjustment for confounding factors in generalized linear models. Conclusions: Brain damage associated with increased iron stores in acute ischemic stroke patients treated with iv. tPA may be mediated by mechanisms linked to excitotoxic damage. The role of inflammation, blood brain barrier disruption and oxidative stress in this condition needs further research. PMID:19096131

Targeting RNS/caveolin-1/MMP signaling cascades to protect against cerebral ischemia-reperfusion injuries: potential application for drug discovery

PubMed Central

Chen, Han-sen; Chen, Xi; Li, Wen-ting; Shen, Jian-gang

2018-01-01

Reactive nitrogen species (RNS) play important roles in mediating cerebral ischemia-reperfusion injury. RNS activate multiple signaling pathways and participate in different cellular events in cerebral ischemia-reperfusion injury. Recent studies have indicated that caveolin-1 and matrix metalloproteinase (MMP) are important signaling molecules in the pathological process of ischemic brain injury. During cerebral ischemia-reperfusion, the production of nitric oxide (NO) and peroxynitrite (ONOO−), two representative RNS, down-regulates the expression of caveolin-1 (Cav-1) and, in turn, further activates nitric oxide synthase (NOS) to promote RNS generation. The increased RNS further induce MMP activation and mediate disruption of the blood-brain barrier (BBB), aggravating the brain damage in cerebral ischemia-reperfusion injury. Therefore, the feedback interaction among RNS/Cav-1/MMPs provides an amplified mechanism for aggravating ischemic brain damage during cerebral ischemia-reperfusion injury. Targeting the RNS/Cav-1/MMP pathway could be a promising therapeutic strategy for protecting against cerebral ischemia-reperfusion injury. In this mini-review article, we highlight the important role of the RNS/Cav-1/MMP signaling cascades in ischemic stroke injury and review the current progress of studies seeking therapeutic compounds targeting the RNS/Cav-1/MMP signaling cascades to attenuate cerebral ischemia-reperfusion injury. Several representative natural compounds, including calycosin-7-O-β-D-glucoside, baicalin, Momordica charantia polysaccharide (MCP), chlorogenic acid, lutein and lycopene, have shown potential for targeting the RNS/Cav-1/MMP signaling pathway to protect the brain in ischemic stroke. Therefore, the RNS/Cav-1/MMP pathway is an important therapeutic target in ischemic stroke treatment. PMID:29595191

Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature.

PubMed

Kleinschnitz, Christoph; Kraft, Peter; Dreykluft, Angela; Hagedorn, Ina; Göbel, Kerstin; Schuhmann, Michael K; Langhauser, Friederike; Helluy, Xavier; Schwarz, Tobias; Bittner, Stefan; Mayer, Christian T; Brede, Marc; Varallyay, Csanad; Pham, Mirko; Bendszus, Martin; Jakob, Peter; Magnus, Tim; Meuth, Sven G; Iwakura, Yoichiro; Zernecke, Alma; Sparwasser, Tim; Nieswandt, Bernhard; Stoll, Guido; Wiendl, Heinz

2013-01-24

We have recently identified T cells as important mediators of ischemic brain damage, but the contribution of the different T-cell subsets is unclear. Forkhead box P3 (FoxP3)-positive regulatory T cells (Tregs) are generally regarded as prototypic anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. In the present study, we examined the role of Tregs after experimental brain ischemia/reperfusion injury. Selective depletion of Tregs in the DEREG mouse model dramatically reduced infarct size and improved neurologic function 24 hours after stroke and this protective effect was preserved at later stages of infarct development. The specificity of this detrimental Treg effect was confirmed by adoptive transfer experiments in wild-type mice and in Rag1(-/-) mice lacking lymphocytes. Mechanistically, Tregs induced microvascular dysfunction in vivo by increased interaction with the ischemic brain endothelium via the LFA-1/ICAM-1 pathway and platelets and these findings were confirmed in vitro. Ablation of Tregs reduced microvascular thrombus formation and improved cerebral reperfusion on stroke, as revealed by ultra-high-field magnetic resonance imaging at 17.6 Tesla. In contrast, established immunoregulatory characteristics of Tregs had no functional relevance. We define herein a novel and unexpected role of Tregs in a primary nonimmunologic disease state.

The Meninges: New Therapeutic Targets For Multiple Sclerosis

PubMed Central

Russi, Abigail E.; Brown, Melissa A.

2014-01-01

The CNS is largely comprised of non-regenerating cells, including neurons and myelin-producing oligodendrocytes, which are particularly vulnerable to immune cell mediated damage. To protect the CNS, mechanisms exist that normally restrict the transit of peripheral immune cells into the brain and spinal cord, conferring an “immune specialized” status. Thus, there has been a long-standing debate as to how these restrictions are overcome in several inflammatory diseases of the CNS, including multiple sclerosis (MS). In this review, we highlight the role of the meninges, tissues that surround and protect the CNS and enclose the cerebral spinal fluid, in promoting chronic inflammation that leads to neuronal damage. Although the meninges have traditionally been considered structures that provide physical protection for the brain and spinal cord, new data has established these tissues as sites of active immunity. It has been hypothesized that the meninges are important players in normal immunosurveillance of the CNS but also serve as initial sites of anti-myelin immune responses. The resulting robust meningeal inflammation elicits loss of localized blood barrier integrity and facilitates a large-scale influx of immune cells into the CNS parenchyma. We propose that targeting of the cells and molecules mediating these inflammatory responses within the meninges offers promising therapies for MS that are free from the constraints imposed by the blood brain barrier. Importantly, such therapies may avoid the systemic immunosuppression often associated with the existing treatments. PMID:25241937

Proliferation zones in the axolotl brain and regeneration of the telencephalon

PubMed Central

2013-01-01

Background Although the brains of lower vertebrates are known to exhibit somewhat limited regeneration after incisional or stab wounds, the Urodele brain exhibits extensive regeneration after massive tissue removal. Discovering whether and how neural progenitor cells that reside in the ventricular zones of Urodeles proliferate to mediate tissue repair in response to injury may produce novel leads for regenerative strategies. Here we show that endogenous neural progenitor cells resident to the ventricular zone of Urodeles spontaneously proliferate, producing progeny that migrate throughout the telencephalon before terminally differentiating into neurons. These progenitor cells appear to be responsible for telencephalon regeneration after tissue removal and their activity may be up-regulated by injury through an olfactory cue. Results There is extensive proliferation of endogenous neural progenitor cells throughout the ventricular zone of the adult axolotl brain. The highest levels are observed in the telencephalon, especially the dorsolateral aspect, and cerebellum. Lower levels are observed in the mesencephalon and rhombencephalon. New cells produced in the ventricular zone migrate laterally, dorsally and ventrally into the surrounding neuronal layer. After migrating from the ventricular zone, the new cells primarily express markers of neuronal differentiative fates. Large-scale telencephalic tissue removal stimulates progenitor cell proliferation in the ventricular zone of the damaged region, followed by proliferation in the tissue that surrounds the healing edges of the wound until the telencephalon has completed regeneration. The proliferative stimulus appears to reside in the olfactory system, because telencephalic regeneration does not occur in the brains of olfactory bulbectomized animals in which the damaged neural tissue simply heals over. Conclusion There is a continual generation of neuronal cells from neural progenitor cells located within the ventricular zone of the axolotl brain. Variable rates of proliferation were detected across brain regions. These neural progenitor cells appear to mediate telencephalic tissue regeneration through an injury-induced olfactory cue. Identification of this cue is our future goal. PMID:23327114

Proliferation zones in the axolotl brain and regeneration of the telencephalon.

PubMed

Maden, Malcolm; Manwell, Laurie A; Ormerod, Brandi K

2013-01-17

Although the brains of lower vertebrates are known to exhibit somewhat limited regeneration after incisional or stab wounds, the Urodele brain exhibits extensive regeneration after massive tissue removal. Discovering whether and how neural progenitor cells that reside in the ventricular zones of Urodeles proliferate to mediate tissue repair in response to injury may produce novel leads for regenerative strategies. Here we show that endogenous neural progenitor cells resident to the ventricular zone of Urodeles spontaneously proliferate, producing progeny that migrate throughout the telencephalon before terminally differentiating into neurons. These progenitor cells appear to be responsible for telencephalon regeneration after tissue removal and their activity may be up-regulated by injury through an olfactory cue. There is extensive proliferation of endogenous neural progenitor cells throughout the ventricular zone of the adult axolotl brain. The highest levels are observed in the telencephalon, especially the dorsolateral aspect, and cerebellum. Lower levels are observed in the mesencephalon and rhombencephalon. New cells produced in the ventricular zone migrate laterally, dorsally and ventrally into the surrounding neuronal layer. After migrating from the ventricular zone, the new cells primarily express markers of neuronal differentiative fates. Large-scale telencephalic tissue removal stimulates progenitor cell proliferation in the ventricular zone of the damaged region, followed by proliferation in the tissue that surrounds the healing edges of the wound until the telencephalon has completed regeneration. The proliferative stimulus appears to reside in the olfactory system, because telencephalic regeneration does not occur in the brains of olfactory bulbectomized animals in which the damaged neural tissue simply heals over. There is a continual generation of neuronal cells from neural progenitor cells located within the ventricular zone of the axolotl brain. Variable rates of proliferation were detected across brain regions. These neural progenitor cells appear to mediate telencephalic tissue regeneration through an injury-induced olfactory cue. Identification of this cue is our future goal.

Anthocyanins abrogate glutamate-induced AMPK activation, oxidative stress, neuroinflammation, and neurodegeneration in postnatal rat brain.

PubMed

Shah, Shahid Ali; Amin, Faiz Ul; Khan, Mehtab; Abid, Muhammad Noman; Rehman, Shafiq Ur; Kim, Tae Hyun; Kim, Min Woo; Kim, Myeong Ok

2016-11-08

Glutamate-induced excitotoxicity, oxidative damage, and neuroinflammation are believed to play an important role in the development of a number of CNS disorders. We recently reported that a high dose of glutamate could induce AMPK-mediated neurodegeneration in the postnatal day 7 (PND7) rat brain. Yet, the mechanism of glutamate-induced oxidative stress and neuroinflammation in the postnatal brain is not well understood. Here, we report for the first time the mechanism of glutamate-induced oxidative damage, neuroinflammation, and neuroprotection by polyphenolic anthocyanins in PND7. PND7 rat brains, SH-SY5Y, and BV2 cells treated either alone with glutamate or in combination with anthocyanins and compound C were examined with Western blot and immunofluorescence techniques. Additionally, reactive oxygen species (ROS) assay and other ELISA kit assays were employed to know the therapeutic efficacy of anthocyanins against glutamate. A single injection of glutamate to developing rats significantly increased brain glutamate levels, activated and phosphorylated AMPK induction, and inhibited nuclear factor-E2-related factor 2 (Nrf2) after 2, 3, and 4 h in a time-dependent manner. In contrast, anthocyanin co-treatment significantly reduced glutamate-induced AMPK induction, ROS production, neuroinflammation, and neurodegeneration in the developing rat brain. Most importantly, anthocyanins increased glutathione (GSH and GSSG) levels and stimulated the endogenous antioxidant system, including Nrf2 and heme oxygenase-1 (HO-1), against glutamate-induced oxidative stress. Interestingly, blocking AMPK with compound C in young rats abolished glutamate-induced neurotoxicity. Similarly, all these experiments were replicated in SH-SY5Y cells by silencing AMPK with siRNA, which suggests that AMPK is the key mediator in glutamate-induced neurotoxicity. Here, we report for the first time that anthocyanins can potentially decrease glutamate-induced neurotoxicity in young rats. Our work demonstrates that glutamate is toxic to the developing rat brain and that anthocyanins can minimize the severity of glutamate-induced neurotoxicity in an AMPK-dependent manner.

Neuroprotective effect of ginger in the brain of streptozotocin-induced diabetic rats.

PubMed

El-Akabawy, Gehan; El-Kholy, Wael

2014-05-01

Diabetes mellitus results in neuronal damage caused by increased intracellular glucose leading to oxidative stress. Recent evidence revealed the potential of ginger for reducing diabetes-induced oxidative stress markers. The aim of this study is to investigate, for the first time, whether the antioxidant properties of ginger has beneficial effects on the structural brain damage associated with diabetes. We investigated the observable neurodegenerative changes in the frontal cortex, dentate gyrus, and cerebellum after 4, 6, and 8 weeks of streptozotocin (STZ)-induced diabetes in rats and the effect(s) of ginger (500 mg/kg/day). Sections of frontal cortex, dentate gyrus, and cerebellum were stained with hematoxylin and eosin and examined using light microscopy. In addition, quantitative immunohistochemical assessments of the expression of inducible NO synthase (iNOS), tumor necrosis factor (TNF)-α, caspase-3, glial fibrillary acidic protein (GFAP), acetylcholinesterase (AChE), and Ki67 were performed. Our results revealed a protective role of ginger on the diabetic brain via reducing oxidative stress, apoptosis, and inflammation. In addition, this study revealed that the beneficial effect of ginger was also mediated by modulating the astroglial response to the injury, reducing AChE expression, and improving neurogenesis. These results represent a new insight into the beneficial effects of ginger on the structural alterations of diabetic brain and suggest that ginger might be a potential therapeutic strategy for the treatment of diabetic-induced damage in brain. Copyright © 2014 Elsevier GmbH. All rights reserved.

Impact of brain death on ischemia/reperfusion injury in liver transplantation.

PubMed

Dziodzio, Tomasz; Biebl, Matthias; Pratschke, Johann

2014-04-01

In liver transplantation, the ischemia/reperfusion injury (IRI) is influenced by factors related to graft quality, organ procurement and the transplant procedure itself. However, in brain-dead donors, the process of death itself also thoroughly affects organ damage through breakdown of the autonomous nervous system and subsequent massive cytokine release. This review highlights the actual knowledge on these proinflammatory effects of brain death on IRI in liver transplantation. Brain death affects IRI either through hemodynamical or molecular effects with proinflammatory activation. Immunological effects are mainly mediated through Kupffer cell activation, leading to TNF-α and TLR4 amplification. Proinflammatory cytokines such as interleukin (IL)-6, IL-10, TNF-β and MIP-1α are released, together with activation of the innate immune system via natural killer cells and natural killer T cells, which promote organ damage and activation of fibrosis. Preprocurement treatment regimens attempt to hamper inflammatory response by the application of methylprednisolone or thymoglobulin to the donor. Selective P-selectin antagonism resulted in improved function in marginal liver grafts. Inhaled nitric oxide was found to reduce apoptosis in liver grafts. Other medications like the immunosuppressant tacrolimus produced conflicting results regarding organ protection. Furthermore, improved organ storage after procurement - such as machine perfusion - can diminish effects of IRI in a clinical setting. Brain death plays a fundamental role in the regulation of molecular markers triggering inflammation and IRI-related tissue damage in liver transplants. Although several treatment options have reached clinical application, to date, the effects of brain death during donor conditioning and organ procurement remain relevant for organ function and survival.

Acidosis mediates recurrent hypoglycemia-induced increase in ischemic brain injury in treated diabetic rats.

PubMed

Rehni, Ashish K; Shukla, Vibha; Perez-Pinzon, Miguel A; Dave, Kunjan R

2018-03-15

Cerebral ischemia is a serious possible manifestation of diabetic vascular disease. Recurrent hypoglycemia (RH) enhances ischemic brain injury in insulin-treated diabetic (ITD) rats. In the present study, we determined the role of ischemic acidosis in enhanced ischemic brain damage in RH-exposed ITD rats. Diabetic rats were treated with insulin and mild/moderate RH was induced for 5 days. Three sets of experiments were performed. The first set evaluated the effects of RH exposure on global cerebral ischemia-induced acidosis in ITD rats. The second set evaluated the effect of an alkalizing agent (Tris-(hydroxymethyl)-aminomethane: THAM) on ischemic acidosis-induced brain injury in RH-exposed ITD rats. The third experiment evaluated the effect of the glucose transporter (GLUT) inhibitor on ischemic acidosis-induced brain injury in RH-exposed ITD rats. Hippocampal pH and lactate were measured during ischemia and early reperfusion for all three experiments. Neuronal survival in Cornu Ammonis 1 (CA1) hippocampus served as a measure of ischemic brain injury. Prior RH exposure increases lactate concentration and decreases pH during ischemia and early reperfusion when compared to controls. THAM and GLUT inhibitor treatments attenuated RH-induced increase in ischemic acidosis. GLUT inhibitor treatment reduced the RH-induced increase in lactate levels. Both THAM and GLUT inhibitor treatments significantly decreased ischemic damage in RH-exposed ITD rats. Ischemia causes increased acidosis in RH-exposed ITD rats via a GLUT-sensitive mechanism. Exploring downstream pathways may help understand mechanisms by which prior exposure to RH increases cerebral ischemic damage. Copyright © 2018 Elsevier Ltd. All rights reserved.

Therapeutic effect of magnesium sulphate on carbon monoxide toxicity-mediated brain lipid peroxidation.

PubMed

Yavuz, Y; Mollaoglu, H; Yürümez, Y; Ucok, K; Duran, L; Tünay, K; Akgün, L

2013-02-01

Carbon monoxide (CO) toxicity primarily results from cellular hypoxia caused by impedance of oxygen delivery. Studies show that CO may cause brain lipid peroxidation and leukocyte-mediated inflammatory changes in the brain. The aim of this study was to investigate whether magnesium sulphate could prevent or diminish brain lipid peroxidation caused by carbon monoxide toxicity in rats. Fourty rats were divided into five groups of 8 rats each. Group l was not received any agent during the experiment. Group 2 was inhaled CO gas followed by intraperitoneally normal saline 30 minutes (min) later. Group 3 was inhaled CO gas followed by 100 mg/kg magnesium sulphate intraperitoneally 30 min later. Group 2 and Group 3 rats was undergone laparotomy and craniotomy while still under anesthesia at 6 hour, and tissue sample was obtained from the cerebrum. Group 4 was inhaled CO gas followed by intraperitoneally normal saline 30 min later. Group 5 was inhaled CO gas followed by 100 mg/kg magnesium sulphate intraperitoneally 30 min later. Group 4 and Group 5 rats was undergone laparotomy and craniotomy while still under anesthesia at 24 hour, and tissue sample was obtained from the cerebrum. Nitric oxide levels were no significantly different between all groups. Malonyldialdehyde levels increased in intoxication group (group 2) and decreased in treatment group (group 3). Activities of superoxide dismutase decreased in intoxication group (group 2) and increased in treatment group (group 3). Activities of catalase increased in intoxication group (group 2) and decreased in treatment group (group 3). Activities of glutathione peroxidase (GSH-Px) decreased in intoxication group (group 4) and increased in treatment group (group 5). CO poisoning caused significant damage, detected within the first 6 hours. Due to antioxidant enzymes, especially GSH-Px activity reaching the top level within 24th hours, significant oxidative damage was not observed. The protective effect against oxidative damage of magnesium sulfate has been identified within the first 6 hours.

Gender differences in alcohol-induced neurotoxicity and brain damage.

PubMed

Alfonso-Loeches, Silvia; Pascual, María; Guerri, Consuelo

2013-09-06

Considerable evidence has demonstrated that women are more vulnerable than men to the toxic effects of alcohol, although the results as to whether gender differences exist in ethanol-induced brain damage are contradictory. We have reported that ethanol, by activating the neuroimmune system and Toll-like receptors 4 (TLR4), can cause neuroinflammation and brain injury. However, whether there are gender differences in alcohol-induced neuroinflammation and brain injury are currently controversial. Using the brains of TLR4(+/+) and TLR4(-/-) (TLR4-KO) mice, we report that chronic ethanol treatment induces inflammatory mediators (iNOS and COX-2), cytokines (IL-1β, TNF-α), gliosis processes, caspase-3 activation and neuronal loss in the cerebral cortex of both female and male mice. Conversely, the levels of these parameters tend to be higher in female than in male mice. Using an in vivo imaging technique, our results further evidence that ethanol treatment triggers higher GFAP levels and lower MAP-2 levels in female than in male mice, suggesting a greater effect of ethanol-induced astrogliosis and less MAP-2(+) neurons in female than in male mice. Our results further confirm the pivotal role of TLR4 in alcohol-induced neuroinflammation and brain damage since the elimination of TLR4 protects the brain of males and females against the deleterious effects of ethanol. In short, the present findings demonstrate that, during the same period of ethanol treatment, females are more vulnerable than males to the neurotoxic/neuroinflammatory effects of ethanol, thus supporting the view that women are more susceptible than men to the medical consequences of alcohol abuse. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

MACF1 regulates the migration of pyramidal neurons via microtubule dynamics and GSK-3 signaling

PubMed Central

Ka, Minhan; Jung, Eui-Man; Mueller, Ulrich; Kim, Woo-Yang

2014-01-01

Neuronal migration and subsequent differentiation play critical roles for establishing functional neural circuitry in the developing brain. However, the molecular mechanisms that regulate these processes are poorly understood. Here, we show that microtubule actin crosslinking factor 1 (MACF1) determines neuronal positioning by regulating microtubule dynamics and mediating GSK-3 signaling during brain development. First, using MACF1 floxed allele mice and in utero gene manipulation, we find that MACF1 deletion suppresses migration of cortical pyramidal neurons and results in aberrant neuronal positioning in the developing brain. The cell autonomous deficit in migration is associated with abnormal dynamics of leading processes and centrosomes. Furthermore, microtubule stability is severely damaged in neurons lacking MACF1, resulting in abnormal microtubule dynamics. Finally, MACF1 interacts with and mediates GSK-3 signaling in developing neurons. Our findings establish a cellular mechanism underlying neuronal migration and provide insights into the regulation of cytoskeleton dynamics in developing neurons. PMID:25224226

MACF1 regulates the migration of pyramidal neurons via microtubule dynamics and GSK-3 signaling.

PubMed

Ka, Minhan; Jung, Eui-Man; Mueller, Ulrich; Kim, Woo-Yang

2014-11-01

Neuronal migration and subsequent differentiation play critical roles for establishing functional neural circuitry in the developing brain. However, the molecular mechanisms that regulate these processes are poorly understood. Here, we show that microtubule actin crosslinking factor 1 (MACF1) determines neuronal positioning by regulating microtubule dynamics and mediating GSK-3 signaling during brain development. First, using MACF1 floxed allele mice and in utero gene manipulation, we find that MACF1 deletion suppresses migration of cortical pyramidal neurons and results in aberrant neuronal positioning in the developing brain. The cell autonomous deficit in migration is associated with abnormal dynamics of leading processes and centrosomes. Furthermore, microtubule stability is severely damaged in neurons lacking MACF1, resulting in abnormal microtubule dynamics. Finally, MACF1 interacts with and mediates GSK-3 signaling in developing neurons. Our findings establish a cellular mechanism underlying neuronal migration and provide insights into the regulation of cytoskeleton dynamics in developing neurons. Copyright © 2014 Elsevier Inc. All rights reserved.

Animal Models of Brain Maldevelopment Induced by Cycad Plant Genotoxins

PubMed Central

Kisby, Glen E.; Moore, Holly; Spencer, Peter S.

2014-01-01

Cycads are long-lived tropical and subtropical plants that contain azoxyglycosides (e.g., cycasin, macrozamin) and neurotoxic amino acids (notably β-N-methylamino-L-alanine L-BMAA), toxins that have been implicated in the etiology of a disappearing neurodegenerative disease, amyotrophic lateral sclerosis and parkinsonism-dementia complex that has been present in high incidence among three genetically distinct populations in the western Pacific. The neuropathology of amyotrophic lateral sclerosis/parkinsonism-dementia complex includes features suggestive of brain maldevelopment, an experimentally proven property of cycasin attributable to the genotoxic action of its aglycone methylazoxymethanol (MAM). This property of MAM has been exploited by neurobiologists as a tool to study perturbations of brain development. Depending on the neurodevelopmental stage, MAM can induce features in laboratory animals that model certain characteristics of epilepsy, schizophrenia, or ataxia. Studies in DNA repair-deficient mice show that MAM perturbs brain development through a DNA damage-mediated mechanism. The brain DNA lesions produced by systemic MAM appear to modulate the expression of genes that regulate neurodevelopment and contribute to neurodegeneration. Epigenetic changes (histone lysine methylation) have also been detected in the underdeveloped brain after MAM administration. The DNA damage and epigenetic changes produced by MAM and, perhaps by chemically related substances (e.g., nitrosamines, nitrosoureas, hydrazines), might be an important mechanism by which early-life exposure to genotoxicants can induce long-term brain dysfunction. PMID:24339036

Neuroprotection and enhanced neurogenesis by extract from the tropical plant Knema laurina after inflammatory damage in living brain tissue.

PubMed

Häke, Ines; Schönenberger, Silvia; Neumann, Jens; Franke, Katrin; Paulsen-Merker, Katrin; Reymann, Klaus; Ismail, Ghazally; Bin Din, Laily; Said, Ikram M; Latiff, A; Wessjohann, Ludger; Zipp, Frauke; Ullrich, Oliver

2009-01-03

Inflammatory reactions in the CNS, resulting from a loss of control and involving a network of non-neuronal and neuronal cells, are major contributors to the onset and progress of several major neurodegenerative diseases. Therapeutic strategies should therefore keep or restore the well-controlled and finely-tuned balance of immune reactions, and protect neurons from inflammatory damage. In our study, we selected plants of the Malaysian rain forest by an ethnobotanic survey, and investigated them in cell-based-assay-systems and in living brain tissue cultures in order to identify anti-inflammatory and neuroprotective effects. We found that alcoholic extracts from the tropical plant Knema laurina (Black wild nutmeg) exhibited highly anti-inflammatory and neuroprotective effects in cell culture experiments, reduced NO- and IL-6-release from activated microglia cells dose-dependently, and protected living brain tissue from microglia-mediated inflammatory damage at a concentration of 30 microg/ml. On the intracellular level, the extract inhibited ERK-1/2-phosphorylation, IkB-phosphorylation and subsequently NF-kB-translocation in microglia cells. K. laurina belongs to the family of Myristicaceae, which have been used for centuries for treatment of digestive and inflammatory diseases and is also a major food plant of the Giant Hornbill. Moreover, extract from K. laurina promotes also neurogenesis in living brain tissue after oxygen-glucose deprivation. In conclusion, extract from K. laurina not only controls and limits inflammatory reaction after primary neuronal damage, it promotes moreover neurogenesis if given hours until days after stroke-like injury.

Loss of the endothelial glycocalyx is associated with increased E-selectin mediated adhesion of lung tumour cells to the brain microvascular endothelium.

PubMed

Rai, Srijana; Nejadhamzeeigilani, Zaynab; Gutowski, Nicholas J; Whatmore, Jacqueline L

2015-09-25

Arrest of metastasising lung cancer cells to the brain microvasculature maybe mediated by interactions between ligands on circulating tumour cells and endothelial E-selectin adhesion molecules; a process likely to be regulated by the endothelial glycocalyx. Using human cerebral microvascular endothelial cells and non-small cell lung cancer (NSCLC) cell lines, we describe how factors secreted by NSCLC cells i.e. cystatin C, cathepsin L, insulin-like growth factor-binding protein 7 (IGFBP7), vascular endothelial growth factor (VEGF) and tumour necrosis factor-alpha (TNF-α), damage the glycocalyx and enhance initial contacts between lung tumour and cerebral endothelial cells. Endothelial cells were treated with tumour secreted-proteins or lung tumour conditioned medium (CM). Surface levels of E-selectin were quantified by ELISA. Adhesion of A549 and SK-MES-1 cells was examined under flow conditions (1 dyne/cm(2)). Alterations in the endothelial glycocalyx were quantified by binding of fluorescein isothiocyanate-linked wheat germ agglutinin (WGA-FITC). A549 and SK-MES-1 CM and secreted-proteins significantly enhanced endothelial surface E-selectin levels after 30 min and 4 h and tumour cell adhesion after 30 min, 4 and 24 h. Both coincided with significant glycocalyx degradation; A549 and SK-MES-1 CM removing 55 ± 12 % and 58 ± 18.7 % of WGA-FITC binding, respectively. Inhibition of E-selectin binding by monoclonal anti-E-selectin antibody completely attenuated tumour cell adhesion. These data suggest that metastasising lung cancer cells facilitate their own adhesion to the brain endothelium by secreting factors that damage the endothelial glycocalyx, resulting in exposure of the previously shielded adhesion molecules and engagement of the E-selectin-mediated adhesion axis.

Copper mediated neurological disorder: visions into amyotrophic lateral sclerosis, Alzheimer and Menkes disease.

PubMed

Ahuja, Anami; Dev, Kapil; Tanwar, Ranjeet S; Selwal, Krishan K; Tyagi, Pankaj K

2015-01-01

Copper (Cu) is a vital redox dynamic metal that is possibly poisonous in superfluous. Metals can traditionally or intricately cause propagation in reactive oxygen species (ROS) accretion in cells and this may effect in programmed cell death. Accumulation of Cu causes necrosis that looks to be facilitated by DNA damage, followed by activation of P53. Cu dyshomeostasis has also been concerned in neurodegenerative disorders such as Alzheimer, Amyotrophic lateral sclerosis (ALS) or Menkes disease and is directly related to neurodegenerative syndrome that usually produces senile dementia. These mortal syndromes are closely related with an immense damage of neurons and synaptic failure in the brain. This review focuses on copper mediated neurological disorders with insights into amyotrophic lateral sclerosis, Alzheimer and Menkes disease. Copyright © 2014 Elsevier GmbH. All rights reserved.

Expression of Shiga toxin 2e glycosphingolipid receptors of primary porcine brain endothelial cells and toxin-mediated breakdown of the blood-brain barrier.

PubMed

Meisen, Iris; Rosenbrück, Regina; Galla, Hans-Joachim; Hüwel, Sabine; Kouzel, Ivan U; Mormann, Michael; Karch, Helge; Müthing, Johannes

2013-06-01

Shiga toxin (Stx) 2e, released by certain Stx-producing Escherichia coli, is presently the best characterized virulence factor responsible for pig edema disease, which is characterized by hemorrhagic lesions, neurological disorders and often fatal outcomes. Although Stx2e-mediated brain vascular injury is the key event in development of neurologic signs, the glycosphingolipid (GSL) receptors of Stx2e and toxin-mediated impairment of pig brain endothelial cells have not been investigated so far. Here, we report on the detailed structural characterization of Stx2e receptors globotriaosylceramide (Gb3Cer) and globotetraosylceramide (Gb4Cer), which make up the major neutral GSLs in primary porcine brain capillary endothelial cells (PBCECs). Various Gb3Cer and Gb4Cer lipoforms harboring sphingenine (d18:1) or sphinganine (d18:0) and mostly a long-chain fatty acid (C20-C24) were detected. A notable batch-to-batch heterogeneity of primary endothelial cells was observed regarding the extent of ceramide hydroxylation of Gb3Cer or Gb4Cer species. Gb3Cer, Gb4Cer and sphingomyelin preferentially distribute to detergent-resistant membrane fractions and can be considered lipid raft markers in PBCECs. Moreover, we employed an in vitro model of the blood-brain barrier (BBB), which exhibited strong cytotoxic effects of Stx2e on the endothelial monolayer and a rapid collapse of the BBB. These data strongly suggest the involvement of Stx2e in cerebral vascular damage with resultant neurological disturbance characteristic of edema disease.

Global gene expression profiles in brain regions reflecting abnormal neuronal and glial functions targeting myelin sheaths after 28-day exposure to cuprizone in rats

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

Abe, Hajime

Both developmental and postpubertal cuprizone (CPZ) exposure impairs hippocampal neurogenesis in rats. We previously found that developmental CPZ exposure alters the expression of genes related to neurogenesis, myelination, and synaptic transmission in specific brain regions of offspring. Here, we examined neuronal and glial toxicity profiles in response to postpubertal CPZ exposure by using expression microarray analysis in the hippocampal dentate gyrus, corpus callosum, cerebral cortex, and cerebellar vermis of 5-week-old male rats exposed to 0, 120, and 600 mg/kg CPZ for 28 days. Genes showing transcript upregulation were subjected to immunohistochemical analysis. We found transcript expression alterations at 600 mg/kgmore » for genes related to synaptic transmission, Ache and Prima1, and cell cycle regulation, Tfap4 and Cdkn1a, in the dentate gyrus, which showed aberrant neurogenesis in the subgranular zone. This dose downregulated myelination-related genes in multiple brain regions, whereas KLOTHO{sup +} oligodendrocyte density was decreased only in the corpus callosum. The corpus callosum showed an increase in transcript levels for inflammatory response-related genes and in the number of CD68{sup +} microglia, MT{sup +} astrocytes, and TUNEL{sup +} apoptotic cells. These results suggest that postpubertal CPZ exposure targets synaptic transmission and cell cycle regulation to affect neurogenesis in the dentate gyrus. CPZ suppressed myelination in multiple brain regions and KLOTHO-mediated oligodendrocyte maturation only in the corpus callosum. The increased number of CD68{sup +} microglia, MT{sup +} astrocytes, and TUNEL{sup +} apoptotic cells in the corpus callosum may be involved in the induction of KLOTHO{sup +} oligodendrocyte death and be a protective mechanism against myelin damage following CPZ exposure. - Highlights: • Target gene expression profiles were examined in rats after 28-day CPZ exposure. • Multiple brain region-specific global gene expression profiling was performed. • CPZ affected synaptic function and cell cycling in the hippocampal dentate gyrus. • CPZ suppressed KLOTHO-mediated oligodendrocyte maturation in the corpus callosum. • CPZ increased metallothionein-mediated protective mechanism against myelin damage.« less

Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury.

PubMed

de Rivero Vaccari, Juan Pablo; Lotocki, George; Alonso, Ofelia F; Bramlett, Helen M; Dietrich, W Dalton; Keane, Robert W

2009-07-01

Traumatic brain injury elicits acute inflammation that in turn exacerbates primary brain damage. A crucial part of innate immunity in the immune privileged central nervous system involves production of proinflammatory cytokines mediated by inflammasome signaling. Here, we show that the nucleotide-binding, leucine-rich repeat pyrin domain containing protein 1 (NLRP1) inflammasome consisting of NLRP1, caspase-1, caspase-11, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), the X-linked inhibitor of apoptosis protein, and pannexin 1 is expressed in neurons of the cerebral cortex. Moderate parasagittal fluid-percussion injury (FPI) induced processing of interleukin-1beta, activation of caspase-1, cleavage of X-linked inhibitor of apoptosis protein, and promoted assembly of the NLRP1 inflammasome complex. Anti-ASC neutralizing antibodies administered immediately after fluid-percussion injury to injured rats reduced caspase-1 activation, X-linked inhibitor of apoptosis protein cleavage, and processing of interleukin-1beta, resulting in a significant decrease in contusion volume. These studies show that the NLRP1 inflammasome constitutes an important component of the innate central nervous system inflammatory response after traumatic brain injury and may be a novel therapeutic target for reducing the damaging effects of posttraumatic brain inflammation.

Closed-loop control of targeted ultrasound drug delivery across the blood–brain/tumor barriers in a rat glioma model

PubMed Central

Sun, Tao; Zhang, Yongzhi; Power, Chanikarn; Alexander, Phillip M.; Sutton, Jonathan T.; Aryal, Muna; Vykhodtseva, Natalia; Miller, Eric L.; McDannold, Nathan J.

2017-01-01

Cavitation-facilitated microbubble-mediated focused ultrasound therapy is a promising method of drug delivery across the blood–brain barrier (BBB) for treating many neurological disorders. Unlike ultrasound thermal therapies, during which magnetic resonance thermometry can serve as a reliable treatment control modality, real-time control of modulated BBB disruption with undetectable vascular damage remains a challenge. Here a closed-loop cavitation controlling paradigm that sustains stable cavitation while suppressing inertial cavitation behavior was designed and validated using a dual-transducer system operating at the clinically relevant ultrasound frequency of 274.3 kHz. Tests in the normal brain and in the F98 glioma model in vivo demonstrated that this controller enables reliable and damage-free delivery of a predetermined amount of the chemotherapeutic drug (liposomal doxorubicin) into the brain. The maximum concentration level of delivered doxorubicin exceeded levels previously shown (using uncontrolled sonication) to induce tumor regression and improve survival in rat glioma. These results confirmed the ability of the controller to modulate the drug delivery dosage within a therapeutically effective range, while improving safety control. It can be readily implemented clinically and potentially applied to other cavitation-enhanced ultrasound therapies. PMID:29133392

Blocking Lymphocyte Trafficking with FTY720 Prevents Inflammation-Sensitized Hypoxic–Ischemic Brain Injury in Newborns

PubMed Central

Yang, Dianer; Sun, Yu-Yo; Bhaumik, Siddhartha Kumar; Li, Yikun; Baumann, Jessica M.; Lin, Xiaoyi; Zhang, Yujin; Lin, Shang-Hsuan; Dunn, R. Scott; Liu, Chia-Yang; Shie, Feng-Shiun; Lee, Yi-Hsuan; Wills-Karp, Marsha; Chougnet, Claire A.; Kallapur, Suhas G.; Lewkowich, Ian P.; Lindquist, Diana M.; Murali-Krishna, Kaja

2014-01-01

Intrauterine infection (chorioamnionitis) aggravates neonatal hypoxic–ischemic (HI) brain injury, but the mechanisms linking systemic inflammation to the CNS damage remain uncertain. Here we report evidence for brain influx of T-helper 17 (TH17)-like lymphocytes to coordinate neuroinflammatory responses in lipopolysaccharide (LPS)-sensitized HI injury in neonates. We found that both infants with histological chorioamnionitis and rat pups challenged by LPS/HI have elevated expression of the interleukin-23 (IL-23) receptor, a marker of early TH17 lymphocytes, in the peripheral blood mononuclear cells. Post-LPS/HI administration of FTY720 (fingolimod), a sphingosine-1-phosphate receptor agonist that blocks lymphocyte trafficking, mitigated the influx of leukocytes through the choroid plexus and acute induction of nuclear factor-κB signaling in the brain. Subsequently, the FTY720 treatment led to attenuated blood–brain barrier damage, fewer cluster of differentiation 4-positive, IL-17A-positive T-cells in the brain, less proinflammatory cytokine, and better preservation of growth and white matter functions. The FTY720 treatment also provided dose-dependent reduction of brain atrophy, rescuing >90% of LPS/HI-induced brain tissue loss. Interestingly, FTY720 neither opposed pure-HI brain injury nor directly inhibited microglia in both in vivo and in vitro models, highlighting its unique mechanism against inflammation-sensitized HI injury. Together, these results suggest that the dual hit of systemic inflammation and neonatal HI injury triggers early onset of the TH17/IL-17-mediated immunity, which causes severe brain destruction but responds remarkably to the therapeutic blockade of lymphocyte trafficking. PMID:25471584

Modulation of Experimental Herpes Encephalitis-Associated Neurotoxicity through Sulforaphane Treatment

PubMed Central

Schachtele, Scott J.; Hu, Shuxian; Lokensgard, James R.

2012-01-01

Reactive oxygen species (ROS) produced by brain-infiltrating macrophages and neutrophils, as well as resident microglia, are pivotal to pathogen clearance during viral brain infection. However, unchecked free radical generation is also responsible for damage to and cytotoxicity of critical host tissue bystander to primary infection. These unwanted effects of excessive ROS are combated by local cellular production of antioxidant enzymes, including heme oxygenase-1 (HO-1) and glutathione peroxidase 1 (Gpx1). In this study, we showed that experimental murine herpes encephalitis triggered robust ROS production, as well as an opposing upregulation of the antioxidants HO-1 and Gpx1. This antioxidant response was insufficient to prevent tissue damage, neurotoxicity, and mortality associated with viral brain infection. Previous studies corroborate our data supporting astrocytes as the major antioxidant producer in brain cell cultures exposed to HSV-1 stimulated microglia. We hypothesized that stimulating opposing antioxidative responses in astrocytes, as well as neurons, would mitigate the effects of ROS-mediated neurotoxicity both in vitro and during viral brain infection in vivo. Here, we demonstrate that the addition of sulforaphane, a potent stimulator of antioxidant responses, enhanced HO-1 and Gpx1 expression in astrocytes through the activation of nuclear factor-E2-related factor 2 (Nrf2). Additionally, sulforaphane treatment was found to be effective in reducing neurotoxicity associated with HSV-stimulated microglial ROS production. Finally, intraperitoneal injections of sulforaphane into mice during active HSV infection reduced neuroinflammation via a decrease in brain-infiltrating leukocytes, macrophage- and neutrophil-produced ROS, and MHCII-positive, activated microglia. These data support a key role for astrocyte-produced antioxidants in modulating oxidative stress and neuronal damage in response to viral infection. PMID:22558388

Inhibition of activated NR2B gene- and caspase-3 protein-expression by glutathione following traumatic brain injury in a rat model

PubMed Central

Arifin, Muhammad Zafrullah; Faried, Ahmad; Shahib, Muhammad Nurhalim; Wiriadisastra, Kahdar; Bisri, Tatang

2011-01-01

Background. Traumatic brain injury (TBI) remains a major cause of death and disability. Oxidative stress is an important element of the injury cascade following TBI. Progressive compromise of antioxidant defenses and free radical-mediated lipid peroxidation are one of the major mechanisms of secondary TBI. NR2B is a glutamate receptor and its activation is caused by TBI increasing a brain cell death, along with caspase-3 as a hall mark of apoptosis. Glutathione is a potent free radical scavenger that might prevent secondary TBI damage and inhibited apoptosis. Materials and Methods. In the present study, it aims to demonstrate the effect of glutathione on inhibition of brain oxidative damage in a TBI rat model. Results. In this study, the expressions of mRNA NR2B in placebo group and groups with glutathione administration at 0, 3, and 6 hours after TBI were 328.14, 229.90, 178.50, and 136.14, respectively (P<0.001). The highest caspase-3 expression was shown in placebo group with 66.7% showing strong positive results (>80%); as expected, glutathione administered in 0, 3, and 6 hours groups had lower strong positive results of 50%, 16.7%, and 16.7%, respectively, (P=0.025). Conclusion. In conclusion, this study showed that glutathione administration in a TBI rat model decreased NR2B gene- and caspase-3 protein-expression that lead to the inhibition of brain cell death. Our results suggest that glutathione, as a potent free radical scavenger, has a brain cell protective effect against oxidative damage and cell death induced by TBI in rat model. PMID:22347327

Poly(ADP-ribose) polymerase-1 regulates microglia mediated decrease of endothelial tight junction integrity.

PubMed

Mehrabadi, Abbas Rezaeian; Korolainen, Minna A; Odero, Gary; Miller, Donald W; Kauppinen, Tiina M

2017-09-01

Alzheimer's disease pathology includes, beside neuronal damage, reactive gliosis and reduced blood-brain barrier (BBB) integrity. Microglia are intimately associated with the BBB and upon AD pathology, pro-inflammatory responses of microglia could contribute to BBB damage. To study whether microglia can directly affect BBB integrity, the effects of amyloid beta (Aβ) -stimulated primary murine microglia on co-cultured mouse brain endothelial cells (bEnd3) and murine astrocyte cultures were assessed. We also assessed whether microglial phenotype modulation via poly(ADP-ribose) polymerase-1 (PARP-1) inhibition/ablation can reverse microglial impact on these BBB forming cells. Unstimulated microglia promoted expression of tight junction proteins (TJPs), zonula ocluden-1 (ZO-1) and occludin in co-cultured endothelia cells, whereas Aβ-stimulated microglia reduced endothelial expression of ZO-1 and occludin. Astrocytes co-cultured with microglia showed elevated glial fibrillary acidic protein (GFAP) expression, which was further increased if microglia had been stimulated with Aβ. Aβ induced microglial release of nitric oxide (NO) and tumour necrosis factor alpha (TNFα), which resulted in reduced endothelial expression of TJPs and increased paracellular permeability. Microglial PARP-1 inhibition attenuated these Aβ-induced events. These findings demonstrate that PARP-1 mediated microglial responses (NO and TNFα) can directly reduce BBB integrity by promoting TJP degradation, increasing endothelial cell permeability and inducing astrogliosis. PARP-1 as a modulator of microglial phenotype can prevent microglial BBB damaging events, and thus is a potential therapeutic target. Copyright © 2017 Elsevier Ltd. All rights reserved.

Extracellular Spermine Exacerbates Ischemic Neuronal Injury through Sensitization of ASIC1a Channels to Extracellular Acidosis

PubMed Central

Duan, Bo; Wang, Yi-Zhi; Yang, Tao; Chu, Xiang-Ping; Yu, Ye; Huang, Yu; Cao, Hui; Hansen, Jillian; Simon, Roger P.; Zhu, Michael X.; Xiong, Zhi-Gang; Xu, Tian-Le

2011-01-01

Ischemic brain injury is a major problem associated with stroke. It has been increasingly recognized that acid-sensing ion channels (ASICs) contribute significantly to ischemic neuronal damage, but the underlying mechanism has remained elusive. Here, we show that extracellular spermine, one of the endogenous polyamines, exacerbates ischemic neuronal injury through sensitization of ASIC1a channels to extracellular acidosis. Pharmacological blockade of ASIC1a or deletion of the ASIC1 gene greatly reduces the enhancing effect of spermine in ischemic neuronal damage both in cultures of dissociated neurons and in a mouse model of focal ischemia. Mechanistically, spermine profoundly reduces desensitization of ASIC1a by slowing down desensitization in the open state, shifting steady-state desensitization to more acidic pH, and accelerating recovery between repeated periods of acid stimulation. Spermine-mediated potentiation of ASIC1a activity is occluded by PcTX1 (psalmotoxin 1), a specific ASIC1a inhibitor binding to its extracellular domain. Functionally, the enhanced channel activity is accompanied by increased acid-induced neuronal membrane depolarization and cytoplasmic Ca2+ overload, which may partially explain the exacerbated neuronal damage caused by spermine. More importantly, blocking endogenous spermine synthesis significantly attenuates ischemic brain injury mediated by ASIC1a but not that by NMDA receptors. Thus, extracellular spermine contributes significantly to ischemic neuronal injury through enhancing ASIC1a activity. Our data suggest new neuroprotective strategies for stroke patients via inhibition of polyamine synthesis and subsequent spermine–ASIC interaction. PMID:21307247

The meninges: new therapeutic targets for multiple sclerosis.

PubMed

Russi, Abigail E; Brown, Melissa A

2015-02-01

The central nervous system (CNS) largely comprises nonregenerating cells, including neurons and myelin-producing oligodendrocytes, which are particularly vulnerable to immune cell-mediated damage. To protect the CNS, mechanisms exist that normally restrict the transit of peripheral immune cells into the brain and spinal cord, conferring an "immune-specialized" status. Thus, there has been a long-standing debate as to how these restrictions are overcome in several inflammatory diseases of the CNS, including multiple sclerosis (MS). In this review, we highlight the role of the meninges, tissues that surround and protect the CNS and enclose the cerebral spinal fluid, in promoting chronic inflammation that leads to neuronal damage. Although the meninges have traditionally been considered structures that provide physical protection for the brain and spinal cord, new data have established these tissues as sites of active immunity. It has been hypothesized that the meninges are important players in normal immunosurveillance of the CNS but also serve as initial sites of anti-myelin immune responses. The resulting robust meningeal inflammation elicits loss of localized blood-brain barrier (BBB) integrity and facilitates a large-scale influx of immune cells into the CNS parenchyma. We propose that targeting the cells and molecules mediating these inflammatory responses within the meninges offers promising therapies for MS that are free from the constraints imposed by the BBB. Importantly, such therapies may avoid the systemic immunosuppression often associated with the existing treatments. Copyright © 2015 Elsevier Inc. All rights reserved.

Tert-butylhydroquinone post-treatment attenuates neonatal hypoxic-ischemic brain damage in rats.

PubMed

Zhang, Juan; Tucker, Lorelei Donovan; DongYan; Lu, Yujiao; Yang, Luodan; Wu, Chongyun; Li, Yong; Zhang, Quanguang

2018-06-01

Hypoxic-ischemic (HI) encephalopathy is a leading cause of dire mortality and morbidity in neonates. Unfortunately, no effective therapies have been developed as of yet. Oxidative stress plays a critical role in pathogenesis and progression of neonatal HI. Previously, as a Nrf2 activator, tert-butylhydroquinone (TBHQ) has been demonstrated to exert neuroprotection on brain trauma and ischemic stroke models, as well as oxidative stress-induced cytotoxicity in neurons. It is, however, still unknown whether TBHQ administration can protect against oxidative stress in neonatal HI brain injury. This study was undertaken to determine the neuroprotective effects and mechanisms of TBHQ post-treatment on neonatal HI brain damage. Using a neonatal HI rat model, we demonstrated that TBHQ markedly abated oxidative stress compared to the HI group, as evidenced by decreased oxidative stress indexes, enhanced Nrf2 nuclear accumulation and DNA binding activity, and up-regulated expression of Nrf2 downstream antioxidative genes. Administration of TBHQ likewise significantly suppressed reactive gliosis and release of inflammatory cytokines, and inhibited apoptosis and neuronal degeneration in the neonatal rat cerebral cortex. In addition, infarct size and neuronal damage were attenuated distinctly. These beneficial effects were accompanied by improved neurological reflex and motor coordination as well as amelioration of spatial learning and memory deficits. Overall, our results provide the first documentation of the beneficial effects of TBHQ in neonatal HI model, in part conferred by activation of Nrf2 mediated antioxidative signaling pathways. Copyright © 2018 Elsevier Ltd. All rights reserved.

Rational modulation of the innate immune system for neuroprotection in ischemic stroke

PubMed Central

Amantea, Diana; Micieli, Giuseppe; Tassorelli, Cristina; Cuartero, María I.; Ballesteros, Iván; Certo, Michelangelo; Moro, María A.; Lizasoain, Ignacio; Bagetta, Giacinto

2015-01-01

The innate immune system plays a dualistic role in the evolution of ischemic brain damage and has also been implicated in ischemic tolerance produced by different conditioning stimuli. Early after ischemia, perivascular astrocytes release cytokines and activate metalloproteases (MMPs) that contribute to blood–brain barrier (BBB) disruption and vasogenic oedema; whereas at later stages, they provide extracellular glutamate uptake, BBB regeneration and neurotrophic factors release. Similarly, early activation of microglia contributes to ischemic brain injury via the production of inflammatory cytokines, including tumor necrosis factor (TNF) and interleukin (IL)-1, reactive oxygen and nitrogen species and proteases. Nevertheless, microglia also contributes to the resolution of inflammation, by releasing IL-10 and tumor growth factor (TGF)-β, and to the late reparative processes by phagocytic activity and growth factors production. Indeed, after ischemia, microglia/macrophages differentiate toward several phenotypes: the M1 pro-inflammatory phenotype is classically activated via toll-like receptors or interferon-γ, whereas M2 phenotypes are alternatively activated by regulatory mediators, such as ILs 4, 10, 13, or TGF-β. Thus, immune cells exert a dualistic role on the evolution of ischemic brain damage, since the classic phenotypes promote injury, whereas alternatively activated M2 macrophages or N2 neutrophils prompt tissue remodeling and repair. Moreover, a subdued activation of the immune system has been involved in ischemic tolerance, since different preconditioning stimuli act via modulation of inflammatory mediators, including toll-like receptors and cytokine signaling pathways. This further underscores that the immuno-modulatory approach for the treatment of ischemic stroke should be aimed at blocking the detrimental effects, while promoting the beneficial responses of the immune reaction. PMID:25972779

Fast therapeutic hypothermia prevents post-cardiac arrest syndrome through cyclophilin D-mediated mitochondrial permeability transition inhibition.

PubMed

Jahandiez, Vincent; Cour, Martin; Bochaton, Thomas; Abrial, Maryline; Loufouat, Joseph; Gharib, Abdallah; Varennes, Annie; Ovize, Michel; Argaud, Laurent

2017-07-01

The opening of the mitochondrial permeability transition pore (PTP), which is regulated by the matrix protein cyclophilin D (CypD), plays a key role in the pathophysiology of post-cardiac arrest (CA) syndrome. We hypothesized that therapeutic hypothermia could prevent post-CA syndrome through a CypD-mediated PTP inhibition in both heart and brain. In addition, we investigated whether specific pharmacological PTP inhibition would confer additive protection to cooling. Adult male New Zealand White rabbits underwent 15 min of CA followed by 120 min of reperfusion. Five groups (n = 10-15/group) were studied: control group (CA only), hypothermia group (HT, hypothermia at 32-34 °C induced by external cooling at reperfusion), NIM group (injection at reperfusion of 2.5 mg/kg NIM811, a specific CypD inhibitor), HT + NIM, and sham group. The following measurements were taken: hemodynamics, echocardiography, and cellular damage markers (including S100β protein and troponin Ic). Oxidative phosphorylation and PTP opening were assessed on mitochondria isolated from both brain and heart. Acetylation of CypD was measured by immunoprecipitation in both the cerebral cortex and myocardium. Hypothermia and NIM811 significantly prevented cardiovascular dysfunction, pupillary areflexia, and early tissue damage. Hypothermia and NIM811 preserved oxidative phosphorylation, limited PTP opening in both brain and heart mitochondria and prevented increase in CypD acetylation in brain. There were no additive beneficial effects in the combination of NIM811 and therapeutic hypothermia. In conclusion, therapeutic hypothermia limited post-CA syndrome by preventing mitochondrial permeability transition mainly through a CypD-dependent mechanism.

Taurine-induced attenuation of MPP+ neurotoxicity in vitro: a possible role for the GABA(A) subclass of GABA receptors.

PubMed

O'Byrne, M B; Tipton, K F

2000-05-01

Taurine is a sulphur-containing beta-amino acid found in high (millimolar) concentrations in excitable tissues such as brain and heart. Its suggested roles include osmoregulator, thermoregulator, neuromodulator, and potential neurotransmitter. This amino acid has also been shown to be released in large concentrations during ischaemia and excitotoxin-induced neuronal damage. Here we report a protective effect of taurine against MPP(+)-induced neurotoxicity in coronal slices from rat brain. Significant protective effects were observed at taurine concentrations of 20 and 1 mM, suggesting a potential role for taurine in cases of neuronal insult. Studies with the synthetic taurine analogues taurine phosphonate, guanidinoethane sulphonate, and trimethyltaurine suggested the observed effect to be mediated via an extracellular mechanism. The use of GABA receptor ligands muscimol and bicuculline indicated the effect to be mediated through activation of GABA(A) receptors.

Repair of astrocytes, blood vessels, and myelin in the injured brain: possible roles of blood monocytes

PubMed Central

2013-01-01

Inflammation in injured tissue has both repair functions and cytotoxic consequences. However, the issue of whether brain inflammation has a repair function has received little attention. Previously, we demonstrated monocyte infiltration and death of neurons and resident microglia in LPS-injected brains (Glia. 2007. 55:1577; Glia. 2008. 56:1039). Here, we found that astrocytes, oligodendrocytes, myelin, and endothelial cells disappeared in the damage core within 1–3 d and then re-appeared at 7–14 d, providing evidence of repair of the brain microenvironment. Since round Iba-1+/CD45+ monocytes infiltrated before the repair, we examined whether these cells were involved in the repair process. Analysis of mRNA expression profiles showed significant upregulation of repair/resolution-related genes, whereas proinflammatory-related genes were barely detectable at 3 d, a time when monocytes filled injury sites. Moreover, Iba-1+/CD45+ cells highly expressed phagocytic activity markers (e.g., the mannose receptors, CD68 and LAMP2), but not proinflammatory mediators (e.g., iNOS and IL1β). In addition, the distribution of round Iba-1+/CD45+ cells was spatially and temporally correlated with astrocyte recovery. We further found that monocytes in culture attracted astrocytes by releasing soluble factor(s). Together, these results suggest that brain inflammation mediated by monocytes functions to repair the microenvironment of the injured brain. PMID:23758980

Amygdala Damage Affects Event-Related Potentials for Fearful Faces at Specific Time Windows

PubMed Central

Rotshtein, Pia; Richardson, Mark P; Winston, Joel S; Kiebel, Stefan J; Vuilleumier, Patrik; Eimer, Martin; Driver, Jon; Dolan, Raymond J

2010-01-01

The amygdala is known to influence processing of threat-related stimuli in distant brain regions, including visual cortex. The time-course of these distant influences is unknown, although this information is important for resolving debates over likely pathways mediating an apparent rapidity in emotional processing. To address this, we recorded event-related potentials (ERPs) to seen fearful face expressions, in preoperative patients with medial temporal lobe epilepsy who had varying degrees of amygdala pathology, plus healthy volunteers. We found that amygdala damage diminished ERPs for fearful versus neutral faces within the P1 time-range, ∼100–150 ms, and for a later component at ∼500–600 ms. Individual severity of amygdala damage determined the magnitude of both these effects, consistent with a causal amygdala role. By contrast, amygdala damage did not affect explicit perception of fearful expressions nor a distinct emotional ERP effect at 150–250 ms. These results demonstrate two distinct time-points at which the amygdala influences fear processing. The data also demonstrate that while not all aspects of expression processing are disrupted by amygdala damage, there is a crucial impact on an early P1 component. These findings are consistent with the existence of multiple processing stages or routes for fearful faces that vary in their dependence on amygdala function. Hum Brain Mapp, 2010. © 2009 Wiley-Liss, Inc. PMID:20017134

Polydatin attenuates d-galactose-induced liver and brain damage through its anti-oxidative, anti-inflammatory and anti-apoptotic effects in mice.

PubMed

Xu, Lie-Qiang; Xie, You-Liang; Gui, Shu-Hua; Zhang, Xie; Mo, Zhi-Zhun; Sun, Chao-Yue; Li, Cai-Lan; Luo, Dan-Dan; Zhang, Zhen-Biao; Su, Zi-Ren; Xie, Jian-Hui

2016-11-09

Accumulating evidence has shown that chronic injection of d-galactose (d-gal) can mimic natural aging, with accompanying liver and brain injury. Oxidative stress and apoptosis play a vital role in the aging process. In this study, the antioxidant ability of polydatin (PD) was investigated using four established in vitro systems. An in vivo study was also conducted to investigate the possible protective effect of PD on d-gal-induced liver and brain damage. The results showed that PD had remarkable in vitro free radical scavenging activity on 2,2-diphenyl-1-picryl-hydrazyl (DPPH˙), 2,2'-azino-bis(3-ethylbenzo-thiazoline-6-sulfonic acid) (ABTS + ˙) radical ions, and hydroxyl and superoxide anions. Results in vivo indicated that, in a group treated with d-gal plus PD, PD remarkably decreased the depression of body weight and organ indexes, reduced the levels of the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and alleviated alterations in liver and brain histopathology. PD also significantly decreased the level of MDA and elevated SOD, GSH-Px, CAT activity and T-AOC levels in the liver and brain. In addition, the levels of inflammatory mediators, such as TNF-α, IL-1β and IL-6 in serum were markedly reduced after PD treatment. Western blotting results revealed that PD treatment noticeably attenuated the d-gal-induced elevation of Bcl-2/Bax ratio and caspase-3 protein expression in liver and brain. Overall, our findings indicate that PD treatment could effectively attenuate d-gal-induced liver and brain damage, and the mechanism might be associated with decreasing the oxidative stress, inflammation and apoptosis caused by d-gal. PD holds good potential for further development into a promising pharmaceutical candidate for the treatment of age-associated diseases.

Soman increases neuronal COX-2 levels: possible link between seizures and protracted neuronal damage.

PubMed

Angoa-Pérez, Mariana; Kreipke, Christian W; Thomas, David M; Van Shura, Kerry E; Lyman, Megan; McDonough, John H; Kuhn, Donald M

2010-12-01

Nerve agent-induced seizures cause neuronal damage in brain limbic and cortical circuits leading to persistent behavioral and cognitive deficits. Without aggressive anticholinergic and benzodiazepine therapy, seizures can be prolonged and neuronal damage progresses for extended periods of time. The objective of this study was to determine the effects of the nerve agent soman on expression of cyclooxygenase-2 (COX-2), the initial enzyme in the biosynthetic pathway of the proinflammatory prostaglandins and a factor that has been implicated in seizure initiation and propagation. Rats were exposed to a toxic dose of soman and scored behaviorally for seizure intensity. Expression of COX-2 was determined throughout brain from 4h to 7 days after exposure by immunohistochemistry and immunoblotting. Microglial activation and astrogliosis were assessed microscopically over the same time-course. Soman increased COX-2 expression in brain regions known to be damaged by nerve agents (e.g., hippocampus, amygdala, piriform cortex and thalamus). COX-2 expression was induced in neurons, and not in microglia or astrocytes, and remained elevated through 7 days. The magnitude of COX-2 induction was correlated with seizure intensity. COX-1 expression was not changed by soman. Increased expression of neuronal COX-2 by soman is a late-developing response relative to other signs of acute physiological distress caused by nerve agents. COX-2-mediated production of prostaglandins is a consequence of the seizure-induced neuronal damage, even after survival of the initial cholinergic crisis is assured. COX-2 inhibitors should be considered as adjunct therapy in nerve agent poisoning to minimize nerve agent-induced seizure activity. Published by Elsevier B.V.

Cobalt-55 positron emission tomography in traumatic brain injury: a pilot study.

PubMed Central

Jansen, H M; van der Naalt, J; van Zomeren, A H; Paans, A M; Veenma-van der Duin, L; Hew, J M; Pruim, J; Minderhoud, J M; Korf, J

1996-01-01

Traumatic brain injury is usually assessed with the Glasgow coma scale (GCS), CT, or MRI. After such injury, the injured brain tissue is characterised by calcium mediated neuronal damage and inflammation. Positron emission tomography with the isotope cobalt-55 (Co-PET) as a calcium tracer enables imaging of affected tissue in traumatic brain injury. The aim was to determine whether additional information can be gained by Co-PET in the diagnosis of moderate traumatic brain injury and to assess any prognostic value of Co-PET. Five patients with recent moderately severe traumatic brain injury were studied. CT was performed on the day of admission, EEG within one week, and MRI and Co-PET within four weeks of injury. Clinical assessment included neurological examination, GCS, neuropsychological testing, and Glasgow outcome scale (GOS) after one year. Co-PET showed focal uptake that extended beyond the morphological abnormalities shown by MRI and CT, in brain regions that were actually diagnosed with EEG. Thus Co-PET is potentially useful for diagnostic localisation of both structural and functional abnormalities in moderate traumatic brain injury. Images PMID:8708661

Differential DNA damage in response to the neonatal and adult excitotoxic hippocampal lesion in rats.

PubMed

Khaing, Z Z; Weickert, C S; Weinberger, D R; Lipska, B K

2000-12-01

We examined the developmental profile of excitotoxin-induced nuclear DNA fragmentation using the transferase dUTP nick-end labelling (TUNEL) technique, as a marker of DNA damage and cell death in rats with neonatal and adult excitotoxic lesions of the ventral hippocampus. We hypothesized that infusion of neurotoxin may result in a differential pattern of cell death in neonatally and adult lesioned rats, both in the infusion site and in remote brain regions presumably involved in mediating behavioural changes observed in these animals. Brains of rats lesioned at 7 days of age and in adulthood were collected at several survival times 1-21 days after the lesion. In the lesioned neonates 1-3 days postlesion, marked increases in TUNEL-positive cells occurred in the ventral hippocampus, the site of neurotoxin infusion, and in a wide surrounding area. Adult lesioned brains showed more positive cells than controls only at the infusion site. In the lesioned neonates, TUNEL-labelled cells were also present in the striatum and nucleus accumbens 1 day postlesion but not at later survival times. Our findings indicate that cell death in remote regions is more prominent in immature than adult brains, that it may lead to distinct alterations in development of these brain regions, and thus may be responsible for functional differences between neonatally and adult lesioned rats.

Systemic Inflammation and the Brain: Novel Roles of Genetic, Molecular, and Environmental Cues as Drivers of Neurodegeneration

PubMed Central

Sankowski, Roman; Mader, Simone; Valdés-Ferrer, Sergio Iván

2015-01-01

The nervous and immune systems have evolved in parallel from the early bilaterians, in which innate immunity and a central nervous system (CNS) coexisted for the first time, to jawed vertebrates and the appearance of adaptive immunity. The CNS feeds from, and integrates efferent signals in response to, somatic and autonomic sensory information. The CNS receives input also from the periphery about inflammation and infection. Cytokines, chemokines, and damage-associated soluble mediators of systemic inflammation can also gain access to the CNS via blood flow. In response to systemic inflammation, those soluble mediators can access directly through the circumventricular organs, as well as open the blood–brain barrier. The resulting translocation of inflammatory mediators can interfere with neuronal and glial well-being, leading to a break of balance in brain homeostasis. This in turn results in cognitive and behavioral manifestations commonly present during acute infections – including anorexia, malaise, depression, and decreased physical activity – collectively known as the sickness behavior (SB). While SB manifestations are transient and self-limited, under states of persistent systemic inflammatory response the cognitive and behavioral changes can become permanent. For example, cognitive decline is almost universal in sepsis survivors, and a common finding in patients with systemic lupus erythematosus. Here, we review recent genetic evidence suggesting an association between neurodegenerative disorders and persistent immune activation; clinical and experimental evidence indicating previously unidentified immune-mediated pathways of neurodegeneration; and novel immunomodulatory targets and their potential relevance for neurodegenerative disorders. PMID:25698933

Glutamate Excitoxicity Is the Key Molecular Mechanism Which Is Influenced by Body Temperature during the Acute Phase of Brain Stroke

PubMed Central

Campos, Francisco; Pérez-Mato, María; Agulla, Jesús; Blanco, Miguel; Barral, David; Almeida, Ángeles; Brea, David; Waeber, Christian; Castillo, José; Ramos-Cabrer, Pedro

2012-01-01

Glutamate excitotoxicity, metabolic rate and inflammatory response have been associated to the deleterious effects of temperature during the acute phase of stroke. So far, the association of temperature with these mechanisms has been studied individually. However, the simultaneous study of the influence of temperature on these mechanisms is necessary to clarify their contributions to temperature-mediated ischemic damage. We used non-invasive Magnetic Resonance Spectroscopy to simultaneously measure temperature, glutamate excitotoxicity and metabolic rate in the brain in animal models of ischemia. The immune response to ischemia was measured through molecular serum markers in peripheral blood. We submitted groups of animals to different experimental conditions (hypothermia at 33°C, normothermia at 37°C and hyperthermia at 39°C), and combined these conditions with pharmacological modulation of glutamate levels in the brain through systemic injections of glutamate and oxaloacetate. We show that pharmacological modulation of glutamate levels can neutralize the deleterious effects of hyperthermia and the beneficial effects of hypothermia, however the analysis of the inflammatory response and metabolic rate, demonstrated that their effects on ischemic damage are less critical than glutamate excitotoxity. We conclude that glutamate excitotoxicity is the key molecular mechanism which is influenced by body temperature during the acute phase of brain stroke. PMID:22952923

Glutamate excitoxicity is the key molecular mechanism which is influenced by body temperature during the acute phase of brain stroke.

PubMed

Campos, Francisco; Pérez-Mato, María; Agulla, Jesús; Blanco, Miguel; Barral, David; Almeida, Angeles; Brea, David; Waeber, Christian; Castillo, José; Ramos-Cabrer, Pedro

2012-01-01

Glutamate excitotoxicity, metabolic rate and inflammatory response have been associated to the deleterious effects of temperature during the acute phase of stroke. So far, the association of temperature with these mechanisms has been studied individually. However, the simultaneous study of the influence of temperature on these mechanisms is necessary to clarify their contributions to temperature-mediated ischemic damage. We used non-invasive Magnetic Resonance Spectroscopy to simultaneously measure temperature, glutamate excitotoxicity and metabolic rate in the brain in animal models of ischemia. The immune response to ischemia was measured through molecular serum markers in peripheral blood. We submitted groups of animals to different experimental conditions (hypothermia at 33°C, normothermia at 37°C and hyperthermia at 39°C), and combined these conditions with pharmacological modulation of glutamate levels in the brain through systemic injections of glutamate and oxaloacetate. We show that pharmacological modulation of glutamate levels can neutralize the deleterious effects of hyperthermia and the beneficial effects of hypothermia, however the analysis of the inflammatory response and metabolic rate, demonstrated that their effects on ischemic damage are less critical than glutamate excitotoxity. We conclude that glutamate excitotoxicity is the key molecular mechanism which is influenced by body temperature during the acute phase of brain stroke.

Neuroprotection by Caffeine in Hyperoxia-Induced Neonatal Brain Injury

PubMed Central

Endesfelder, Stefanie; Weichelt, Ulrike; Strauß, Evelyn; Schlör, Anja; Sifringer, Marco; Scheuer, Till; Bührer, Christoph; Schmitz, Thomas

2017-01-01

Sequelae of prematurity triggered by oxidative stress and free radical-mediated tissue damage have coined the term “oxygen radical disease of prematurity”. Caffeine, a potent free radical scavenger and adenosine receptor antagonist, reduces rates of brain damage in preterm infants. In the present study, we investigated the effects of caffeine on oxidative stress markers, anti-oxidative response, inflammation, redox-sensitive transcription factors, apoptosis, and extracellular matrix following the induction of hyperoxia in neonatal rats. The brain of a rat pups at postnatal Day 6 (P6) corresponds to that of a human fetal brain at 28–32 weeks gestation and the neonatal rat is an ideal model in which to investigate effects of oxidative stress and neuroprotection of caffeine on the developing brain. Six-day-old Wistar rats were pre-treated with caffeine and exposed to 80% oxygen for 24 and 48 h. Caffeine reduced oxidative stress marker (heme oxygenase-1, lipid peroxidation, hydrogen peroxide, and glutamate-cysteine ligase catalytic subunit (GCLC)), promoted anti-oxidative response (superoxide dismutase, peroxiredoxin 1, and sulfiredoxin 1), down-regulated pro-inflammatory cytokines, modulated redox-sensitive transcription factor expression (Nrf2/Keap1, and NFκB), reduced pro-apoptotic effectors (poly (ADP-ribose) polymerase-1 (PARP-1), apoptosis inducing factor (AIF), and caspase-3), and diminished extracellular matrix degeneration (matrix metalloproteinases (MMP) 2, and inhibitor of metalloproteinase (TIMP) 1/2). Our study affirms that caffeine is a pleiotropic neuroprotective drug in the developing brain due to its anti-oxidant, anti-inflammatory, and anti-apoptotic properties. PMID:28106777

B7-H3 Augments Inflammatory Responses and Exacerbates Brain Damage via Amplifying NF-κB p65 and MAPK p38 Activation during Experimental Pneumococcal Meningitis.

PubMed

Chen, Xuqin; Li, Yan; Blankson, Siobhan; Liu, Min; Huang, Danping; Redmond, H Paul; Huang, Jing; Wang, Jiang Huai; Wang, Jian

2017-01-01

The costimulatory protein B7-H3 has been shown to play a contributory role in the development and progression of experimental pneumococcal meningitis by augmentation of the innate immunity-associated inflammatory response via a TLR2-dependent manner. This study aimed to clarify the component(s) of TLR2-mediated signal transduction pathways responsible for B7-H3-augmented inflammatory response and subsequent brain damage during experimental pneumococcal meningitis. Administration of B7-H3 did not augment expression of TLR2 and other TLR2 upstream components, but led to an enhanced formation of MyD88-IRAK immunocomplex in the brain of S. pneumoniae-infected mice. Furthermore, B7-H3 substantially augmented S. pneumoniae-induced activation of TLR2 downstream NF-κB p65 and MAPK p38 pathways in the brain of S. pneumoniae-infected mice. Notably, blockage of NF-κB p65 and/or MAPK p38 with their specific inhibitors strongly attenuated B7-H3-amplified inflammatory response with significantly reduced proinflammatory cytokine and chemokine production, and markedly ameliorated B7-H3-exacerbated disruption of blood-brain barrier and severity of disease status in S. pneumoniae-infected mice. These results indicate that targeting NF-κB p65 and/or MAPK p38 may represent a promising therapeutic option for amelioration of overwhelming inflammatory response-associated brain injury frequently observed during pneumococcal meningitis.

Neuroprotection by Caffeine in Hyperoxia-Induced Neonatal Brain Injury.

PubMed

Endesfelder, Stefanie; Weichelt, Ulrike; Strauß, Evelyn; Schlör, Anja; Sifringer, Marco; Scheuer, Till; Bührer, Christoph; Schmitz, Thomas

2017-01-18

Sequelae of prematurity triggered by oxidative stress and free radical-mediated tissue damage have coined the term "oxygen radical disease of prematurity". Caffeine, a potent free radical scavenger and adenosine receptor antagonist, reduces rates of brain damage in preterm infants. In the present study, we investigated the effects of caffeine on oxidative stress markers, anti-oxidative response, inflammation, redox-sensitive transcription factors, apoptosis, and extracellular matrix following the induction of hyperoxia in neonatal rats. The brain of a rat pups at postnatal Day 6 (P6) corresponds to that of a human fetal brain at 28-32 weeks gestation and the neonatal rat is an ideal model in which to investigate effects of oxidative stress and neuroprotection of caffeine on the developing brain. Six-day-old Wistar rats were pre-treated with caffeine and exposed to 80% oxygen for 24 and 48 h. Caffeine reduced oxidative stress marker (heme oxygenase-1, lipid peroxidation, hydrogen peroxide, and glutamate-cysteine ligase catalytic subunit (GCLC)), promoted anti-oxidative response (superoxide dismutase, peroxiredoxin 1, and sulfiredoxin 1), down-regulated pro-inflammatory cytokines, modulated redox-sensitive transcription factor expression (Nrf2/Keap1, and NFκB), reduced pro-apoptotic effectors (poly (ADP-ribose) polymerase-1 (PARP-1), apoptosis inducing factor (AIF), and caspase-3), and diminished extracellular matrix degeneration (matrix metalloproteinases (MMP) 2, and inhibitor of metalloproteinase (TIMP) 1/2). Our study affirms that caffeine is a pleiotropic neuroprotective drug in the developing brain due to its anti-oxidant, anti-inflammatory, and anti-apoptotic properties.

BDNF in schizophrenia, depression and corresponding animal models.

PubMed

Angelucci, F; Brenè, S; Mathé, A A

2005-04-01

Understanding the etiology and pathogenesis schizophrenia and depression is a major challenge facing psychiatry. One hypothesis is that these disorders are secondary to a malfunction of neurotrophic factors. Inappropriate neurotrophic support during brain development could lead to structural disorganisation in which neuronal networks are established in a nonoptimal manner. Inadequate neurotrophic support in adult individuals could ultimately be an underlying mechanism leading to decreased capacity of brain to adaptive changes and increased vulnerability to neurotoxic damage. Brain-derived neurotrophic factor (BDNF) is a mediator involved in neuronal survival and plasticity of dopaminergic, cholinergic, and serotonergic neurons in the central nervous system (CNS). In this review, we summarize findings regarding altered BDNF in schizophrenia and depression and animal models, as well as the effects of antipsychotic and antidepressive treatments on the expression of BDNF.

Apoptosis and brain ischaemia.

PubMed

Love, Seth

2003-04-01

There is increasing evidence that some neuronal death after brain ischaemia is mediated by the action of cysteine-requiring aspartate-directed proteases (caspases), the proteases responsible for apoptosis in mammals, although this form of neuronal death is not always accompanied by the morphological changes that are typical of apoptosis in other tissues. Caspase-mediated neuronal death is more extensive after transient than permanent focal brain ischaemia and may contribute to delayed loss of neurons from the penumbral region of infarcts. The activation of caspases after brain ischaemia is largely consequent on the translocation of Bax, Bak, and other BH3-only members of the Bcl-2 family to the mitochondrial outer membrane and the release of cytochrome c, procaspase-9, and apoptosis activating factor-1 (Apaf-1) from the mitochondrial intermembrane space. How exactly ischaemia induces this translocation is still poorly understood. NF-kappaB, the c-jun N-terminal kinase-c-Jun pathway, p53, E2F1, and other transcription factors are probably all involved in regulating the expression of BH3-only proteins after brain ischaemia, and mitochondrial translocation of Bad from sequestering cytosolic proteins is promoted by inactivation of the serine-threonine kinase, Akt. Other processes that are probably involved in the activation of caspases after brain ischaemia include the mitochondrial release of the second mitochondrial activator of caspases (Smac) or direct inhibitor-of-apoptosis-binding protein with low pI (DIABLO), the accumulation of products of lipid peroxidation, a marked reduction in protein synthesis, and the aberrant reentry of neurons into the cell cycle. Non-caspase-mediated neuronal apoptosis may also occur, but there is little evidence to date that this makes a significant contribution to brain damage after ischaemia. The intracellular processes that contribute to caspase-mediated neuronal death after ischaemia are all potential targets for therapy. However, anti-apoptotic interventions in stroke patients will require detailed evaluation using a range of outcome measures, as some such interventions seem simply to delay neuronal death and others to preserve neurons but not neuronal function.

Early detection of subclinical visual damage after blast-mediated TBI enables prevention of chronic visual deficit by treatment with P7C3-S243.

PubMed

Dutca, Laura M; Stasheff, Steven F; Hedberg-Buenz, Adam; Rudd, Danielle S; Batra, Nikhil; Blodi, Frederick R; Yorek, Matthew S; Yin, Terry; Shankar, Malini; Herlein, Judith A; Naidoo, Jacinth; Morlock, Lorraine; Williams, Noelle; Kardon, Randy H; Anderson, Michael G; Pieper, Andrew A; Harper, Matthew M

2014-12-02

Traumatic brain injury (TBI) frequently leads to chronic visual dysfunction. The purpose of this study was to investigate the effect of TBI on retinal ganglion cells (RGCs), and to test whether treatment with the novel neuroprotective compound P7C3-S243 could prevent in vivo functional deficits in the visual system. Blast-mediated TBI was modeled using an enclosed over-pressure blast chamber. The RGC physiology was evaluated using a multielectrode array and pattern electroretinogram (PERG). Histological analysis of RGC dendritic field and cell number were evaluated at the end of the study. Visual outcome measures also were evaluated based on treatment of mice with P7C3-S243 or vehicle control. We show that deficits in neutral position PERG after blast-mediated TBI occur in a temporally bimodal fashion, with temporary recovery 4 weeks after injury followed by chronically persistent dysfunction 12 weeks later. This later time point is associated with development of dendritic abnormalities and irreversible death of RGCs. We also demonstrate that ongoing pathologic processes during the temporary recovery latent period (including abnormalities of RGC physiology) lead to future dysfunction of the visual system. We report that modification of PERG to provocative postural tilt testing elicits changes in PERG measurements that correlate with a key in vitro measures of damage: the spontaneous and light-evoked activity of RGCs. Treatment with P7C3-S243 immediately after injury and throughout the temporary recovery latent period protects mice from developing chronic visual system dysfunction. Provocative PERG testing serves as a noninvasive test in the living organism to identify early damage to the visual system, which may reflect corresponding damage in the brain that is not otherwise detectable by noninvasive means. This provides the basis for developing an earlier diagnostic test to identify patients at risk for developing chronic CNS and visual system damage after TBI at an earlier stage when treatments may be more effective in preventing these sequelae. In addition, treatment with the neuroprotective agent P7C3-S243 after TBI protects from visual system dysfunction after TBI. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Early Detection of Subclinical Visual Damage After Blast-Mediated TBI Enables Prevention of Chronic Visual Deficit by Treatment With P7C3-S243

PubMed Central

Dutca, Laura M.; Stasheff, Steven F.; Hedberg-Buenz, Adam; Rudd, Danielle S.; Batra, Nikhil; Blodi, Frederick R.; Yorek, Matthew S.; Yin, Terry; Shankar, Malini; Herlein, Judith A.; Naidoo, Jacinth; Morlock, Lorraine; Williams, Noelle; Kardon, Randy H.; Anderson, Michael G.; Pieper, Andrew A.; Harper, Matthew M.

2014-01-01

Purpose. Traumatic brain injury (TBI) frequently leads to chronic visual dysfunction. The purpose of this study was to investigate the effect of TBI on retinal ganglion cells (RGCs), and to test whether treatment with the novel neuroprotective compound P7C3-S243 could prevent in vivo functional deficits in the visual system. Methods. Blast-mediated TBI was modeled using an enclosed over-pressure blast chamber. The RGC physiology was evaluated using a multielectrode array and pattern electroretinogram (PERG). Histological analysis of RGC dendritic field and cell number were evaluated at the end of the study. Visual outcome measures also were evaluated based on treatment of mice with P7C3-S243 or vehicle control. Results. We show that deficits in neutral position PERG after blast-mediated TBI occur in a temporally bimodal fashion, with temporary recovery 4 weeks after injury followed by chronically persistent dysfunction 12 weeks later. This later time point is associated with development of dendritic abnormalities and irreversible death of RGCs. We also demonstrate that ongoing pathologic processes during the temporary recovery latent period (including abnormalities of RGC physiology) lead to future dysfunction of the visual system. We report that modification of PERG to provocative postural tilt testing elicits changes in PERG measurements that correlate with a key in vitro measures of damage: the spontaneous and light-evoked activity of RGCs. Treatment with P7C3-S243 immediately after injury and throughout the temporary recovery latent period protects mice from developing chronic visual system dysfunction. Conclusions. Provocative PERG testing serves as a noninvasive test in the living organism to identify early damage to the visual system, which may reflect corresponding damage in the brain that is not otherwise detectable by noninvasive means. This provides the basis for developing an earlier diagnostic test to identify patients at risk for developing chronic CNS and visual system damage after TBI at an earlier stage when treatments may be more effective in preventing these sequelae. In addition, treatment with the neuroprotective agent P7C3-S243 after TBI protects from visual system dysfunction after TBI. PMID:25468886

Choline exposure reduces potentiation of N-methyl-D-aspartate toxicity by corticosterone in the developing hippocampus.

PubMed

Mulholland, Patrick J; Self, Rachel L; Harris, Barton R; Littleton, John M; Prendergast, Mark A

2004-11-25

Exposure to high levels of glucocorticoids (GCs) may adversely affect neuronal viability, particularly in the developing hippocampus, via increased function or sensitivity of N-methyl-D-aspartate (NMDA)-type glutamate receptors. Conversely, choline supplementation in the developing brain may reduce the severity of subsequent insult. The present studies aimed to examine the extent to which short-term exposure to high concentrations of corticosterone would produce neuronal injury mediated by NMDA receptor activity. These studies also assessed the ability of choline to prevent this form of injury via interactions with nicotinic acetylcholine receptors (nAChRs) expressing the alpha7 subunit. Organotypic hippocampal slice cultures derived from neonatal rat were pre-treated for 72 h with corticosterone (100 nM) alone or with choline (0.1-10 mM), prior to a brief (1 h) NMDA exposure (5 microM). NMDA exposure produced significant cellular damage, reflected as increased fluorescence of the non-vital marker propidium iodide, in the CA1 region. While exposure to corticosterone alone did not produce damage, pre-treatment of cultures with corticosterone markedly exacerbated NMDA-induced toxicity. Pre-treatment with choline (> or =1 mM) alone or in combination with corticosterone markedly reduced subsequent NMDA toxicity, effects blocked by co-exposure to methyllycaconitine (100 nM), an antagonist active at nAChRs expressing the alpha7 subunit. These data suggest that even short-term exposure to high concentrations of GCs may adversely affect neuronal viability and that choline supplementation protects the brain from NMDA receptor-mediated damage, including that associated with hypercortisolemia.

Lead Intoxication Synergies of the Ethanol-Induced Toxic Responses in Neuronal Cells--PC12.

PubMed

Kumar, V; Tripathi, V K; Jahan, S; Agrawal, M; Pandey, A; Khanna, V K; Pant, A B

2015-12-01

Lead (Pb)-induced neurodegeneration and its link with widespread neurobehavioral changes are well documented. Experimental evidences suggest that ethanol could enhance the absorption of metals in the body, and alcohol consumption may increase the susceptibility to metal intoxication in the brain. However, the underlying mechanism of ethanol action in affecting metal toxicity in brain cells is poorly understood. Thus, an attempt was made to investigate the modulatory effect of ethanol on Pb intoxication in PC12 cells, a rat pheochromocytoma. Cells were co-exposed to biological safe doses of Pb (10 μM) and ethanol (200 mM), and data were compared to the response of cells which received independent exposure to these chemicals at similar doses. Ethanol (200 mM) exposure significantly aggravated the Pb-induced alterations in the end points associated with oxidative stress and apoptosis. The finding confirms the involvement of reactive oxygen species (ROS)-mediated oxidative stress, and impairment of mitochondrial membrane potential, which subsequently facilitate the translocation of triggering proteins between cytoplasm and mitochondria. We further confirmed the apoptotic changes due to induction of mitochondria-mediated caspase cascade. These cellular changes were found to recover significantly, if the cells are exposed to N-acetyl cysteine (NAC), a known antioxidant. Our data suggest that ethanol may potentiate Pb-induced cellular damage in brain cells, but such damaging effects could be recovered by inhibition of ROS generation. These results open up further possibilities for the design of new therapeutics based on antioxidants to prevent neurodegeneration and associated health problems.

Traumatic brain injury: an overview of pathobiology with emphasis on military populations

PubMed Central

Cernak, Ibolja; Noble-Haeusslein, Linda J

2010-01-01

This review considers the pathobiology of non-impact blast-induced neurotrauma (BINT). The pathobiology of traumatic brain injury (TBI) has been historically studied in experimental models mimicking features seen in the civilian population. These brain injuries are characterized by primary damage to both gray and white matter and subsequent evolution of secondary pathogenic events at the cellular, biochemical, and molecular levels, which collectively mediate widespread neurodegeneration. An emerging field of research addresses brain injuries related to the military, in particular blast-induced brain injuries. What is clear from the effort to date is that the pathobiology of military TBIs, particularly BINT, has characteristics not seen in other types of brain injury, despite similar secondary injury cascades. The pathobiology of primary BINT is extremely complex. It comprises systemic, local, and cerebral responses interacting and often occurring in parallel. Activation of the autonomous nervous system, sudden pressure-increase in vital organs such as lungs and liver, and activation of neuroendocrine-immune system are among the most important mechanisms significantly contributing to molecular changes and cascading injury mechanisms in the brain. PMID:19809467

Apigenin protects blood-brain barrier and ameliorates early brain injury by inhibiting TLR4-mediated inflammatory pathway in subarachnoid hemorrhage rats.

PubMed

Zhang, Tingting; Su, Jingyuan; Guo, Bingyu; Wang, Kaiwen; Li, Xiaoming; Liang, Guobiao

2015-09-01

Early brain injury (EBI) following subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. Inflammation has been considered as the major contributor to brain damage after SAH. SAH induces a systemic increase in pro-inflammatory cytokines and chemokines. Disruption of blood-brain barrier (BBB) facilitates the influx of inflammatory cells. It has been reported that the activation of toll-like receptor 4 (TLR4)/NF-κB signaling pathway plays a vital role in the central nervous system diseases. Apigenin, a common plant flavonoid, possesses anti-inflammation effect. In this study, we focused on the effects of apigenin on EBI following SAH and its anti-inflammation mechanism. Our results showed that apigenin (20mg/kg) administration significantly attenuated EBI (including brain edema, BBB disruption, neurological deficient, severity of SAH, and cell apoptosis) after SAH in rats by suppressing the expression of TLR4, NF-κB and their downstream pro-inflammatory cytokines in the cortex and by up-regulating the expression of tight junction proteins of BBB. Double immunofluorescence staining demonstrated that TLR4 was activated following SAH in neurons, microglia cells, and endothelial cells but not in astrocytes. Apigenin could suppress the activation of TLR4 induced by SAH and inhibit apoptosis of cells in the cortex. These results suggested that apigenin could attenuate EBI after SAH in rats by suppressing TLR4-mediated inflammation and protecting against BBB disruption. Copyright © 2015 Elsevier B.V. All rights reserved.

Antioxidant mediated response of Scoparia dulcis in noise-induced redox imbalance and immunohistochemical changes in rat brain.

PubMed

Wankhar, Wankupar; Srinivasan, Sakthivel; Rajan, Ravindran; Sheeladevi, Rathinasamy

2017-01-19

Noise has been regarded as an environmental/occupational stressor that causes damages to both auditory and non-auditory organs. Prolonged exposure to these mediators of stress has often resulted in detrimental effect, where oxidative/nitrosative stress plays a major role. Hence, it would be appropriate to examine the possible role of free radicals in brain discrete regions and the "antioxidants" mediated response of S. dulcis. Animals were subjected to noise stress for 15 days (100 dB/4 hours/day) and estimation of endogenous free radical and antioxidant activity were carried out on brain discrete regions (the cerebral cortex, cerebellum, brainstem, striatum, hippocampus and hypothalamus). The result showed that exposure to noise could alleviate endogenous free radical generation and altered antioxidant status in brain discrete regions when compared to that of the control groups. This alleviated free radical generation (H 2 O 2 and NO) is well supported by an upregulated protein expression on immunohistochemistry of both iNOS and nNOS in the cerebral cortex on exposure to noise stress. These findings suggest that increased free radical generation and altered anti-oxidative status can cause redox imbalance in the brain discrete regions. However, free radical scavenging activity of the plant was evident as the noise exposed group treated with S. dulcis[200 mg/(kg·b·w)] displayed a therapeutic effect by decreasing the free radical level and regulate the anti-oxidative status to that of control animals. Hence, it can be concluded that the efficacy of S. dulcis could be attributed to its free radical scavenging activity and anti-oxidative property.

Antioxidant mediated response of Scoparia dulcis in noise-induced redox imbalance and immunohistochemical changes in rat brain

PubMed Central

Wankhar, Wankupar; Srinivasan, Sakthivel; Rajan, Ravindran; Sheeladevi, Rathinasamy

2017-01-01

Noise has been regarded as an environmental/occupational stressor that causes damages to both auditory and non-auditory organs. Prolonged exposure to these mediators of stress has often resulted in detrimental effect, where oxidative/nitrosative stress plays a major role. Hence, it would be appropriate to examine the possible role of free radicals in brain discrete regions and the "antioxidants" mediated response of S. dulcis. Animals were subjected to noise stress for 15 days (100 dB/4 hours/day) and estimation of endogenous free radical and antioxidant activity were carried out on brain discrete regions (the cerebral cortex, cerebellum, brainstem, striatum, hippocampus and hypothalamus). The result showed that exposure to noise could alleviate endogenous free radical generation and altered antioxidant status in brain discrete regions when compared to that of the control groups. This alleviated free radical generation (H2O2 and NO) is well supported by an upregulated protein expression on immunohistochemistry of both iNOS and nNOS in the cerebral cortex on exposure to noise stress. These findings suggest that increased free radical generation and altered anti-oxidative status can cause redox imbalance in the brain discrete regions. However, free radical scavenging activity of the plant was evident as the noise exposed group treated with S. dulcis[200 mg/(kg·b·w)] displayed a therapeutic effect by decreasing the free radical level and regulate the anti-oxidative status to that of control animals. Hence, it can be concluded that the efficacy of S. dulcis could be attributed to its free radical scavenging activity and anti-oxidative property. PMID:28808196

Comprehension of Idioms in Turkish Aphasic Participants.

PubMed

Aydin, Burcu; Barin, Muzaffer; Yagiz, Oktay

2017-12-01

Brain damaged participants offer an opportunity to evaluate the cognitive and linguistic processes and make assumptions about how the brain works. Cognitive linguists have been investigating the underlying mechanisms of idiom comprehension to unravel the ongoing debate on hemispheric specialization in figurative language comprehension. The aim of this study is to evaluate and compare the comprehension of idiomatic expressions in left brain damaged (LBD) aphasic, right brain damaged (RBD) and healthy control participants. Idiom comprehension in eleven LBD aphasic participants, ten RBD participants and eleven healthy control participants were assessed with three tasks: String to Picture Matching Task, Literal Sentence Comprehension Task and Oral Idiom Definition Task. The results of the tasks showed that in overall idiom comprehension category, the left brain-damaged aphasic participants interpret idioms more literally compared to right brain-damaged participants. What is more, there is a significant difference in opaque idiom comprehension implying that left brain-damaged aphasic participants perform worse compared to right brain-damaged participants. On the other hand, there is no statistically significant difference in scores of transparent idiom comprehension between the left brain-damaged aphasic and right brain-damaged participants. This result also contribute to the idea that while figurative processing system is damaged in LBD aphasics, the literal comprehension mechanism is spared to some extent. The results of this study support the view that idiom comprehension sites are mainly left lateralized. Furthermore, the results of this study are in consistence with the Giora's Graded Salience Hypothesis.

Selective deficit in personal moral judgment following damage to ventromedial prefrontal cortex.

PubMed

Ciaramelli, Elisa; Muccioli, Michela; Làdavas, Elisabetta; di Pellegrino, Giuseppe

2007-06-01

Recent fMRI evidence has detected increased medial prefrontal activation during contemplation of personal moral dilemmas compared to impersonal ones, which suggests that this cortical region plays a role in personal moral judgment. However, functional imaging results cannot definitively establish that a brain area is necessary for a particular cognitive process. This requires evidence from lesion techniques, such as studies of human patients with focal brain damage. Here, we tested 7 patients with lesions in the ventromedial prefrontal cortex and 12 healthy individuals in personal moral dilemmas, impersonal moral dilemmas and non-moral dilemmas. Compared to normal controls, patients were more willing to judge personal moral violations as acceptable behaviors in personal moral dilemmas, and they did so more quickly. In contrast, their performance in impersonal and non-moral dilemmas was comparable to that of controls. These results indicate that the ventromedial prefrontal cortex is necessary to oppose personal moral violations, possibly by mediating anticipatory, self-focused, emotional reactions that may exert strong influence on moral choice and behavior.

Neuropsychology and the neurochemical lesion: evolution, applications and extensions.

PubMed

Hartman, D E

1988-01-01

The evolution of neuropsychology into a method for neurotoxic damage detection is reviewed. When neuropsychology is transformed into "neuropsychological toxicology", fundamental philosophical assumptions of the field are altered; the search for brain-behavior relationships must extend from structural damage into the analysis of neurochemical systems. The complementary relationship of human neuropsychology to basic toxicological and animal research is discussed. The great numbers of human "natural experiments" whose employment, medical history or substance abuse subjects them to contact with neurotoxic substances, suggest that there is a great need for expanded human investigations involving neuropsychological testing procedures in the service of research and clinical identification of neurotoxic syndromes. Further, it is argued that neurobehavioral procedures originally developed to detect industrial neurotoxic exposure will prove additionally useful assessing other brain-behavior disruptions mediated by neurochemistry or neurotoxicity rather than structural lesion. These frontiers include physical or emotional illness, substance abuse, effects of abused or prescription drugs as well as little-researched areas deserving of closer study, e.g., allergens or biotoxic exposure.

Selective deficit in personal moral judgment following damage to ventromedial prefrontal cortex

PubMed Central

Ciaramelli, Elisa; Muccioli, Michela; Làdavas, Elisabetta

2007-01-01

Recent fMRI evidence has detected increased medial prefrontal activation during contemplation of personal moral dilemmas compared to impersonal ones, which suggests that this cortical region plays a role in personal moral judgment. However, functional imaging results cannot definitively establish that a brain area is necessary for a particular cognitive process. This requires evidence from lesion techniques, such as studies of human patients with focal brain damage. Here, we tested 7 patients with lesions in the ventromedial prefrontal cortex and 12 healthy individuals in personal moral dilemmas, impersonal moral dilemmas and non-moral dilemmas. Compared to normal controls, patients were more willing to judge personal moral violations as acceptable behaviors in personal moral dilemmas, and they did so more quickly. In contrast, their performance in impersonal and non-moral dilemmas was comparable to that of controls. These results indicate that the ventromedial prefrontal cortex is necessary to oppose personal moral violations, possibly by mediating anticipatory, self-focused, emotional reactions that may exert strong influence on moral choice and behavior. PMID:18985127

Silencing microRNA-143 protects the integrity of the blood-brain barrier: implications for methamphetamine abuse

PubMed Central

Bai, Ying; Zhang, Yuan; Hua, Jun; Yang, Xiangyu; Zhang, Xiaotian; Duan, Ming; Zhu, Xinjian; Huang, Wenhui; Chao, Jie; Zhou, Rongbin; Hu, Gang; Yao, Honghong

2016-01-01

MicroRNA-143 (miR-143) plays a critical role in various cellular processes; however, the role of miR-143 in the maintenance of blood-brain barrier (BBB) integrity remains poorly defined. Silencing miR-143 in a genetic animal model or via an anti-miR-143 lentivirus prevented the BBB damage induced by methamphetamine. miR-143, which targets p53 unregulated modulator of apoptosis (PUMA), increased the permeability of human brain endothelial cells and concomitantly decreased the expression of tight junction proteins (TJPs). Silencing miR-143 increased the expression of TJPs and protected the BBB integrity against the effects of methamphetamine treatment. PUMA overexpression increased the TJP expression through a mechanism that involved the NF-κB and p53 transcription factor pathways. Mechanistically, methamphetamine mediated up-regulation of miR-143 via sigma-1 receptor with sequential activation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3′ kinase (PI3K)/Akt and STAT3 pathways. These results indicated that silencing miR-143 could provide a novel therapeutic strategy for BBB damage-related vascular dysfunction. PMID:27767041

Dendritic Degeneration, Neurovascular Defects, and Inflammation Precede Neuronal Loss in a Mouse Model for Tau-Mediated Neurodegeneration

PubMed Central

Jaworski, Tomasz; Lechat, Benoit; Demedts, David; Gielis, Lies; Devijver, Herman; Borghgraef, Peter; Duimel, Hans; Verheyen, Fons; Kügler, Sebastian; Van Leuven, Fred

2011-01-01

Adeno-associated virus (AAV)–mediated expression of wild-type or mutant P301L protein tau produces massive degeneration of pyramidal neurons without protein tau aggregation. We probed this novel model for genetic and structural factors and early parameters of pyramidal neurodegeneration. In yellow fluorescent protein–expressing transgenic mice, intracerebral injection of AAV-tauP301L revealed early damage to apical dendrites of CA1 pyramidal neurons, whereas their somata remained normal. Ultrastructurally, more and enlarged autophagic vacuoles were contained in degenerating dendrites and manifested as dark, discontinuous, vacuolated processes surrounded by activated astrocytes. Dendritic spines were lost in AAV-tauP301L–injected yellow fluorescent protein–expressing transgenic mice, and ultrastructurally, spines appeared dark and degenerating. In CX3CR1EGFP/EGFP-deficient mice, microglia were recruited early to neurons expressing human tau. The inflammatory response was accompanied by extravasation of plasma immunoglobulins. α2-Macroglobulin, but neither albumin nor transferrin, became lodged in the brain parenchyma. Large proteins, but not Evans blue, entered the brain of mice injected with AAV-tauP301L. Ultrastructurally, brain capillaries were constricted and surrounded by swollen astrocytes with extensions that contacted degenerating dendrites and axons. Together, these data corroborate the hypothesis that neuroinflammation participates essentially in tau-mediated neurodegeneration, and the model recapitulates early dendritic defects reminiscent of “dendritic amputation” in Alzheimer's disease. PMID:21839061

Is slack an intrinsic seizure terminator?

PubMed

Igelström, Kajsa M

2013-06-01

Understanding how epileptic seizures are initiated and propagated across large brain networks is difficult, but an even greater mystery is what makes them stop. Failure of spontaneous seizure termination leads to status epilepticus-a state of uninterrupted seizure activity that can cause death or permanent brain damage. Global factors, like changes in neuromodulators and ion concentrations, are likely to play major roles in spontaneous seizure cessation, but individual neurons also have intrinsic active ion currents that may contribute. The recently discovered gene Slack encodes a sodium-activated potassium channel that mediates a major proportion of the outward current in many neurons. Although given little attention, the current flowing through this channel may have properties consistent with a role in seizure termination.

Magnolol protects against oxidative stress-mediated neural cell damage by modulating mitochondrial dysfunction and PI3K/Akt signaling.

PubMed

Dong, Liqun; Zhou, Shu; Yang, Xiaohua; Chen, Qianming; He, Yang; Huang, Wen

2013-07-01

Magnolol, an orally available compound from Magnolia officinalis used widely in traditional herbal medicine against a variety of neuronal diseases, possesses potent antioxidant properties and protects the brain against oxidative damage. The aim of the work is to examine the protective mechanisms of magnolol on human neuroblastoma SH-SY5Y cells against apoptosis induced by the neurotoxin acrolein, which can cause neurodegenerative disorders by inducing oxidative stress. By investigating the effect of magnolol on neural cell damage induced by the neurotoxin acrolein, we found that magnolol pretreatment significantly attenuated acrolein-induced oxidative stress through inhibiting reactive oxygen species accumulation caused by intracellular glutathione depletion and nicotinamide adenine dinucleotide phosphate oxidase activation. We next examined the signaling cascade(s) involved in magnolol-mediated antiapoptotic effects. The results showed that acrolein induced SH-SY5Y cell apoptosis by activating mitochondria/caspase and MEK/ERK signaling pathways. Our findings provide the first evidence that magnolol protects SH-SY5Y cells against acrolein-induced oxidative stress and prolongs SH-SY5Y cell survival through regulating JNK/mitochondria/caspase, PI3K/MEK/ERK, and PI3K/Akt/FoxO1 signaling pathways.

6-mercaptopurine (6-MP) induces p53-mediated apoptosis of neural progenitor cells in the developing fetal rodent brain.

PubMed

Kanemitsu, H; Yamauchi, H; Komatsu, M; Yamamoto, S; Okazaki, S; Uchida, K; Nakayama, H

2009-01-01

6-mercaptopurine (6-MP), a DNA-damaging agent, induces apoptosis of neural progenitor cells, and causes malformation in the fetal brain. The aim of the present study is to clarify the molecular pathway of 6-MP-induced apoptosis of neural progenitor cells in the fetal telencephalon of rats and mice. p53 protein is activated by DNA damage and induces apoptosis through either the intrinsic pathway involving the mitochondria or the extrinsic pathway triggered by death receptors. In this study, the expression of puma and cleaved caspase-9 proteins, which are specific intrinsic pathway factors, increased in the rat telencephalon after 6-MP treatment. 6-MP-induced apoptosis of neural progenitor cells was completely absent in p53-deficient mice. On the other hand, the expression of Fas protein, an extrinsic pathway factor, did not change throughout the experimental period in the rat telencephalon treated with 6-MP. The number of apoptotic neural progenitor cells was similar among Fas-mutated lpr/lpr and wild-type mice, suggesting that the Fas pathway does not play a significant role in 6-MP-induced apoptosis of neural progenitor cells. These results may suggest that the p53-mediated intrinsic pathway is essential for 6-MP-induced apoptosis of neural progenitor cells in the developing telencephalon of rats and mice.

2-Chlorohexadecanoic acid induces ER stress and mitochondrial dysfunction in brain microvascular endothelial cells.

PubMed

Bernhart, Eva; Kogelnik, Nora; Prasch, Jürgen; Gottschalk, Benjamin; Goeritzer, Madeleine; Depaoli, Maria Rosa; Reicher, Helga; Nusshold, Christoph; Plastira, Ioanna; Hammer, Astrid; Fauler, Günter; Malli, Roland; Graier, Wolfgang F; Malle, Ernst; Sattler, Wolfgang

2018-05-01

Peripheral leukocytes induce blood-brain barrier (BBB) dysfunction through the release of cytotoxic mediators. These include hypochlorous acid (HOCl) that is formed via the myeloperoxidase-H 2 O 2 -chloride system of activated phagocytes. HOCl targets the endogenous pool of ether phospholipids (plasmalogens) generating chlorinated inflammatory mediators like e.g. 2-chlorohexadecanal and its conversion product 2-chlorohexadecanoic acid (2-ClHA). In the cerebrovasculature these compounds inflict damage to brain microvascular endothelial cells (BMVEC) that form the morphological basis of the BBB. To follow subcellular trafficking of 2-ClHA we synthesized a 'clickable' alkyne derivative (2-ClHyA) that phenocopied the biological activity of the parent compound. Confocal and superresolution structured illumination microscopy revealed accumulation of 2-ClHyA in the endoplasmic reticulum (ER) and mitochondria of human BMVEC (hCMEC/D3 cell line). 2-ClHA and its alkyne analogue interfered with protein palmitoylation, induced ER-stress markers, reduced the ER ATP content, and activated transcription and secretion of interleukin (IL)-6 as well as IL-8. 2-ClHA disrupted the mitochondrial membrane potential and induced procaspase-3 and PARP cleavage. The protein kinase R-like ER kinase (PERK) inhibitor GSK2606414 suppressed 2-ClHA-mediated activating transcription factor 4 synthesis and IL-6/8 secretion, but showed no effect on endothelial barrier dysfunction and cleavage of procaspase-3. Our data indicate that 2-ClHA induces potent lipotoxic responses in brain endothelial cells and could have implications in inflammation-induced BBB dysfunction. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Caveolin-1 mediates tissue plasminogen activator-induced MMP-9 up-regulation in cultured brain microvascular endothelial cells.

PubMed

Jin, Xinchun; Sun, Yanyun; Xu, Ji; Liu, Wenlan

2015-03-01

Thrombolysis with tissue plasminogen activator (tPA) increases matrix metalloproteinase-9 (MMP-9) activity in the ischemic brain, which exacerbates blood-brain barrier injury and increases the risk of symptomatic cerebral hemorrhage. The mechanism through which tPA enhances MMP-9 activity is not well understood. Here we report an important role of caveolin-1 in mediating tPA-induced MMP-9 synthesis. Brain microvascular endothelial cell line bEnd3 cells were incubated with 5 or 20 μg/ml tPA for 24 hrs before analyzing MMP-9 levels in the conditioned media and cellular extracts by gelatin zymography. tPA at a dose of 20 μg/mL tPA, but not 5 μg/mL, significantly increased MMP-9 level in cultured media while decreasing it in cellular extracts. Concurrently, tPA treatment induced a 2.3-fold increase of caveolin-1 protein levels in endothelial cells. Interestingly, knockdown of Cav-1 with siRNA inhibited tPA-induced MMP-9 mRNA up-regulation and MMP-9 increase in the conditioned media, but did not affect MMP-9 decrease in cellular extracts. These results suggest that caveolin-1 critically contributes to tPA-mediated MMP-9 up-regulation, but may not facilitate MMP-9 secretion in endothelial cells. Thrombolysis with tissue plasminogen activator (tPA) increases matrix metalloproteinase-9 (MMP-9) activity in the ischemic brain, which exacerbates ischemic blood brain barrier (BBB) injury and increases the risk of symptomatic cerebral hemorrhage. Our results suggest a novel mechanism underlying this tPA-MMP 9 axis. In response to tPA treatment, caveolin-1 protein levels increased in endothelial cells, which mediate MMP-9 mRNA up-regulation and its secretion into extracellular space. Caveolin-1 may, however, not facilitate MMP-9 secretion in endothelial cells. Our data suggest caveolin-1 as a novel therapeutic target for protecting the BBB against ischemic damage. The schematic outlines tPA-induced MMP-9 upreguation. © 2015 International Society for Neurochemistry.

HO-1-mediated macroautophagy: a mechanism for unregulated iron deposition in aging and degenerating neural tissues.

PubMed

Zukor, Hillel; Song, Wei; Liberman, Adrienne; Mui, Jeannie; Vali, Hojatollah; Fillebeen, Carine; Pantopoulos, Kostas; Wu, Ting-Di; Guerquin-Kern, Jean-Luc; Schipper, Hyman M

2009-05-01

Oxidative stress, deposition of non-transferrin iron, and mitochondrial insufficiency occur in the brains of patients with Alzheimer disease (AD) and Parkinson disease (PD). We previously demonstrated that heme oxygenase-1 (HO-1) is up-regulated in AD and PD brain and promotes the accumulation of non-transferrin iron in astroglial mitochondria. Herein, dynamic secondary ion mass spectrometry (SIMS) and other techniques were employed to ascertain (i) the impact of HO-1 over-expression on astroglial mitochondrial morphology in vitro, (ii) the topography of aberrant iron sequestration in astrocytes over-expressing HO-1, and (iii) the role of iron regulatory proteins (IRP) in HO-1-mediated iron deposition. Astroglial hHO-1 over-expression induced cytoplasmic vacuolation, mitochondrial membrane damage, and macroautophagy. HO-1 promoted trapping of redox-active iron and sulfur within many cytopathological profiles without impacting ferroportin, transferrin receptor, ferritin, and IRP2 protein levels or IRP1 activity. Thus, HO-1 activity promotes mitochondrial macroautophagy and sequestration of redox-active iron in astroglia independently of classical iron mobilization pathways. Glial HO-1 may be a rational therapeutic target in AD, PD, and other human CNS conditions characterized by the unregulated deposition of brain iron.

Causes of CNS inflammation and potential targets for anticonvulsants.

PubMed

Falip, Mercé; Salas-Puig, Xavier; Cara, Carlos

2013-08-01

Inflammation is one of the most important endogenous defence mechanisms in an organism. It has been suggested that inflammation plays an important role in the pathophysiology of a number of human epilepsies and convulsive disorders, and there is clinical and experimental evidence to suggest that inflammatory processes within the CNS may either contribute to or be a consequence of epileptogenesis. This review discusses evidence from human studies on the role of inflammation in epilepsy and highlights potential new targets in the inflammatory cascade for antiepileptic drugs. A number of mechanisms have been shown to be involved in CNS inflammatory reactions. These include an inflammatory response at the level of the blood-brain barrier (BBB), immune-mediated damage to the CNS, stress-induced release of inflammatory mediators and direct neuronal dysfunction or damage as a result of inflammatory reactions. Mediators of inflammation in the CNS include interleukin (IL)-1β, tumour necrosis factor-α, nuclear factor-κB and toll-like receptor-4 (TLR4). IL-1β, BBB and high-mobility group box-1-TLR4 signalling appear to be the most promising targets for anticonvulsant agents directed at inflammation. Such agents may provide effective therapy for drug-resistant epilepsies in the future.

Morus alba leaf extract mediates neuroprotection against glyphosate-induced toxicity and biochemical alterations in the brain.

PubMed

Rebai, Olfa; Belkhir, Manel; Boujelben, Adnen; Fattouch, Sami; Amri, Mohamed

2017-04-01

Recent studies demonstrate that glyphosate exposure is associated with oxidative stress and some neurological disorders such as Parkinson's pathology. Therefore, phytochemicals, in particular phenolic compounds, have attracted increasing attention as potential agents for neuroprotection. In the present study, we investigate the impact of glyphosate on the rat brain following i.p. injection and the possible molecular target of neuroprotective activity of the phenolic fraction from Morus alba leaf extract (MALE) and its ability to reduce oxidative damage in the brain. Wistar rats from 180 to 240 g were i.p. treated with a single dose of glyphosate (100 mg kg -1 b.w.) or MALE (100 μg mL -1  kg -1 b.w.) for 2 weeks. Brain homogenates were used to evaluate neurotoxicity induced by the pesticide. For this, biochemical parameters were measured. Data shows that MALE regulated oxidative stress and counteracted glyphosate-induced deleterious effects and oxidative damage in the brain, as it abrogated LDH, protein carbonyls, and malonyldialdehyde. MALE also appears to be able to scavenge H 2 O 2 levels, maintain iron and Ca 2+ homeostasis, and increase SOD activity. Thus, in vivo results showed that mulberry leaf extract is a potent protector against glyphosate-induced toxicity, and its protective effect could result from synergism or antagonism between the various bioactive phenolic compounds in the acetonic fraction from M. alba leaf extract.

NNZ-2566 treatment inhibits neuroinflammation and pro-inflammatory cytokine expression induced by experimental penetrating ballistic-like brain injury in rats

PubMed Central

Wei, Hans H; Lu, Xi-Chun M; Shear, Deborah A; Waghray, Anu; Yao, Changping; Tortella, Frank C; Dave, Jitendra R

2009-01-01

Background Inflammatory cytokines play a crucial role in the pathophysiology of traumatic brain injury (TBI), exerting either deleterious effects on the progression of tissue damage or beneficial roles during recovery and repair. NNZ-2566, a synthetic analogue of the neuroprotective tripeptide Glypromate®, has been shown to be neuroprotective in animal models of brain injury. The goal of this study was to determine the effects of NNZ-2566 on inflammatory cytokine expression and neuroinflammation induced by penetrating ballistic-like brain injury (PBBI) in rats. Methods NNZ-2566 or vehicle (saline) was administered intravenously as a bolus injection (10 mg/kg) at 30 min post-injury, immediately followed by a continuous infusion of NNZ-2566 (3 mg/kg/h), or equal volume of vehicle, for various durations. Inflammatory cytokine gene expression from the brain tissue of rats exposed to PBBI was evaluated using microarray, quantitative real time PCR (QRT-PCR), and enzyme-linked immunosorbent assay (ELISA) array. Histopathology of the injured brains was examined using hematoxylin and eosin (H&E) and immunocytochemistry of inflammatory cytokine IL-1β. Results NNZ-2566 treatment significantly reduced injury-mediated up-regulation of IL-1β, TNF-α, E-selectin and IL-6 mRNA during the acute injury phase. ELISA cytokine array showed that NZ-2566 treatment significantly reduced levels of the pro-inflammatory cytokines IL-1β, TNF-α and IFN-γ in the injured brain, but did not affect anti-inflammatory cytokine IL-6 levels. Conclusion Collectively, these results suggest that the neuroprotective effects of NNZ-2566 may, in part, be functionally attributed to the compound's ability to modulate expression of multiple neuroinflammatory mediators in the injured brain. PMID:19656406

Hemispheric processing of vocal emblem sounds.

PubMed

Neumann-Werth, Yael; Levy, Erika S; Obler, Loraine K

2013-01-01

Vocal emblems, such as shh and brr, are speech sounds that have linguistic and nonlinguistic features; thus, it is unclear how they are processed in the brain. Five adult dextral individuals with left-brain damage and moderate-severe Wernicke's aphasia, five adult dextral individuals with right-brain damage, and five Controls participated in two tasks: (1) matching vocal emblems to photographs ('picture task') and (2) matching vocal emblems to verbal translations ('phrase task'). Cross-group statistical analyses on items on which the Controls performed at ceiling revealed lower accuracy by the group with left-brain damage (than by Controls) on both tasks, and lower accuracy by the group with right-brain damage (than by Controls) on the picture task. Additionally, the group with left-brain damage performed significantly less accurately than the group with right-brain damage on the phrase task only. Findings suggest that comprehension of vocal emblems recruits more left- than right-hemisphere processing.

Neuroinflammation markers and methyl alcohol induced toxic brain damage.

PubMed

Zakharov, Sergey; Hlusicka, Jiri; Nurieva, Olga; Kotikova, Katerina; Lischkova, Lucie; Kacer, Petr; Kacerova, Tereza; Urban, Pavel; Vaneckova, Manuela; Seidl, Zdenek; Diblik, Pavel; Kuthan, Pavel; Heissigerova, Jarmila; Lesovsky, Jiri; Rulisek, Jan; Vojtova, Lucie; Hubacek, Jaroslav A; Navratil, Tomas

2018-05-04

Methyl alcohol intoxication is a global problem with high mortality and long-term visual sequelae and severe brain damage in survivors. The role of neuroinflammation in the mechanisms of methyl alcohol-induced toxic brain damage has not been well studied. We measured the acute concentrations and dynamics of lipoxins LxA4 and LxB4 and the interleukins IL-4, IL-5, IL-9, IL-10, and IL-13 in the serum of patients treated with methyl alcohol poisoning and the follow-up concentrations in survivors two years after discharge from the hospital. A series of acute measurements was performed in 28 hospitalized patients (mean age 54.2 ± 5.2 years, mean observation time 88 ± 20 h) and the follow-up measurements were performed in 36 subjects who survived poisoning (including 12/28 survivors from the acute group). Visual evoked potentials (VEP) and magnetic resonance imaging of the brain (MRI) were performed to detect long-term visual and brain sequelae of intoxication. The acute concentrations of inflammatory mediators were higher than the follow-up concentrations: LxA4, 62.0 ± 6.0 vs. 30.0 ± 5.0 pg/mL; LxB4, 64.0 ± 7.0 vs. 34.0 ± 4.0 pg/mL; IL-4, 29.0 ± 4.0 vs. 15.0 ± 1.0 pg/mL; IL-5, 30.0 ± 4.0 vs. 13.0 ± 1.0 pg/mL; IL-9, 30.0 ± 4.0 vs. 13.0 ± 1.0 pg/mL; IL-10, 38.0 ± 5.0 vs. 16.0 ± 1.0 pg/mL; IL-13, 35.0 ± 4.0 vs. 14.0 ± 1.0 pg/mL (all p < 0.001). The patients with higher follow-up IL-5 concentration had prolonged latency P1 (r = 0.413; p = 0.033) and lower amplitude N1P1 (r = -0.498; p = 0.010) of VEP. The higher follow-up IL-10 concentration was associated with MRI signs of brain necrotic damage (r = 0.533; p = 0.001) and brain hemorrhage (r = 0.396; p = 0.020). Our findings suggest that neuroinflammation plays an important role in the mechanisms of toxic brain damage in acute methyl alcohol intoxication. Copyright © 2018 Elsevier B.V. All rights reserved.

B7-H3 Augments Inflammatory Responses and Exacerbates Brain Damage via Amplifying NF-κB p65 and MAPK p38 Activation during Experimental Pneumococcal Meningitis

PubMed Central

Chen, Xuqin; Li, Yan; Blankson, Siobhan; Liu, Min; Huang, Danping; Redmond, H. Paul; Huang, Jing; Wang, Jiang Huai; Wang, Jian

2017-01-01

The costimulatory protein B7-H3 has been shown to play a contributory role in the development and progression of experimental pneumococcal meningitis by augmentation of the innate immunity-associated inflammatory response via a TLR2-dependent manner. This study aimed to clarify the component(s) of TLR2-mediated signal transduction pathways responsible for B7-H3-augmented inflammatory response and subsequent brain damage during experimental pneumococcal meningitis. Administration of B7-H3 did not augment expression of TLR2 and other TLR2 upstream components, but led to an enhanced formation of MyD88-IRAK immunocomplex in the brain of S. pneumoniae-infected mice. Furthermore, B7-H3 substantially augmented S. pneumoniae-induced activation of TLR2 downstream NF-κB p65 and MAPK p38 pathways in the brain of S. pneumoniae-infected mice. Notably, blockage of NF-κB p65 and/or MAPK p38 with their specific inhibitors strongly attenuated B7-H3-amplified inflammatory response with significantly reduced proinflammatory cytokine and chemokine production, and markedly ameliorated B7-H3-exacerbated disruption of blood-brain barrier and severity of disease status in S. pneumoniae-infected mice. These results indicate that targeting NF-κB p65 and/or MAPK p38 may represent a promising therapeutic option for amelioration of overwhelming inflammatory response-associated brain injury frequently observed during pneumococcal meningitis. PMID:28141831

Role of the ubiquitin-proteasome system in brain ischemia: friend or foe?

PubMed

Caldeira, Margarida V; Salazar, Ivan L; Curcio, Michele; Canzoniero, Lorella M T; Duarte, Carlos B

2014-01-01

The ubiquitin-proteasome system (UPS) is a catalytic machinery that targets numerous cellular proteins for degradation, thus being essential to control a wide range of basic cellular processes and cell survival. Degradation of intracellular proteins via the UPS is a tightly regulated process initiated by tagging a target protein with a specific ubiquitin chain. Neurons are particularly vulnerable to any change in protein composition, and therefore the UPS is a key regulator of neuronal physiology. Alterations in UPS activity may induce pathological responses, ultimately leading to neuronal cell death. Brain ischemia triggers a complex series of biochemical and molecular mechanisms, such as an inflammatory response, an exacerbated production of misfolded and oxidized proteins, due to oxidative stress, and the breakdown of cellular integrity mainly mediated by excitotoxic glutamatergic signaling. Brain ischemia also damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated proteins, contribute to the accumulation of ubiquitin-containing proteinaceous deposits. Despite recent advances, the factors leading to deposition of such aggregates after cerebral ischemic injury remain poorly understood. This review discusses the current knowledge on the role of the UPS in brain function and the molecular mechanisms contributing to UPS dysfunction in brain ischemia with consequent accumulation of ubiquitin-containing proteins. Chemical inhibitors of the proteasome and small molecule inhibitors of deubiquitinating enzymes, which promote the degradation of proteins by the proteasome, were both shown to provide neuroprotection in brain ischemia, and this apparent contradiction is also discussed in this review. Copyright © 2013 Elsevier Ltd. All rights reserved.

Mechanisms of neurotoxicity induced in the developing brain of mice and rats by DNA-damaging chemicals.

PubMed

Doi, Kunio

2011-01-01

It is not widely known how the developing brain responds to extrinsic damage, although the developing brain is considered to be sensitive to diverse environmental factors including DNA-damaging agents. This paper reviews the mechanisms of neurotoxicity induced in the developing brain of mice and rats by six chemicals (ethylnitrosourea, hydroxyurea, 5-azacytidine, cytosine arabinoside, 6-mercaptopurine and etoposide), which cause DNA damage in different ways, especially from the viewpoints of apoptosis and cell cycle arrest in neural progenitor cells. In addition, this paper also reviews the repair process following damage in the developing brain.

Emergence of realism: Enhanced visual artistry and high accuracy of visual numerosity representation after left prefrontal damage.

PubMed

Takahata, Keisuke; Saito, Fumie; Muramatsu, Taro; Yamada, Makiko; Shirahase, Joichiro; Tabuchi, Hajime; Suhara, Tetsuya; Mimura, Masaru; Kato, Motoichiro

2014-05-01

Over the last two decades, evidence of enhancement of drawing and painting skills due to focal prefrontal damage has accumulated. It is of special interest that most artworks created by such patients were highly realistic ones, but the mechanism underlying this phenomenon remains to be understood. Our hypothesis is that enhanced tendency of realism was associated with accuracy of visual numerosity representation, which has been shown to be mediated predominantly by right parietal functions. Here, we report a case of left prefrontal stroke, where the patient showed enhancement of artistic skills of realistic painting after the onset of brain damage. We investigated cognitive, functional and esthetic characteristics of the patient׳s visual artistry and visual numerosity representation. Neuropsychological tests revealed impaired executive function after the stroke. Despite that, the patient׳s visual artistry related to realism was rather promoted across the onset of brain damage as demonstrated by blind evaluation of the paintings by professional art reviewers. On visual numerical cognition tasks, the patient showed higher performance in comparison with age-matched healthy controls. These results paralleled increased perfusion in the right parietal cortex including the precuneus and intraparietal sulcus. Our data provide new insight into mechanisms underlying change in artistic style due to focal prefrontal lesion. Copyright © 2014 Elsevier Ltd. All rights reserved.

Paeoniflorin protects against ischemia-induced brain damages in rats via inhibiting MAPKs/NF-κB-mediated inflammatory responses.

PubMed

Guo, Ruo-Bing; Wang, Guo-Feng; Zhao, An-Peng; Gu, Jun; Sun, Xiu-Lan; Hu, Gang

2012-01-01

Paeoniflorin (PF), the principal component of Paeoniae Radix prescribed in traditional Chinese medicine, has been reported to exhibit many pharmacological effects including protection against ischemic injury. However, the mechanisms underlying the protective effects of PF on cerebral ischemia are still under investigation. The present study showed that PF treatment for 14 days could significantly inhibit transient middle cerebral artery occlusion (MCAO)-induced over-activation of astrocytes and microglia, and prevented up-regulations of pro-inflamamtory mediators (TNFα, IL-1β, iNOS, COX(2) and 5-LOX) in plasma and brain. Further study demonstrated that chronic treatment with PF suppressed the activations of JNK and p38 MAPK, but enhanced ERK activation. And PF could reverse ischemia-induced activation of NF-κB signaling pathway. Moreover, our in vitro study revealed that PF treatment protected against TNFα-induced cell apoptosis and neuronal loss. Taken together, the present study demonstrates that PF produces a delayed protection in the ischemia-injured rats via inhibiting MAPKs/NF-κB mediated peripheral and cerebral inflammatory response. Our study reveals that PF might be a potential neuroprotective agent for stroke.

Nicotine and estrogen synergistically exacerbate cerebral ischemic injury.

PubMed

Raval, A P; Hirsch, N; Dave, K R; Yavagal, D R; Bramlett, H; Saul, I

2011-05-05

The greater incidence of myocardial infarction, cardiac arrest, and ischemic stroke among women who smoke and use oral contraception (OC) compared to women who do not smoke and who do or do not use OC may be due in part to how nicotine influences endocrine function in women. For example, we recently demonstrated that chronic exposure to nicotine, the addictive agent in tobacco smoke responsible for the elevated risk of cardiac arrest, abolishes the endogenous or exogenous 17β-estradiol-conferred protection of the hippocampus against global cerebral ischemia (a potential outcome of cardiac arrest) in naive or ovariectomized female rats. In the current study we examined the hypotheses that (1) a synergistic deleterious effect of nicotine plus oral contraceptives exacerbates post-ischemic hippocampal damage in female rats, and (2) nicotine directly inhibits estrogen-mediated intracellular signaling in the hippocampus. To test first hypothesis and to simulate smoking behavior-induced nicotine levels in the human body, we implanted osmotic pumps containing nicotine in the female rats for 16 days. Furthermore, we mimicked the use of oral contraceptives in females by administering oral contraceptives orally to the rat. Rats exposed to either nicotine alone or in combination with oral contraceptives were subjected to an episode of cerebral ischemia and the resultant brain damage was quantified. These results showed for the first time that nicotine with oral contraceptives did indeed exacerbate post-ischemic CA1 damage as compared to nicotine alone in naive female rats. In ex vivo hippocampal slice cultures, we found that nicotine alone or with 17β-estradiol directly hinders estrogen receptors-mediated phosphorylation of cyclic-AMP element binding protein, a process required for neuronal survival and also exacerbates ischemic damage. Thus, nicotine can affect the outcome of cerebral ischemia by influencing brain endocrine function directly rather than through indirect systemic effects. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

The role of mitochondrial superoxide anion (O2(-)) on physiological aging in C57BL/6J mice.

PubMed

Miyazawa, Masaki; Ishii, Takamasa; Yasuda, Kayo; Noda, Setsuko; Onouchi, Hiromi; Hartman, Philip S; Ishii, Naoaki

2009-01-01

Much attention has been focused on the mitochondrial superoxide anion (O2(-)), which is also a critical free radial produced by ionizing radiation. The specific role of the mitochondrial O2(-) on physiological aging in mammals is still unclear despite wide-spread evidence that oxidative stress is involved in aging and age-related diseases. The major endogenous source of O2(-) is generated as a byproduct of energy metabolism from mitochondria. In order to better understand how O2(-)relates to metazoan aging, we have comprehensively examined age-related changes in the levels of oxidative damage, mitochondrial O2(-) production, mitochondrial antioxidant enzyme activity and apoptosis induction in key organs of an inbred mouse strain (C57BL/6J). Oxidative damage accumulated and excess apoptosis occurred in the brain, oculus and kidney with aging, but comparatively little occurred in the heart and muscle. These rates are correlated with O2(-) levels. Mitochondrial O2(-) production levels increased with aging in the brain, oculus and kidney, and did not significantly increased in the heart and muscle. In contrast to O2(-) production, mitochondrial SOD activities increased in heart and muscle, and remained unchanged in the brain, oculus and kidney with aging. These results suggest that O2(-) production has high organ specificity, and oxidative damage by O2(-) from mitochondria mediated apoptosis can lead to organ atrophy and physiological dysfunction. In addition, O2(-) from mitochondria plays a core role in physiological aging.

Gene inactivation of Na+/H+ exchanger isoform 1 attenuates apoptosis and mitochondrial damage following transient focal cerebral ischemia

PubMed Central

Wang, Yanping; Luo, Jing; Chen, Xinzhi; Chen, Hai; Cramer, Sam W.; Sun, Dandan

2010-01-01

We investigated mechanisms underlying the Na+/H+ exchanger isoform 1 (NHE1)-mediated neuronal damage in transient focal ischemia. Physiological parameters, body and tympanic temperatures, and regional cerebral blood flow during 30 min middle cerebral artery occlusion (MCAO) were similar in wild-type NHE1 (NHE1+/+) and NHE1 heterozygous (NHE1+/−) mice. NHE1+/+ mice developed infarct volume of 57.3 ± 8.8 mm3 at 24 h reperfusion (Rp), which progressed to 86.1 ± 10.0 mm3 at 72 h Rp. This delayed cell death was preceded by release of mitochondrial cytochrome c (Cyt. C), nuclear translocation of apoptosis-inducing factor (AIF), activation of caspase-3, and TUNEL-positive staining and chromatin condensation in the ipsilateral hemispheres of NHE1+/+ brains. In contrast, NHE1+/− mice had a significantly smaller infarct volume and improved neurological function. A similar neuroprotection was obtained with NHE1 inhibitor HOE 642. The number of apoptotic cells, release of AIF and Cyt. C or levels of active caspase-3 was significantly reduced in NHE1+/− brains. These data imply that NHE1 activity may contribute to ischemic apoptosis. Ischemic brains did not exhibit changes of NHE1 protein expression. In contrast, up-regulation of NHE1 expression was found in NHE1+/+ neurons after in vitro ischemia. These data suggest that NHE1 activation following cerebral ischemia contributes to mitochondrial damage and ischemic apoptosis. PMID:18662334

Omega-3 polyunsaturated fatty acid supplementation attenuates microglial-induced inflammation by inhibiting the HMGB1/TLR4/NF-κB pathway following experimental traumatic brain injury.

PubMed

Chen, Xiangrong; Wu, Shukai; Chen, Chunnuan; Xie, Baoyuan; Fang, Zhongning; Hu, Weipeng; Chen, Junyan; Fu, Huangde; He, Hefan

2017-07-24

Microglial activation and the subsequent inflammatory response in the central nervous system play important roles in secondary damage after traumatic brain injury (TBI). High-mobility group box 1 (HMGB1) protein, an important mediator in late inflammatory responses, interacts with transmembrane receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs) to activate downstream signaling pathways, such as the nuclear factor (NF)-κB signaling pathway, leading to a cascade amplification of inflammatory responses, which are related to neuronal damage after TBI. Omega-3 polyunsaturated fatty acid (ω-3 PUFA) is a commonly used clinical immunonutrient, which has antioxidative and anti-inflammatory effects. However, the effects of ω-3 PUFA on HMGB1 expression and HMGB1-mediated activation of the TLR4/NF-κB signaling pathway are not clear. The Feeney DM TBI model was adopted to induce brain injury in rats. Modified neurological severity scores, brain water content, and Nissl staining were employed to determine the neuroprotective effects of ω-3 PUFA supplementation. Assessment of microglial activation in lesioned sites and protein markers for proinflammatory, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, interferon (IFN)-γ, and HMGB1 were used to evaluate neuroinflammatory responses and anti-inflammation effects of ω-3 PUFA supplementation. Immunofluorescent staining and western blot analysis were used to detect HMGB1 nuclear translocation, secretion, and HMGB1-mediated activation of the TLR4/NF-κB signaling pathway to evaluate the effects of ω-3 PUFA supplementation and gain further insight into the mechanisms underlying the development of the neuroinflammatory response after TBI. It was found that ω-3 PUFA supplementation inhibited TBI-induced microglial activation and expression of inflammatory factors (TNF-α, IL-1β, IL-6, and IFN-γ), reduced brain edema, decreased neuronal apoptosis, and improved neurological functions after TBI. We further demonstrated that ω-3 PUFA supplementation inhibited HMGB1 nuclear translocation and secretion and decreased expression of HMGB1 in neurons and microglia in the lesioned areas. Moreover, ω-3 PUFA supplementation inhibited microglial activation and the subsequent inflammatory response by regulating HMGB1 and the TLR4/NF-κB signaling pathway. The results of this study suggest that microglial activation and the subsequent neuroinflammatory response as well as the related HMGB1/TLR4/NF-κB signaling pathway play essential roles in secondary injury after TBI. Furthermore, ω-3 PUFA supplementation inhibited TBI-induced microglial activation and the subsequent inflammatory response by regulating HMGB1 nuclear translocation and secretion and also HMGB1-mediated activation of the TLR4/NF-κB signaling pathway, leading to neuroprotective effects.

Taurine reverses sodium fluoride-mediated increase in inflammation, caspase-3 activity, and oxidative damage along the brain-pituitary-gonadal axis in male rats.

PubMed

Adedara, Isaac A; Olabiyi, Bolanle F; Ojuade, TeminiJesu D; Idris, Umar F; Onibiyo, Esther M; Farombi, Ebenezer O

2017-09-01

Excessive exposure to fluoride is associated with male reproductive dysfunction in humans and animals. Taurine (2-aminoethane sulfonic acid) is a free intracellular β-amino acid with antioxidant, anti-inflammatory, and neuroprotective properties. However, the effect of taurine on fluoride-induced reproductive toxicity has not been reported. The present study investigated the influence of taurine on sodium fluoride (NaF)-induced functional changes along the brain-pituitary-gonadal axis in male rats. NaF was administered singly in drinking water at 15 mg·L -1 alone or orally co-administered by gavage with taurine at 100 and 200 mg·(kg body mass) -1 for 45 consecutive days. Results showed that taurine significantly prevented NaF-induced increase in oxidative stress indices as well as augmented antioxidant enzymes activities and glutathione level in the brain, testes, and epididymis of the treated rats. Moreover, taurine reversed NaF-induced elevation in inflammatory biomarkers and caspase-3 activity as well as histological damage in the brain, testes, and epididymis of the treated rats. The significant reversal of NaF-induced decreases in testosterone level and testicular activities of acid phosphatase, alkaline phosphatase, and lactate dehydrogenase by taurine was accompanied by enhancement of sperm functional characteristics in the treated rats. Taurine may be a possible chemopreventive candidate against reproductive dysfunction resulting from fluoride exposure.

Interferon-β Modulates Inflammatory Response in Cerebral Ischemia.

PubMed

Kuo, Ping-Chang; Scofield, Barbara A; Yu, I-Chen; Chang, Fen-Lei; Ganea, Doina; Yen, Jui-Hung

2016-01-08

Stroke is a leading cause of death in the world. In >80% of strokes, the initial acute phase of ischemic injury is due to the occlusion of a blood vessel resulting in severe focal hypoperfusion, excitotoxicity, and oxidative damage. Interferon-β (IFNβ), a cytokine with immunomodulatory properties, was approved by the US Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis for more than a decade. Its anti-inflammatory properties and well-characterized safety profile suggest that IFNβ has therapeutic potential for the treatment of ischemic stroke. We investigated the therapeutic effect of IFNβ in the mouse model of transient middle cerebral artery occlusion/reperfusion. We found that IFNβ not only reduced infarct size in ischemic brains but also lessened neurological deficits in ischemic stroke animals. Further, multiple molecular mechanisms by which IFNβ modulates ischemic brain inflammation were identified. IFNβ reduced central nervous system infiltration of monocytes/macrophages, neutrophils, CD4(+) T cells, and γδ T cells; inhibited the production of inflammatory mediators; suppressed the expression of adhesion molecules on brain endothelial cells; and repressed microglia activation in the ischemic brain. Our results demonstrate that IFNβ exerts a protective effect against ischemic stroke through its anti-inflammatory properties and suggest that IFNβ is a potential therapeutic agent, targeting the reperfusion damage subsequent to the treatment with tissue plasminogen activator. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Immunology of Cryptococcal Infections: Developing a Rational Approach to Patient Therapy

PubMed Central

Elsegeiny, Waleed; Marr, Kieren A.; Williamson, Peter R.

2018-01-01

Cryptococcal meningoencephalitis is responsible for upwards of 15% of HIV-related deaths worldwide and is currently the most common cause of non-viral meningitis in the US, affecting both previously healthy and people with immune suppression caused by cancer chemotherapy, transplantation, and biologic therapies. Despite a continued 30–50% attributable mortality, recommended therapeutic strategies have remained largely unchanged since the 1950s. Recent murine models and human studies examining the role of the immune system in both susceptibility to the infection as well as host damage have begun to influence patient care decisions. The Damage Framework Response, originally proposed in 1999, was recently used to discuss dichotomous etiologies of host damage in cryptococcal disease. These include patients suffering microbiological damage with low host immunity (especially those immunosuppressed with HIV) and those having low (live) microbiological burden but high immune-mediated damage (HIV-related immune reconstitution syndrome and non-HIV-related postinfectious inflammatory response syndrome). Cryptococcal disease in previously healthy hosts, albeit rare, has been known for a long time. Immunophenotyping and dendritic cell-T cell signaling studies on cerebral spinal fluid of these rare patients reveal immune capacity for recognition and T-cell activation pathways including increased levels of HLA-DR and CD56. However, despite effective T-cell signals, brain biopsy and autopsy specimens demonstrated an M2 alternative macrophage polarization and poor phagocytosis of fungal cells. These studies expand the paradigm for cryptococcal disease susceptibility to include a prominent role for immune-mediated damage and suggest a need for careful individual consideration of immune activation during therapy of cryptococcal disease in diverse hosts. PMID:29670625

Immunology of Cryptococcal Infections: Developing a Rational Approach to Patient Therapy.

PubMed

Elsegeiny, Waleed; Marr, Kieren A; Williamson, Peter R

2018-01-01

Cryptococcal meningoencephalitis is responsible for upwards of 15% of HIV-related deaths worldwide and is currently the most common cause of non-viral meningitis in the US, affecting both previously healthy and people with immune suppression caused by cancer chemotherapy, transplantation, and biologic therapies. Despite a continued 30-50% attributable mortality, recommended therapeutic strategies have remained largely unchanged since the 1950s. Recent murine models and human studies examining the role of the immune system in both susceptibility to the infection as well as host damage have begun to influence patient care decisions. The Damage Framework Response, originally proposed in 1999, was recently used to discuss dichotomous etiologies of host damage in cryptococcal disease. These include patients suffering microbiological damage with low host immunity (especially those immunosuppressed with HIV) and those having low (live) microbiological burden but high immune-mediated damage (HIV-related immune reconstitution syndrome and non-HIV-related postinfectious inflammatory response syndrome). Cryptococcal disease in previously healthy hosts, albeit rare, has been known for a long time. Immunophenotyping and dendritic cell-T cell signaling studies on cerebral spinal fluid of these rare patients reveal immune capacity for recognition and T-cell activation pathways including increased levels of HLA-DR and CD56. However, despite effective T-cell signals, brain biopsy and autopsy specimens demonstrated an M2 alternative macrophage polarization and poor phagocytosis of fungal cells. These studies expand the paradigm for cryptococcal disease susceptibility to include a prominent role for immune-mediated damage and suggest a need for careful individual consideration of immune activation during therapy of cryptococcal disease in diverse hosts.

Transcriptional Regulation of Brain-Derived Neurotrophic Factor (BDNF) by Methyl CpG Binding Protein 2 (MeCP2): a Novel Mechanism for Re-Myelination and/or Myelin Repair Involved in the Treatment of Multiple Sclerosis (MS).

PubMed

KhorshidAhmad, Tina; Acosta, Crystal; Cortes, Claudia; Lakowski, Ted M; Gangadaran, Surendiran; Namaka, Michael

2016-03-01

Multiple sclerosis (MS) is a chronic progressive, neurological disease characterized by the targeted immune system-mediated destruction of central nervous system (CNS) myelin. Autoreactive CD4+ T helper cells have a key role in orchestrating MS-induced myelin damage. Once activated, circulating Th1-cells secrete a variety of inflammatory cytokines that foster the breakdown of blood-brain barrier (BBB) eventually infiltrating into the CNS. Inside the CNS, they become reactivated upon exposure to the myelin structural proteins and continue to produce inflammatory cytokines such as tumor necrosis factor α (TNFα) that leads to direct activation of antibodies and macrophages that are involved in the phagocytosis of myelin. Proliferating oligodendrocyte precursors (OPs) migrating to the lesion sites are capable of acute remyelination but unable to completely repair or restore the immune system-mediated myelin damage. This results in various permanent clinical neurological disabilities such as cognitive dysfunction, fatigue, bowel/bladder abnormalities, and neuropathic pain. At present, there is no cure for MS. Recent remyelination and/or myelin repair strategies have focused on the role of the neurotrophin brain-derived neurotrophic factor (BDNF) and its upstream transcriptional repressor methyl CpG binding protein (MeCP2). Research in the field of epigenetic therapeutics involving histone deacetylase (HDAC) inhibitors and lysine acetyl transferase (KAT) inhibitors is being explored to repress the detrimental effects of MeCP2. This review will address the role of MeCP2 and BDNF in remyelination and/or myelin repair and the potential of HDAC and KAT inhibitors as novel therapeutic interventions for MS.

The protective effects of dexmedetomidine on ischemic brain injury: A meta-analysis.

PubMed

Jiang, Lianxiang; Hu, Meizhu; Lu, Yan; Cao, Ya; Chang, Yan; Dai, Zeping

2017-08-01

Intracranial lesions, trauma or surgery-related damage activate immune inflammation and neuroendocrine responses, causing ischemic brain injury. Studies have shown that inflammatory cascade mediated by neuroendocrine hormones and proinflammatory mediators is implicated in the pathophysiology of ischemic brain injury. Alpha2-adrenoceptor agonists, dexmedetomidine, is widely used as neuroprotectants in anesthesia practice. However, it is still lack of a comprehensive meta-analysis to evaluate the neuroprotection of dexmedetomidine against ischemic brain injury via suppressing these two physiological responses. Searched the Cochrane Library, Pub-Med, EMBASE, EBSCO, Ovid, Chinese biological and medical database (CBM). Related literatures published in English or Chinese before January 2017 were enrolled. We assessed the quality of eligible studies and synthesized predefined outcomes with a random-effects model or fixed-effects model. Nineteen Randomized Controlled Trials including 879 patients were included. Findings for meta-analysis of various outcomes were summarised. Primary results shown that compared with placebo, dexmedetomidine reduced a surge of TNF-α [SMD=-2.34, 95%CI (-3.25, -1.44)], IL-6 [SMD=-2.44, 95%CI (-3.40, -1.47)], S100-β [SMD=-2.73, 95%CI (-3.65, -1.82)], NSE [SMD=-1.69, 95%CI (-2.77, -0.61)], cortisol [SMD=-2.48, 95%CI (-3.38, -1.58)] and glucose [SMD=-1.44, 95%CI (-1.85, -1.04)]; maintained the level of SOD [SMD=1.36, 95%CI (0.62, 2.10)]; decreased the rise in CRP level at postoperative one day. In response to stress reaction, dexmedetomidine attenuated the stress-related increasing of MAP, HR and intracranial pressure without significant effects on cerebral oxygen metabolism. Alpha2-adrenoceptor agonists, dexmedetomidine, could reduce the release of inflammatory mediators and neuroendocrine hormones as well as maintain intracranial homoeostasis, alleviating ischemic brain injury and exerting an effect on brain protection. Copyright © 2017 Elsevier Inc. All rights reserved.

Impact of the Innate Immune Response in the Actions of Ethanol on the Central Nervous System.

PubMed

Montesinos, Jorge; Alfonso-Loeches, Silvia; Guerri, Consuelo

2016-11-01

The innate immune response in the central nervous system (CNS) participates in both synaptic plasticity and neural damage. Emerging evidence from human and animal studies supports the role of the neuroimmune system response in many actions of ethanol (EtOH) on the CNS. Research studies have shown that alcohol stimulates brain immune cells, microglia, and astrocytes, by activating innate immune receptors Toll-like receptors (TLRs) and NOD-like receptors (inflammasome NLRs) triggering signaling pathways, which culminate in the production of pro-inflammatory cytokines and chemokines that lead to neuroinflammation. This review focuses on evidence that indicates the participation of TLRs and the inflammasome NLRs signaling response in many effects of EtOH on the CNS, such as neuroinflammation associated with brain damage, cognitive and behavioral dysfunction, and adolescent brain development alterations. It also reviews findings that indicate the role of TLR4-dependent signaling immune molecules in alcohol consumption, reward, and addiction. The research data suggest that overactivation of TLR4 or NLRs increases pro-inflammatory cytokines and mediators to cause neural damage in the cerebral cortex and hippocampus, while modest TLR4 activation, along with the generation of certain cytokines and chemokines in specific brain areas (e.g., amygdala, ventral tegmental area), modulate neurotransmission, alcohol drinking, and alcohol rewards. Elimination of TLR4 and NLRP3 abolishes many neuroimmune effects of EtOH. Despite much progress being made in this area, there are some research gaps and unanswered questions that this review discusses. Finally, potential therapies that target neuroimmune pathways to treat neuropathological and behavioral consequences of alcohol abuse are also evaluated. Copyright © 2016 by the Research Society on Alcoholism.

Phloretin ameliorates 2-chlorohexadecanal-mediated brain microvascular endothelial cell dysfunction in vitro

PubMed Central

Üllen, Andreas; Fauler, Günter; Bernhart, Eva; Nusshold, Christoph; Reicher, Helga; Leis, Hans-Jörg; Malle, Ernst; Sattler, Wolfgang

2012-01-01

2-Chlorohexadecanal (2-ClHDA), a chlorinated fatty aldehyde, is formed via attack on ether-phospholipids by hypochlorous acid (HOCl) that is generated by the myeloperoxidase–hydrogen peroxide–chloride system of activated leukocytes. 2-ClHDA levels are elevated in atherosclerotic lesions, myocardial infarction, and neuroinflammation. Neuroinflammatory conditions are accompanied by accumulation of neutrophils (an ample source of myeloperoxidase) in the brain. Microvessel damage by inflammatory mediators and/or reactive oxidants can induce blood–brain barrier (BBB) dysfunction, a pathological condition leading to cerebral edema, brain hemorrhage, and neuronal death. In this in vitro study we investigated the impact of 2-ClHDA on brain microvascular endothelial cells (BMVEC), which constitute the morphological basis of the BBB. We show that exogenously added 2-ClHDA is subject to rapid uptake and metabolism by BMVEC. Using C16 structural analogues of 2-ClHDA we found that the cytotoxic potential decreases in the following order: 2-ClHDA>hexadecanal>palmitic acid>2-ClHDA-dimethylacetal. 2-ClHDA induces loss of barrier function, mitochondrial dysfunction, apoptosis via activation of caspase 3, and altered intracellular redox balance. Finally we investigated potential protective effects of several natural polyphenols on in vitro BBB function. Of the compounds tested, phloretin almost completely abrogated 2-ClHDA-induced BMVEC barrier dysfunction and cell death. These data suggest that 2-ClHDA has the potential to induce BBB breakdown under inflammatory conditions and that phloretin confers protection in this experimental setting. PMID:22982051

Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity.

PubMed

Li, Minshu; Li, Zhiguo; Yao, Yang; Jin, Wei-Na; Wood, Kristofer; Liu, Qiang; Shi, Fu-Dong; Hao, Junwei

2017-01-17

Astrocytes are believed to bridge interactions between infiltrating lymphocytes and neurons during brain ischemia, but the mechanisms for this action are poorly understood. Here we found that interleukin-15 (IL-15) is dramatically up-regulated in astrocytes of postmortem brain tissues from patients with ischemic stroke and in a mouse model of transient focal brain ischemia. We generated a glial fibrillary acidic protein (GFAP) promoter-controlled IL-15-expressing transgenic mouse (GFAP-IL-15 tg ) line and found enlarged brain infarcts, exacerbated neurodeficits after the induction of brain ischemia. In addition, knockdown of IL-15 in astrocytes attenuated ischemic brain injury. Interestingly, the accumulation of CD8 + T and natural killer (NK) cells was augmented in these GFAP-IL-15 tg mice after brain ischemia. Of note, depletion of CD8 + T or NK cells attenuated ischemic brain injury in GFAP-IL-15 tg mice. Furthermore, knockdown of the IL-15 receptor α or blockade of cell-to-cell contact diminished the activation and effector function of CD8 + T and NK cells in GFAP-IL-15 tg mice, suggesting that astrocytic IL-15 is delivered in trans to target cells. Collectively, these findings indicate that astrocytic IL-15 could aggravate postischemic brain damage via propagation of CD8 + T and NK cell-mediated immunity.

Receptor-mediated transcytosis of cyclophilin B through the blood-brain barrier.

PubMed

Carpentier, M; Descamps, L; Allain, F; Denys, A; Durieux, S; Fenart, L; Kieda, C; Cecchelli, R; Spik, G

1999-07-01

Cyclophilin B (CyPB) is a cyclosporin A (CsA)-binding protein mainly located in intracellular vesicles and secreted in biological fluids. In previous works, we demonstrated that CyPB interacts with T lymphocytes and enhances in vitro cellular incorporation and activity of CsA. In addition to its immunosuppressive activity, CsA is able to promote regeneration of damaged peripheral nerves. However, the crossing of the drug from plasma to neural tissue is restricted by the relative impermeability of the blood-brain barrier. To know whether CyPB might also participate in the delivery of CsA into the brain, we have analyzed the interactions of CyPB with brain capillary endothelial cells. First, we demonstrated that CyPB binds to two types of binding sites present at the surface of capillary endothelial cells from various species of tissues. The first type of binding sites (K(D) = 300 nM; number of sites = 3 x 10(6)) is related to interactions with negatively charged compounds such as proteoglycans. The second type of binding sites, approximately 50,000 per cell, exhibits a higher affinity for CyPB (K(D) = 15 nM) and is involved in an endocytosis process, indicating it might correspond to a functional receptor. Finally, the use of an in vitro model of blood-brain barrier allowed us to demonstrate that CyPB is transcytosed by a receptor-mediated pathway (flux = 16.5 fmol/cm2/h). In these conditions, CyPB did not significantly modify the passage of CsA, indicating that it is unlikely to provide a pathway for CsA brain delivery.

Mathematical modelling of blood-brain barrier failure and edema

NASA Astrophysics Data System (ADS)

Waters, Sarah; Lang, Georgina; Vella, Dominic; Goriely, Alain

2015-11-01

Injuries such as traumatic brain injury and stroke can result in increased blood-brain barrier permeability. This increase may lead to water accumulation in the brain tissue resulting in vasogenic edema. Although the initial injury may be localised, the resulting edema causes mechanical damage and compression of the vasculature beyond the original injury site. We employ a biphasic mixture model to investigate the consequences of blood-brain barrier permeability changes within a region of brain tissue and the onset of vasogenic edema. We find that such localised changes can indeed result in brain tissue swelling and that the type of damage that results (stress damage or strain damage) depends on the ability of the brain to clear edema fluid.

The Design and Delivery of a Thermally Responsive Peptide to Inhibit S100B Mediated Neurodegeneration

PubMed Central

Hearst, Scoty M; Walker, Leslie R; Shao, Qingmei; Lopez, Mariper; Raucher, Drazen; Vig, Parminder J S

2011-01-01

S100B, a glial secreted protein is believed to play a major role in neurodegeneration in Alzheimer's disease, Down syndrome, traumatic brain injury and spinocerebellar ataxia type 1 (SCA1). SCA1 is a trinucleotide repeat disorder in which the expanded polyglutamine mutation in the protein ataxin-1 primarily targets Purkinje cells (PCs) of the cerebellum. Currently, the exact mechanism of S100B mediated PC damage in SCA1 is not clear. However, here we show that S100B may act via the activation of the RAGE signaling pathway resulting in oxidative stress mediated injury to mutant ataxin-1 expressing neurons. To combat S100B mediated neurodegeneration, we have designed a selective thermally responsive S100B inhibitory peptide, Synb1-ELP-TRTK. Our therapeutic polypeptide was developed using three key elements: (1) the elastin-like polypeptide (ELP), a thermally responsive polypeptide, (2) the TRTK12 peptide, a known S100B inhibitory peptide and (3) a cell penetrating peptide, Synb1, to enhance intracellular delivery. Binding studies revealed that our peptide, Synb1-ELP-TRTK, interacts with its molecular target S100B and maintains a high S100B binding affinity as comparable with the TRTK12 peptide alone. In addition, in vitro studies revealed that Synb1-ELP-TRTK treatment reduces S100B uptake in SHSY5Y cells. Furthermore, the Synb1-ELP-TRTK peptide decreased S100B induced oxidative damage to mutant ataxin-1 expressing neurons. To test the delivery capabilities of ELP based therapeutic peptides to the cerebellum; we treated mice with fluorescently labeled Synb1-ELP and observed that thermal targeting enhanced peptide delivery to the cerebellum. Here, we have laid the framework for thermal based therapeutic targeting to regions of the brain, particularly the cerebellum. Overall, our data suggests that thermal targeting of ELP based therapeutic peptides to the cerebellum is a novel treatment strategy for cerebellar neurodegenerative disorders. PMID:21958864

The protective role of isorhamnetin on human brain microvascular endothelial cells from cytotoxicity induced by methylglyoxal and oxygen-glucose deprivation.

PubMed

Li, Wenlu; Chen, Zhigang; Yan, Min; He, Ping; Chen, Zhong; Dai, Haibin

2016-02-01

As the first target of stroke, cerebral endothelial cells play a key role in brain vascular repair and maintenance, and their function is impeded in diabetes. Methylglyoxal (MGO), a reactive dicarbonyl produced during glucose metabolism, accumulates in diabetic patients. MGO and MGO-induced advanced glycation end-products (AGEs) could ameliorate stroke-induced brain vascular damage, closely related with ECs dysfunction. Using MGO plus oxygen-glucose deprivation (OGD) to mimic diabetic stroke, we reported the protective effect of isorhamnetin on OGD-induced cytotoxicity after MGO treatment on primary human brain microvascular endothelial cells (HBMEC) and explored the underlying mechanisms. Treatment of MGO for 24 h significantly enhanced 3-h OGD-induced HBMEC toxic effect, which was inhibited by pretreatment of isorhamnetin (100 μmol/L). Moreover, the protective effect of isorhamnetin is multiple function dependent, which includes anti-inflammation, anti-oxidative stress and anti-apoptosis effects. Besides its well-known inhibition on the mitochondria-dependent or intrinsic apoptotic pathway, isorhamnetin also reduced activation of the extrinsic apoptotic pathway, as characterized by the decreased expression and activity of caspase 3 and caspase 8. Furthermore, pretreatment with isorhamnetin specifically inhibited FAS/FASL expression and suppressed nuclear factor-kappa B nuclear translocation. Taken together, our results indicated that isorhamnetin protected against OGD-induced cytotoxicity after MGO treatment in cultured HBMEC due to its multiple protective effects and could inhibit Fas-mediated extrinsic apoptosis. Therefore, isorhamnetin is a promising reagent for the treatment of hyperglycemia and ischemia-induced cerebral vascular degeneration. A proposed model of the potential protective mechanism of isorhamnetin, a metabolite of quercetin, on methylglyoxal (MGO) treatment plus oxygen-glucose deprivation (OGD) exposure-induced cytotoxicity in cultured human brain microvascular endothelial cells. Isorhamnetin inhibits FasL-mediated extrinsic apoptosis and neurotrophic factor κB (NF-κB) nuclear translocation, which can induce the cell DNA damage. Therefore, the protective effect of isorhamnetin occurs through multiple functions, including anti-inflammation, anti-oxidative stress and anti-apoptosis. Therefore, isorhamnetin is a promising reagent for the treatment of hyperglycemia and ischemia-induced cerebral vascular degeneration. © 2015 International Society for Neurochemistry.

Meningeal mast cells affect early T cell central nervous system infiltration and blood-brain barrier integrity through TNF: a role for neutrophil recruitment?

PubMed

Sayed, Blayne A; Christy, Alison L; Walker, Margaret E; Brown, Melissa A

2010-06-15

Mast cells contribute to the pathogenesis of experimental autoimmune encephalomyelitis, a rodent model of the human demyelinating disease multiple sclerosis. Yet their site and mode of action is unknown. In both diseases, myelin-specific T cells are initially activated in peripheral lymphoid organs. However, for disease to occur, these cells must enter the immunologically privileged CNS through a breach in the relatively impermeable blood-brain barrier. In this study, we demonstrate that a dense population of resident mast cells in the meninges, structures surrounding the brain and spinal cord, regulate basal CNS barrier function, facilitating initial T cell CNS entry. Through the expression of TNF, mast cells recruit an early wave of neutrophils to the CNS. We propose that neutrophils in turn promote the blood-brain barrier breach and together with T cells lead to further inflammatory cell influx and myelin damage. These findings provide specific targets for intervention in multiple sclerosis as well as other immune-mediated CNS diseases.

Outdoor Ambient Air Pollution and Neurodegenerative Diseases: the Neuroinflammation Hypothesis.

PubMed

Jayaraj, Richard L; Rodriguez, Eric A; Wang, Yi; Block, Michelle L

2017-06-01

Accumulating research indicates that ambient outdoor air pollution impacts the brain and may affect neurodegenerative diseases, yet the potential underlying mechanisms are poorly understood. The neuroinflammation hypothesis holds that elevation of cytokines and reactive oxygen species in the brain mediates the deleterious effects of urban air pollution on the central nervous system (CNS). Studies in human and animal research document that neuroinflammation occurs in response to several inhaled pollutants. Microglia are a prominent source of cytokines and reactive oxygen species in the brain, implicated in the progressive neuron damage in diverse neurodegenerative diseases, and activated by inhaled components of urban air pollution through both direct and indirect pathways. The MAC1-NOX2 pathway has been identified as a mechanism through which microglia respond to different forms of air pollution, suggesting a potential common deleterious pathway. Multiple direct and indirect pathways in response to air pollution exposure likely interact in concert to exert CNS effects.

Ataxia with Parkinsonism and dystonia after intentional inhalation of liquefied petroleum gas.

PubMed

Godani, Massimiliano; Canavese, Francesca; Migliorini, Sonia; Del Sette, Massimo

2015-01-01

The practice of inhaling liquefied petroleum gas (LPG) to commit suicide is uncommon and almost exclusively a prerogative of the prison population. Numerous cases of sudden deaths caused by intentional propane and/or butane inhalation have been described, but these cases survived and a description of the consequences is very rare. We describe a prisoner who survived after voluntary inhalation of LPG, and who developed ataxia, Parkinsonism, and dystonia. Brain MRI showed bilateral hyperintensity in the basal ganglia and in the cerebellar hemispheres. The clinical evolution and the MRI abnormalities are similar to those described in cases of poisoning by CO where the mechanism of brain injury is related to histotoxic hypoxia. We believe that LPG, considered until now a mixture of gas with low neurotoxic power, may have caused direct toxic damage to the brain, mediated by a mechanism of hypoxia, such as in CO intoxication.

A Neurology of the Conservative-Liberal Dimension of Political Ideology.

PubMed

Mendez, Mario F

2017-01-01

Differences in political ideology are a major source of human disagreement and conflict. There is increasing evidence that neurobiological mechanisms mediate individual differences in political ideology through effects on a conservative-liberal axis. This review summarizes personality, evolutionary and genetic, cognitive, neuroimaging, and neurological studies of conservatism-liberalism and discusses how they might affect political ideology. What emerges from this highly variable literature is evidence for a normal right-sided "conservative-complex" involving structures sensitive to negativity bias, threat, disgust, and avoidance. This conservative-complex may be damaged with brain disease, sometimes leading to a pathological "liberal shift" or a reduced tendency to conservatism in political ideology. Although not deterministic, these findings recommend further research on politics and the brain.

Abulia following penetrating brain injury during endoscopic sinus surgery with disruption of the anterior cingulate circuit: case report.

PubMed

Grunsfeld, Alexander A; Login, Ivan S

2006-01-23

It is common knowledge that the frontal lobes mediate complex human behavior and that damage to these regions can cause executive dysfunction, apathy, disinhibition and personality changes. However, it is less well known that subcortical structures such as the caudate and thalamus are part of functionally segregated fronto-subcortical circuits, that can also alter behavior after injury. CASE PRESENTATION We present a 57 year old woman who suffered penetrating brain injury during endoscopic sinus surgery causing right basal ganglia injury which resulted in an abulic syndrome. Abulia does not result solely from cortical injury but can occur after disruption anywhere in the anterior cingulate circuit--in the case of our patient, most prominently at the right caudate.

Protection against Recurrent Stroke with Resveratrol: Endothelial Protection

PubMed Central

Clark, Darren; Tuor, Ursula I.; Thompson, Roger; Institoris, Adam; Kulynych, Angela; Zhang, Xu; Kinniburgh, David W.; Bari, Ferenc; Busija, David W.; Barber, Philip A.

2012-01-01

Despite increased risk of a recurrent stroke following a minor stroke, information is minimal regarding the interaction between injurious mild cerebral ischemic episodes and the possible treatments which might be effective. The aim of the current study was to investigate recurrent ischemic stroke and whether resveratrol, a nutritive polyphenol with promising cardio- and neuro- protective properties, could ameliorate the associated brain damage. Experiments in adult rats demonstrated that a mild ischemic stroke followed by a second mild cerebral ischemia exacerbated brain damage, and, daily oral resveratrol treatment after the first ischemic insult reduced ischemic cell death with the recurrent insult (P<0.002). Further investigation demonstrated reduction of both inflammatory changes and markers of oxidative stress in resveratrol treated animals. The protection observed with resveratrol treatment could not be explained by systemic effects of resveratrol treatment including effects either on blood pressure or body temperature measured telemetrically. Investigation of resveratrol effects on the blood-brain barrier in vivo demonstrated that resveratrol treatment reduced blood-brain barrier disruption and edema following recurrent stroke without affecting regional cerebral blood flow. Investigation of the mechanism in primary cell culture studies demonstrated that resveratrol treatment significantly protected endothelial cells against an in vitro ‘ischemia’ resulting in improved viability against oxygen and glucose deprivation (39.6±6.6% and 81.3±9.5% in vehicle and resveratrol treated cells, respectively). An inhibition of nitric oxide synthesis did not prevent the improved cell viability following oxygen glucose deprivation but SIRT-1 inhibition with sirtinol partially blocked the protection (P<0.001) suggesting endothelial protection is to some extent SIRT-1 dependent. Collectively, the results support that oral resveratrol treatment provides a low risk strategy to protect the brain from enhanced damage produced by recurrent stroke which is mediated in part by a protective effect of resveratrol on the endothelium of the cerebrovasculature. PMID:23082218

Does white matter structure or hippocampal volume mediate associations between cortisol and cognitive ageing?

PubMed Central

Cox, Simon R.; MacPherson, Sarah E.; Ferguson, Karen J.; Royle, Natalie A.; Maniega, Susana Muñoz; Hernández, Maria del C. Valdés; Bastin, Mark E.; MacLullich, Alasdair M.J.; Wardlaw, Joanna M.; Deary, Ian J.

2015-01-01

Elevated glucocorticoid (GC) levels putatively damage specific brain regions, which in turn may accelerate cognitive ageing. However, many studies are cross-sectional or have relatively short follow-up periods, making it difficult to relate GCs directly to changes in cognitive ability with increasing age. Moreover, studies combining endocrine, MRI and cognitive variables are scarce, measurement methods vary considerably, and formal tests of the underlying causal hypothesis (cortisol → brain → cognition) are absent. In this study, 90 men, aged 73 years, provided measures of fluid intelligence, processing speed and memory, diurnal and reactive salivary cortisol and two measures of white matter (WM) structure (WM hyperintensity volume from structural MRI and mean diffusivity averaged across 12 major tracts from diffusion tensor MRI), hippocampal volume, and also cognitive ability at age 11. We tested whether negative relationships between cognitive ageing differences (over more than 60 years) and salivary cortisol were significantly mediated by WM and hippocampal volume. Significant associations between reactive cortisol at 73 and cognitive ageing differences between 11 and 73 (r = −.28 to −.36, p < .05) were partially mediated by both WM structural measures, but not hippocampal volume. Cortisol-WM relationships were modest, as was the degree to which WM structure attenuated cortisol–cognition associations (<15%). These data support the hypothesis that GCs contribute to cognitive ageing differences from childhood to the early 70s, partly via brain WM structure. PMID:26298692

Neuroprotective effect of mesenchymal stem cell through complement component 3 downregulation after transient focal cerebral ischemia in mice.

PubMed

Jung, Hye-Seon; Jeong, Si-Yeon; Yang, Jiwon; Kim, So-Dam; Zhang, Baojin; Yoo, Hyun Seung; Song, Sun U; Jeon, Myung-Shin; Song, Yun Seon

2016-10-28

Bone marrow-derived mesenchymal stem cells (MSCs) are used in stroke treatment despite the poor understanding of its mode of action. The immune suppressive and anti-inflammatory properties of MSCs possibly play important roles in regulating neuroinflammation after stroke. We investigated whether MSCs reduce the inflammatory complement component 3 (C3) levels, thus, providing neuroprotection during stroke. Mice were subjected to transient focal cerebral ischemia (tFCI), after which MSCs were intravenously injected. The infarct volume of the brain was reduced in MSC-injected tFCI mice, and C3 expression was significantly reduced in both the brain and the blood. Additionally, the profiles of other inflammatory mediators demonstrated neuroprotective changes in the MSCs-treated group. In order to analyze the effect of MSCs on neurons during cerebral ischemia, primary cortical neurons were co-cultured with MSCs under oxygen-glucose deprivation (OGD). Primary neurons co-cultured with MSCs exhibited reduced levels of C3 expression and increased protection against OGD, indicating that treatment with MSCs reduces excessive C3 expression and rescues ischemia-induced neuronal damage. Our finding suggests that reduction of C3 expression by MSCs can help to ameliorate ischemic brain damage, offering a new neuroprotective strategy in stroke therapy. Copyright © 2016. Published by Elsevier Ireland Ltd.

Dexamethasone prevents hypoxia/ischemia-induced reductions in cerebral glucose utilization and high-energy phosphate metabolites in immature brain.

PubMed

Tuor, U I; Yager, J Y; Bascaramurty, S; Del Bigio, M R

1997-11-01

We examined the potential importance of dexamethasone-mediated alterations in energy metabolism in providing protection against hypoxic-ischemic brain damage in immature rats. Seven-day-old rats (n = 165) that had been treated with dexamethasone (0.1 mg/kg, i.p.) or vehicle were assigned to control or hypoxic-ischemic groups (unilateral carotid artery occlusion plus 2-3 h of 8% oxygen at normothermia). The systemic availability of alternate fuels such as beta-hydroxybutyrate, lactate, pyruvate, and free fatty acids was not altered by dexamethasone treatment, and, except for glucose, brain levels were also unaffected. At the end of hypoxia, levels of cerebral high-energy phosphates (ATP and phosphocreatine) were decreased in vehicle- but relatively preserved in dexamethasone-treated animals. The local cerebral metabolic rate of glucose utilization (lCMRgl) was decreased modestly under control conditions in dexamethasone-treated animals, whereas cerebral energy use measured in a model of decapitation ischemia did not differ significantly between groups. The lCMRgl increased markedly during hypoxia-ischemia (p < 0.05) and remained elevated throughout ischemia in dexamethasone- but not vehicle-treated groups, indicating an enhanced glycolytic flux with dexamethasone treatment. Thus, dexamethasone likely provides protection against hypoxic-ischemic damage in immature rats by preserving cerebral ATP secondary to a maintenance of glycolytic flux.

Neuroprotective effects of scutellarin against hypoxic-ischemic-induced cerebral injury via augmentation of antioxidant defense capacity.

PubMed

Guo, Hong; Hu, Li-Min; Wang, Shao-Xia; Wang, Yu-Lin; Shi, Fang; Li, Hui; Liu, Yang; Kang, Li-Yuan; Gao, Xiu-Mei

2011-12-31

An increasing number of studies has indicated that hypoxic-ischemic-induced cerebral injury is partly mediated via oxidative stress. Recent researches have focused on searching for drug and herbal manipulations to protect against hypoxic-ischemic-induced oxidative cell damage. Scutellarin is a flavonoid derived from the Erigeron breviscapus (vant.) and has been reported to exhibit neuroprotective properties. However, its precise mechanism, particularly its antioxidation mechanism, remains elusive. In the present study, we investigated the neuroprotective effects of scutellarin on middle cerebral artery occlusion (MCAO)-induced brain damage in rats, and oxygen-glucose deprivation (OGD)-induced toxicity in primary culture of rat cortical neurons. In vivo, intraperitoneal injections of scutellarin (20 and 60 mg/kg) improved the neurological score and diminished the percentage of brain infarct volume. At the same time, scutellarin significantly increased superoxide dismutase (SOD), catalase (CAT) activities and glutathione (GSH) level in ischemic brain tissues, enhancing endogenous antioxidant activity. Moreover, pretreatment of scutellarin (25, 50 and 100 μM) protected neurons against lethal stimuli, decreased the percentage of apoptotic cells and inhibited reactive oxygen species (ROS) generation in OGD-induced primary cortical neurons in vitro. These results suggest that the preventive and therapeutic potential of scutellarin in cerebral injury patients is, at least in part, ascribed to augmentation of cellular antioxidant defense capacity.

Lack of a p21waf1/cip -dependent G1/S checkpoint in neural stem and progenitor cells after DNA damage in vivo.

PubMed

Roque, Telma; Haton, Céline; Etienne, Olivier; Chicheportiche, Alexandra; Rousseau, Laure; Martin, Ludovic; Mouthon, Marc-André; Boussin, François D

2012-03-01

The cyclin-dependent kinase inhibitor p21(waf1/cip) mediates the p53-dependent G1/S checkpoint, which is generally considered to be a critical requirement to maintain genomic stability after DNA damage. We used staggered 5-ethynyl-2'deoxyuridine/5-bromo-2'-deoxyuridine double-labeling in vivo to investigate the cell cycle progression and the role of p21(waf1/cip) in the DNA damage response of neural stem and progenitor cells (NSPCs) after exposure of the developing mouse cortex to ionizing radiation. We observed a radiation-induced p21-dependent apoptotic response in migrating postmitotic cortical cells. However, neural stem and progenitor cells (NSPCs) did not initiate a p21(waf1/cip1) -dependent G1/S block and continued to enter S-phase at a similar rate to the non-irradiated controls. The G1/S checkpoint is not involved in the mechanisms underlying the faithful transmission of the NSPC genome and/or the elimination of critically damaged cells. These processes typically involve intra-S and G2/M checkpoints that are rapidly activated after irradiation. p21 is normally repressed in neural cells during brain development except at the G1 to G0 transition. Lack of activation of a G1/S checkpoint and apoptosis of postmitotic migrating cells after DNA damage appear to depend on the expression of p21 in neural cells, since substantial cell-to-cell variations are found in the irradiated cortex. This suggests that repression of p21 during brain development prevents the induction of the G1/S checkpoint after DNA damage. Copyright © 2011 AlphaMed Press.

Paraquat-induced ultrastructural changes and DNA damage in the nervous system is mediated via oxidative-stress-induced cytotoxicity in Drosophila melanogaster.

PubMed

Mehdi, Syed Hassan; Qamar, Ayesha

2013-08-01

Paraquat (PQ), a quaternary nitrogen herbicide, is commonly used as a pesticide despite of its high toxicity. Our study evaluated the effect of subchronic PQ exposure on the neuropathology, genotoxicity, and antioxidant activity on the nervous tissue of Drosophila melanogaster. We also explored the behavioral effect of PQ on D. melanogaster. Furthermore, we attempted to validate the mechanism by evaluating PQ-induced cytotoxicity on the D-Mel2 cell lines. The fruit fly D. melanogaster serves as a feasible model to understand the mechanism of neurodegenerative diseases. Our study shows a dose-dependent PQ-induced neuropathology in the brain tissue of D. melanogaster as evidenced by hematoxylin and eosin staining, silver nitrate staining, and transmission electron microscopy. Electron microscopic study of D. melanogaster brain tissue exhibited vacuolar degeneration and significant neuronal damage across the nervous tissue structure in comparison with control. Our findings also indicate a dose-dependent locomotor impairment and decreased superoxide dismutase (SOD) specific activity in PQ-treated D. melanogaster. These PQ-induced neuroanatomical changes and decreased SOD specific activity showed a significant association with oxidative DNA damage as observed by alkaline comet assay. Additionally, we show, for the first time, a dose-dependent PQ-induced cytotoxicity in the D-Mel2 cells suggesting loss of neuronal cell viability via cytotoxic damage. Our data suggest that PQ exposure results in neurodegeneration in D. melanogaster and that fruit fly is a suitable in vivo model for correlating the neuroanatomical changes with neurotoxic damages to nervous system.

Oxidative damage mediated iNOS and UCP-2 upregulation in rat brain after sub-acute cyanide exposure: dose and time-dependent effects.

PubMed

Bhattacharya, Rahul; Singh, Poonam; John, Jebin Jacob; Gujar, Niranjan L

2018-04-03

Cyanide-induced chemical hypoxia is responsible for pronounced oxidative damage in the central nervous system. The disruption of mitochondrial oxidative metabolism has been associated with upregulation of uncoupling proteins (UCPs). The present study addresses the dose- and time-dependent effect of sub-acute cyanide exposure on various non-enzymatic and enzymatic oxidative stress markers and their correlation with inducible-nitric oxide synthase (iNOS) and uncoupling protein-2 (UCP-2) expression. Animals received (oral) triple distilled water (vehicle control), 0.25 LD50 potassium cyanide (KCN) or 0.50 LD50 KCN daily for 21 d. Animals were sacrificed on 7, 14 and 21 d post-exposure to measure serum cyanide and nitrite, and brain malondialdehyde (MDA), reduced glutathione (GSH), glutathione disulfide (GSSG), cytochrome c oxidase (CCO), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and catalase (CA) levels, together with iNOS and UCP-2 expression, and DNA damage. The study revealed that a dose- and time-dependent increase in cyanide concentration was accompanied by corresponding CCO inhibition and elevated MDA levels. Decrease in GSH levels was not followed by reciprocal change in GSSG levels. Diminution of SOD, GPx, GR and CA activity was congruent with elevated nitrite levels and upregulation of iNOS and UCP-2 expression, without any DNA damage. It was concluded that long-term cyanide exposure caused oxidative stress, accompanied by upregulation of iNOS. The upregulation of UCP-2 further sensitized the cells to cyanide and accentuated the oxidative stress, which was independent of DNA damage.

Magnetic Enhancement of Stem Cell-Targeted Delivery into the Brain Following MR-Guided Focused Ultrasound for Opening the Blood-Brain Barrier.

PubMed

Shen, Wei-Bin; Anastasiadis, Pavlos; Nguyen, Ben; Yarnell, Deborah; Yarowsky, Paul J; Frenkel, Victor; Fishman, Paul S

2017-07-01

Focused ultrasound (FUS)-mediated blood-brain barrier disruption (BBBD) can enable even large therapeutics such as stem cells to enter the brain from the bloodstream. However, the efficiency is relatively low. Our previous study showed that human neural progenitor cells (hNPCs) loaded with superparamagnetic iron oxide nanoparticles (SPIONs) in culture were attracted by an external magnetic field. In vivo, enhanced brain retention was observed near a magnet mounted on the skull in a rat model of traumatic brain injury, where BBBD also occurs. The goal of the current study was to determine whether magnetic attraction of SPION-loaded hNPCs would also enhance their retention in the brain after FUS-mediated BBBD. A small animal magnetic resonance imaging (MRI)-guided FUS system operating at 1.5 MHz was used to treat rats (∼120 g) without tissue damage or hemorrhage. Evidence of successful BBBD was validated with both radiologic enhancement of gadolinium on postsonication TI MRI and whole brain section visualization of Evans blue dye. The procedure was then combined with the application of a powerful magnet to the head directly after intravenous injection of the hNPCs. Validation of cells within the brain was performed by staining with Perls' Prussian blue for iron and by immunohistochemistry with a human-specific antigen. By injecting equal numbers of iron oxide (SPIONs) and noniron oxide nanoparticles-loaded hNPCs, each labeled with a different fluorophore, we found significantly greater numbers of SPIONs-loaded cells retained in the brain at the site of BBBD as compared to noniron loaded cells. This result was most pronounced in regions of the brain closest to the skull (dorsal cortex) in proximity to the magnet surface. A more powerful magnet and a Halbach magnetic array resulted in more effective retention of SPION-labeled cells in even deeper brain regions such as the striatum and ventral cortex. There, up to 90% of hNPCs observed contained SPIONs compared to 60% to 70% with the less powerful magnet. Fewer cells were observed at 24 h posttreatment compared to 2 h (primarily in the dorsal cortex). These results demonstrate that magnetic attraction can substantially enhance the retention of stem cells after FUS-mediated BBBD. This procedure could provide a safer and less invasive approach for delivering stem cells to the brain, compared to direct intracranial injections, substantially reducing the risk of bleeding and infection.

Nanomedicine and its application in treatment of microglia-mediated neuroinflammation.

PubMed

Baby, N; Patnala, R; Ling, Eng-Ang; Dheen, S T

2014-01-01

Nanomedicine, an emerging therapeutic tool in current medical frontiers, offers targeted drug delivery for many neurodegenerative disorders. Neuroinflammation, a hallmark of many neurodegenerative disorders, is mediated by microglia, the resident immunocompetent cells of the central nervous system (CNS). Microglial cells respond to various stimuli in the CNS resulting in their activation which may have a beneficial or a detrimental effect. In general, the activated microglia remove damaged neurons and infectious agents by phagocytosis, therefore being neuroprotective. However, their chronic activation exacerbates neuronal damage through excessive release of proinflammatory cytokines, chemokines and other inflammatory mediators which contribute to neuroinflammation and subsequent neurodegeneration in the CNS. Hence, controlling microglial inflammatory response and their proliferation has been considered as an important aspect in treating neurodegenerative disorders. Regulatory factors that control microglial activation and proliferation also play an important role in microglia-mediated neuroinflammation and neurotoxicity. Various anti-inflammatory drugs and herbal compounds have been identified in treating microglia-mediated neuroinflammation in the CNS. However, hurdles in crossing blood brain barrier (BBB), expression of metabolic enzymes, presence of efflux pumps and several other factors prevent the entry of these drugs into the CNS. Use of non-degradable delivery systems and microglial activation in response to the drug delivery system further complicate drug delivery to the CNS. Nanomedicine, a nanoparticle-mediated drug delivery system, exhibits immense potential to overcome these hurdles in drug delivery to the CNS enabling new alternatives with significant promises in revolutionising the field of neurodegenerative disease therapy. This review attempts to summarise various regulatory factors in microglia, existing therapeutic strategies in controlling microglial activation, and how nanotechnology can serve to improve the delivery of therapeutic drugs across the BBB for treating microglia- mediated neuroinflammation and neurodegeneration.

From the Bottom-Up: Chemotherapy and Gut-Brain Axis Dysregulation.

PubMed

Bajic, Juliana E; Johnston, Ian N; Howarth, Gordon S; Hutchinson, Mark R

2018-01-01

The central nervous system and gastrointestinal tract form the primary targets of chemotherapy-induced toxicities. Symptoms associated with damage to these regions have been clinically termed chemotherapy-induced cognitive impairment and mucositis. Whilst extensive literature outlines the complex etiology of each pathology, to date neither chemotherapy-induced side-effect has considered the potential impact of one on the pathogenesis of the other disorder. This is surprising considering the close bidirectional relationship shared between each organ; the gut-brain axis. There are complex multiple pathways linking the gut to the brain and vice versa in both normal physiological function and disease. For instance, psychological and social factors influence motility and digestive function, symptom perception, and behaviors associated with illness and pathological outcomes. On the other hand, visceral pain affects central nociception pathways, mood and behavior. Recent interest highlights the influence of functional gut disorders, such as inflammatory bowel diseases and irritable bowel syndrome in the development of central comorbidities. Gut-brain axis dysfunction and microbiota dysbiosis have served as key portals in understanding the potential mechanisms associated with these functional gut disorders and their effects on cognition. In this review we will present the role gut-brain axis dysregulation plays in the chemotherapy setting, highlighting peripheral-to-central immune signaling mechanisms and their contribution to neuroimmunological changes associated with chemotherapy exposure. Here, we hypothesize that dysregulation of the gut-brain axis plays a major role in the intestinal, psychological and neurological complications following chemotherapy. We pay particular attention to evidence surrounding microbiota dysbiosis, the role of intestinal permeability, damage to nerves of the enteric and peripheral nervous systems and vagal and humoral mediated changes.

The scaffold protein Nde1 safeguards the brain genome during S phase of early neural progenitor differentiation

PubMed Central

Houlihan, Shauna L; Feng, Yuanyi

2014-01-01

Successfully completing the S phase of each cell cycle ensures genome integrity. Impediment of DNA replication can lead to DNA damage and genomic disorders. In this study, we show a novel function for NDE1, whose mutations cause brain developmental disorders, in safeguarding the genome through S phase during early steps of neural progenitor fate restrictive differentiation. Nde1 mutant neural progenitors showed catastrophic DNA double strand breaks concurrent with the DNA replication. This evoked DNA damage responses, led to the activation of p53-dependent apoptosis, and resulted in the reduction of neurons in cortical layer II/III. We discovered a nuclear pool of Nde1, identified the interaction of Nde1 with cohesin and its associated chromatin remodeler, and showed that stalled DNA replication in Nde1 mutants specifically occurred in mid-late S phase at heterochromatin domains. These findings suggest that NDE1-mediated heterochromatin replication is indispensible for neuronal differentiation, and that the loss of NDE1 function may lead to genomic neurological disorders. DOI: http://dx.doi.org/10.7554/eLife.03297.001 PMID:25245017

Inflammation and Alzheimer’s disease

PubMed Central

Akiyama, Haruhiko; Barger, Steven; Barnum, Scott; Bradt, Bonnie; Bauer, Joachim; Cole, Greg M.; Cooper, Neil R.; Eikelenboom, Piet; Emmerling, Mark; Fiebich, Berndt L.; Finch, Caleb E.; Frautschy, Sally; Griffin, W.S.T.; Hampel, Harald; Hull, Michael; Landreth, Gary; Lue, Lih–Fen; Mrak, Robert; Mackenzie, Ian R.; McGeer, Patrick L.; O’Banion, M. Kerry; Pachter, Joel; Pasinetti, Guilio; Plata–Salaman, Carlos; Rogers, Joseph; Rydel, Russell; Shen, Yong; Streit, Wolfgang; Strohmeyer, Ronald; Tooyoma, Ikuo; Van Muiswinkel, Freek L.; Veerhuis, Robert; Walker, Douglas; Webster, Scott; Wegrzyniak, Beatrice; Wenk, Gary; Wyss–Coray, Tony

2013-01-01

Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimer’s disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble amyloid β peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, microlocalized, and present from early preclinical to terminal stages of AD, local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators is also discrete, microlocalized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to significantly exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clinical studies, although still in their infancy, strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder. PMID:10858586

Evaluation and Education of Children with Brain Damage.

ERIC Educational Resources Information Center

Bortner, Morton, Ed.

Ten papers consider brain damaged children. Brain damage is considered as an educational category, and the following aspects of evaluation are treated: disorders of oral communication, hearing impairment, psychological deficit, psychiatric factors, and neurological considerations. Educational strategies discussed include the educational methods of…

Modulation of taurine release by glutamate receptors and nitric oxide.

PubMed

Oja, S S; Saransaari, P

2000-11-01

Taurine is held to function as a modulator and osmoregulator in the central nervous system, being of particular importance in the immature brain. In view of the possible involvement of excitatory pathways in the regulation of taurine function in the brain, the interference of glutamate receptors with taurine release from different tissue preparations in vitro and from the brain in vivo is of special interest. The release of taurine from the brain is enhanced by glutamate receptor agonists. This enhancement is inhibited by the respective receptor antagonists both in vitro and in vivo. The ionotropic N-methyl-D-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor agonists appear to be the most effective in enhancing taurine release, their effects being receptor-mediated. Kainate is less effective, particularly in adults. Of the glutamate receptors, the NMDA class seems to be the most susceptible to modulation by nitric oxide. Nitric oxide also modulates taurine release, enhancing the basal release in both immature and mature hippocampus, whereas the K(+)-stimulated release is generally inhibited. Metabotropic glutamate receptors also participate in the regulation of taurine release, group I metabotropic glutamate receptors potentiating the release in the developing hippocampus, while group III receptors may be involved in the adult. Under various cell-damaging conditions, including ischemia, hypoxia and hypoglycemia, taurine release is enhanced, together with an enhanced release of excitatory amino acids. The increase in extracellular taurine upon excessive stimulation of glutamate receptors and under cell-damaging conditions may serve as an important protective mechanism against excitotoxicity, being particularly effective in the immature brain.

Molecular Regulation of DNA Damage-Induced Apoptosis in Neurons of Cerebral Cortex

PubMed Central

Liu, Zhiping; Pipino, Jacqueline; Chestnut, Barry; Landek, Melissa A.

2009-01-01

Cerebral cortical neuron degeneration occurs in brain disorders manifesting throughout life, but the mechanisms are understood poorly. We used cultured embryonic mouse cortical neurons and an in vivo mouse model to study mechanisms of DNA damaged-induced apoptosis in immature and differentiated neurons. p53 drives apoptosis of immature and differentiated cortical neurons through its rapid and prominent activation stimulated by DNA strand breaks induced by topoisomerase-I and -II inhibition. Blocking p53-DNA transactivation with α-pifithrin protects immature neurons; blocking p53-mitochondrial functions with μ-pifithrin protects differentiated neurons. Mitochondrial death proteins are upregulated in apoptotic immature and differentiated neurons and have nonredundant proapoptotic functions; Bak is more dominant than Bax in differentiated neurons. p53 phosphorylation is mediated by ataxia telangiectasia mutated (ATM) kinase. ATM inactivation is antiapoptotic, particularly in differentiated neurons, whereas inhibition of c-Abl protects immature neurons but not differentiated neurons. Cell death protein expression patterns in mouse forebrain are mostly similar to cultured neurons. DNA damage induces prominent p53 activation and apoptosis in cerebral cortex in vivo. Thus, DNA strand breaks in cortical neurons induce rapid p53-mediated apoptosis through actions of upstream ATM and c-Abl kinases and downstream mitochondrial death proteins. This molecular network operates through variations depending on neuron maturity. PMID:18820287

Lymphotropic Virions Affect Chemokine Receptor-Mediated Neural Signaling and Apoptosis: Implications for Human Immunodeficiency Virus Type 1-Associated Dementia

PubMed Central

Zheng, Jialin; Ghorpade, Anuja; Niemann, Douglas; Cotter, Robin L.; Thylin, Michael R.; Epstein, Leon; Swartz, Jennifer M.; Shepard, Robin B.; Liu, Xiaojuan; Nukuna, Adeline; Gendelman, Howard E.

1999-01-01

Chemokine receptors pivotal for human immunodeficiency virus type 1 (HIV-1) infection in lymphocytes and macrophages (CCR3, CCR5, and CXCR4) are expressed on neural cells (microglia, astrocytes, and/or neurons). It is these cells which are damaged during progressive HIV-1 infection of the central nervous system. We theorize that viral coreceptors could effect neural cell damage during HIV-1-associated dementia (HAD) without simultaneously affecting viral replication. To these ends, we studied the ability of diverse viral strains to affect intracellular signaling and apoptosis of neurons, astrocytes, and monocyte-derived macrophages. Inhibition of cyclic AMP, activation of inositol 1,4,5-trisphosphate, and apoptosis were induced by diverse HIV-1 strains, principally in neurons. Virions from T-cell-tropic (T-tropic) strains (MN, IIIB, and Lai) produced the most significant alterations in signaling of neurons and astrocytes. The HIV-1 envelope glycoprotein, gp120, induced markedly less neural damage than purified virions. Macrophage-tropic (M-tropic) strains (ADA, JR-FL, Bal, MS-CSF, and DJV) produced the least neural damage, while 89.6, a dual-tropic HIV-1 strain, elicited intermediate neural cell damage. All T-tropic strain-mediated neuronal impairments were blocked by the CXCR4 antibody, 12G5. In contrast, the M-tropic strains were only partially blocked by 12G5. CXCR4-mediated neuronal apoptosis was confirmed in pure populations of rat cerebellar granule neurons and was blocked by HA1004, an inhibitor of calcium/calmodulin-dependent protein kinase II, protein kinase A, and protein kinase C. Taken together, these results suggest that progeny HIV-1 virions can influence neuronal signal transduction and apoptosis. This process occurs, in part, through CXCR4 and is independent of CD4 binding. T-tropic viruses that traffic in and out of the brain during progressive HIV-1 disease may play an important role in HAD neuropathogenesis. PMID:10482576

Resveratrol counteracts lipopolysaccharide-mediated microglial inflammation by modulating a SOCS-1 dependent signaling pathway.

PubMed

Dragone, Teresa; Cianciulli, Antonia; Calvello, Rosa; Porro, Chiara; Trotta, Teresa; Panaro, Maria Antonietta

2014-09-01

Brain damage or exposure to inflammatory agents provokes the activation of microglia and secretion of pro-inflammatory and neurotoxic mediators responsible for neuronal loss. Several lines of evidence show that resveratrol, a natural non-flavonoid polyphenol, may exert a neuroprotective action in neurodegenerative diseases. Suppressor of cytokine signaling (SOCS) proteins are a family of eight members expressed by immune cells and the central nervous system (CNS) cells, that regulate immune processes within the CNS, including microglia activation. We demonstrate that resveratrol had anti-inflammatory effects in murine N13 microglial cells stimulated with lipopolysaccharide (LPS), through up-regulating SOCS-1 expression. Interestingly, in SOCS-1-silenced cells resveratrol failed to play a protective role after LPS treatment. Our data demonstrate that resveratrol can impair microglia activation by activating a SOCS-1 mediated signaling pathway. Copyright © 2014 Elsevier Ltd. All rights reserved.

Interhemispheric and Intrahemispheric Control of Emotion: A Focus on Unilateral Brain Damage.

ERIC Educational Resources Information Center

Borod, Joan C.

1992-01-01

Discusses neocortical contributions to emotional processing. Examines parameters critical to neuropsychological study of emotion: interhemispheric and intrahemispheric factors, processing mode, and communication channel. Describes neuropsychological theories of emotion. Reviews studies of right-brain-damaged, left-brain-damaged, and normal adults,…

Multiple sessions of liposomal doxorubicin delivery via focused ultrasound mediated blood-brain barrier disruption: a safety study.

PubMed

Aryal, Muna; Vykhodtseva, Natalia; Zhang, Yong-Zhi; McDannold, Nathan

2015-04-28

Transcranial MRI-guided focused ultrasound is a rapidly advancing method for delivering therapeutic and imaging agents to the brain. It has the ability to facilitate the passage of therapeutics from the vasculature to the brain parenchyma, which is normally protected by the blood-brain barrier (BBB). The method's main advantages are that it is both targeted and noninvasive, and that it can be easily repeated. Studies have shown that liposomal doxorubicin (Lipo-DOX), a chemotherapy agent with promise for tumors in the central nervous system, can be delivered into the brain across BBB. However, prior studies have suggested that doxorubicin can be significantly neurotoxic, even at small concentrations. Here, we studied whether multiple sessions of Lipo-DOX administered after FUS-induced BBB disruption (FUS-BBBD) induces severe adverse events in the normal brain tissues. First, we used fluorometry to measure the doxorubicin concentrations in the brain after FUS-BBBD to ensure that a clinically relevant doxorubicin concentration was achieved in the brain. Next, we performed three weekly sessions with FUS-BBBD±Lipo-DOX administration. Five to twelve targets were sonicated each week, following a schedule described previously in a survival study in glioma-bearing rats (Aryal et al., 2013). Five rats received three weekly sessions where i.v. injected Lipo-DOX was combined with FUS-BBBD; an additional four rats received FUS-BBBD only. Animals were euthanized 70days from the first session and brains were examined in histology. We found that clinically-relevant concentrations of doxorubicin (4.8±0.5μg/g) were delivered to the brain with the sonication parameters (0.69MHz; 0.55-0.81MPa; 10ms bursts; 1Hz PRF; 60s duration), microbubble concentration (Definity, 10μl/kg), and the administered Lipo-DOX dose (5.67mg/kg) used. The resulting concentration of Lipo-DOX was reduced by 32% when it was injected 10min after the last sonication compared to cases where the agent was delivered before sonication. In histology, the severe neurotoxicity observed in some previous studies with doxorubicin by other investigators was not observed here. However, four of the five rats who received FUS-BBBD and Lipo-DOX had regions (dimensions: 0.5-2mm) at the focal targets with evidence of minor prior damage, either a small scar (n=4) or a small cyst (n=1). The focal targets were unaffected in rats who received FUS-BBBD alone. The result indicates that while delivery of Lipo-DOX to the rat brain might result in minor damage, the severe neurotoxicity seen in earlier works does not appear to occur with delivery via FUS-BBB disruption. The damage may be related to capillary damage produced by inertial cavitation, which might have resulted in excessive doxorubicin concentrations in some areas. Copyright © 2015 Elsevier B.V. All rights reserved.

The blood-brain barrier as a target in traumatic brain injury treatment.

PubMed

Thal, Serge C; Neuhaus, Winfried

2014-11-01

Traumatic brain injury (TBI) is one of the most frequent causes of death in the young population. Several clinical trials have unsuccessfully focused on direct neuroprotective therapies. Recently immunotherapeutic strategies shifted into focus of translational research in acute CNS diseases. Cross-talk between activated microglia and blood-brain barrier (BBB) could initiate opening of the BBB and subsequent recruitment of systemic immune cells and mediators into the brain. Stabilization of the BBB after TBI could be a promising strategy to limit neuronal inflammation, secondary brain damage and acute neurodegeneration. This review provides an overview on the pathophysiology of TBI and brain edema formation including definitions and classification of TBI, current clinical treatment strategies, as well as current understanding on the underlying cellular processes. A summary of in vivo and in vitro models to study different aspects of TBI is presented. Three mechanisms proposed for stabilization of the BBB, myosin light chain kinases, glucocorticoid receptors and peroxisome proliferator-activated receptors are reviewed for their influence on barrier-integrity and outcome after TBI. In conclusion, the BBB is recommended as a promising target for the treatment of traumatic brain injury, and it is suggested that a combination of BBB stabilization and neuroprotectants may improve therapeutic success. Copyright © 2015 IMSS. Published by Elsevier Inc. All rights reserved.

Let thy left brain know what thy right brain doeth: Inter-hemispheric compensation of functional deficits after brain damage.

PubMed

Bartolomeo, Paolo; Thiebaut de Schotten, Michel

2016-12-01

Recent evidence revealed the importance of inter-hemispheric communication for the compensation of functional deficits after brain damage. This review summarises the biological consequences observed using histology as well as the longitudinal findings measured with magnetic resonance imaging methods in brain damaged animals and patients. In particular, we discuss the impact of post-stroke brain hyperactivity on functional recovery in relation to time. The reviewed evidence also suggests that the proportion of the preserved functional network both in the lesioned and in the intact hemispheres, rather than the simple lesion location, determines the extent of functional recovery. Hence, future research exploring longitudinal changes in patients with brain damage may unveil potential biomarkers underlying functional recovery. Copyright © 2016 Elsevier Ltd. All rights reserved.

Focused ultrasound-mediated noninvasive blood-brain barrier modulation: preclinical examination of efficacy and safety in various sonication parameters.

PubMed

Shin, Jaewoo; Kong, Chanho; Cho, Jae Sung; Lee, Jihyeon; Koh, Chin Su; Yoon, Min-Sik; Na, Young Cheol; Chang, Won Seok; Chang, Jin Woo

2018-02-01

OBJECTIVE The application of pharmacological therapeutics in neurological disorders is limited by the ability of these agents to penetrate the blood-brain barrier (BBB). Focused ultrasound (FUS) has recently gained attention for its potential application as a method for locally opening the BBB and thereby facilitating drug delivery into the brain parenchyma. However, this method still requires optimization to maximize its safety and efficacy for clinical use. In the present study, the authors examined several sonication parameters of FUS influencing BBB opening in small animals. METHODS Changes in BBB permeability were observed during transcranial sonication using low-intensity FUS in 20 adult male Sprague-Dawley rats. The authors examined the effects of FUS sonication with different sonication parameters, varying acoustic pressure, center frequency, burst duration, microbubble (MB) type, MB dose, pulse repetition frequency (PRF), and total exposure time. The focal region of BBB opening was identified by Evans blue dye. Additionally, H & E staining was used to identify blood vessel damage. RESULTS Acoustic pressure amplitude and burst duration were closely associated with enhancement of BBB opening efficiency, but these parameters were also highly correlated with tissue damage in the sonicated region. In contrast, MB types, MB dose, total exposure time, and PRF had an influence on BBB opening without conspicuous tissue damage after FUS sonication. CONCLUSIONS The study aimed to identify these influential conditions and provide safety and efficacy values for further studies. Future work based on the current results is anticipated to facilitate the implementation of FUS sonication for drug delivery in various CNS disease states in the near future.

Molecular mechanisms of neuroprotective action of immunosuppressants--facts and hypotheses.

PubMed

Kaminska, Bozena; Gaweda-Walerych, Katarzyna; Zawadzka, Malgorzata

2004-01-01

Cyclosporin A (CsA) and FK506 (Tacrolimus) are short polypeptides which block the activation of lymphocytes and other immune system cells. Immunosuppressants exert neuroprotective and neurotrophic action in traumatic brain injury, sciatic nerve injury, focal and global ischemia in animals. Their neuroprotective actions are not understood and many hypotheses have been formed to explain such effects. We discuss a role of drug target--calcineurin in neuroprotective action of immunosuppressants. Protein dephosphorylation by calcineurin plays an important role in neuronal signal transduction due to its ability to regulate the activity of ion channels, glutamate release, and synaptic plasticity. In vitro FK506 protects cortex neurons from NMDA-induced death, augments NOS phosphorylation inhibiting its activity and NO synthesis. However, in vivo experiments demonstrated that FK506 in neuroprotective doses did not block excitotoxic cell death nor did it alter NO production during ischemia/reperfusion. Tissue damage in ischemia is the result of a complex pathophysiological cascade, which comprises a variety of distinct pathological events. Resident non-neuronal brain cells respond rapidly to neuronal cell death and may have both deleterious and useful role in neuronal damage. There is increasing evidence that reactive gliosis and post-ischemic inflammation involving microglia contribute to ischemic damage. We have demonstrated that FK506 modulates hypertrophic/proliferative responses and proinflammatory cytokine expression in astrocytes and microglia in vitro and in focal transient brain ischemia. Our findings suggest that astrocytes and microglia are direct targets of FK506 and modulation of glial response and inflammation is a possible mechanism of FK506-mediated neuroprotection in ischemia.

CCL11 promotes migration and proliferation of mouse neural progenitor cells.

PubMed

Wang, Feifei; Baba, Nobuyasu; Shen, Yuan; Yamashita, Tatsuyuki; Tsuru, Emi; Tsuda, Masayuki; Maeda, Nagamasa; Sagara, Yusuke

2017-02-07

Neonatal hypoxia-ischemia induces massive brain damage during the perinatal period, resulting in long-term consequences to central nervous system structural and functional maturation. Although neural progenitor cells (NPCs) migrate through the parenchyma and home in to injury sites in the rodent brain, the molecular mechanisms are unknown. We examined the role of chemokines in mediating NPC migration after neonatal hypoxic-ischemic brain injury. Nine-day-old mice were exposed to a 120-minute hypoxia following unilateral carotid occlusion. Chemokine levels were quantified in mouse brain extract. Migration and proliferation assays were performed using embryonic and infant mouse NPCs. The neonatal hypoxic-ischemic brain injury resulted in an ipsilateral lesion, which was extended to the cortical and striatal areas. NPCs migrated toward an injured area, where a marked increase of CC chemokines was detected. In vitro studies showed that incubation of NPCs with recombinant mouse CCL11 promoted migration and proliferation. These effects were partly inhibited by a CCR3 antagonist, SB297006. Our data implicate an important effect of CCL11 for mouse NPCs. The effective activation of NPCs may offer a promising strategy for neuroregeneration in neonatal hypoxic-ischemic brain injury.

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

Gilat, E.; Kadar, T.; Levy, A.

Centrally mediated seizures and convulsions are common consequences of exposure to organophosphates (OPs). These seizures rapidly progress to status epilepticus (SE) and contribute to profound brain injury. Effective management of these seizures is critical for minimization of brain damage. Nasal application of midazolam (1.5 mg/kg) after 5 min of sarin-induced electrographic seizure activity (EGSA) ameliorated EGSA and convulsive behavior (238 {+-} 90 s). Identical treatment after 30 min was not sufficient to ameliorate ECoG paradoxical activity and convulsive behavior. Nasal midazolam (1.5 mg/kg), together with scopolamine (1 mg/kg, im) after 5 min of EGSA, exerted a powerful and rapid anticonvulsantmore » effect (53 {+-} 10 s). Delaying the same treatment to 30 min of EGSA leads to attenuation of paroxysmal ECoG activity in all cases but total cessation of paroxysmal activity was not observed in most animals tested. Cognitive tests utilizing the Morris Water Maze demonstrated that nasal midazolam alone or together with scopolamine (im), administered after 5 min of convulsions, abolished the effect of sarin on learning. Both these treatments, when given after 30 min of convulsions, only decreased the sarin-induced learning impairments. Whereas rats which were not subject to the anticonvulsant agents did not show any memory for the platform location, both treatments (at 5 min as well as at 30 min) completely abolished the memory deficits. Both treatments equally blocked the impairment of reversal learning when given at 5 min. However, when administered after 30 min, midazolam alone reversed the impairments in reversal learning, while midazolam with scopolamine did not. Rats exposed to sarin and treated with the therapeutic regimen with the exclusion of midazolam exhibited severe brain lesions that encountered the hippocampus, pyriform cortex, and thalamus. Nasal midazolam at 5 min prevented brain damage, while delaying the midazolam treatment to 30 min of EGSA resulted in brain damage. The addition of scopolamine to midazolam did not alter the above observation. In summary, nasal midazolam treatment briefly after initiation of OP-induced seizure leads to cessation of EGSA and prevented brain lesions and behavioral deficiencies in the rat model.« less

Influence of mild traumatic brain injury during pediatric stage on short-term memory and hippocampal apoptosis in adult rats.

PubMed

Park, Mi-Sook; Oh, Hyean-Ae; Ko, Il-Gyu; Kim, Sung-Eun; Kim, Sang-Hoon; Kim, Chang-Ju; Kim, Hyun-Bae; Kim, Hong

2014-06-01

Traumatic brain injury (TBI) is a leading cause of neurological deficit in the brain, which induces short- and long-term brain damage, cognitive impairment with/without structural alteration, motor deficits, emotional problems, and death both in children and adults. In the present study, we evaluated whether mild TBI in childhood causes persisting memory impairment until adulthood. Moreover, we investigated the influence of mild TBI on memory impairment in relation with hippocampal apoptosis. For this, step-down avoidance task, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, and immunohistochemistry for caspase-3 were performed. Male Sprague-Dawley rats were used in the experiments. The animals were randomly divided into two groups: sham-operation group and TBI-induction group. The mild TBI model was created with an electromagnetic contusion device activated at a velocity of 3.0 m/sec. The results showed that mild TBI during the pediatric stage significantly decreased memory retention. The numbers of TUNEL-positive and caspase-3-positive cells were increased in the TBI-induction group compared to those in the sham-operation group. Defective memory retention and apoptosis sustained up to the adult stage. The present results shows that mild TBI induces long-lasting cognitive impairment from pediatric to adult stages in rats through the high level of apoptosis. The finding of this study suggests that children with mild TBI may need intensive treatments for the reduction of long-lasting cognitive impairment by secondary neuronal damage.

Neuregulin-1 is Neuroprotective in a Rat Model of Organophosphate-Induced Delayed Neuronal Injury

PubMed Central

Li, Yonggang; Lein, Pamela J.; Liu, Cuimei; Bruun, Donald A.; Giulivi, Cecilia; Ford, Gregory; Tewolde, Teclemichael; Ross-Inta, Catherine; Ford, Byron D.

2012-01-01

Current medical countermeasures against organophosphate (OP) nerve agents are effective in reducing mortality, but do not sufficiently protect the CNS from delayed brain damage and persistent neurological symptoms. In this study, we examined the efficacy of neuregulin-1 (NRG-1) in protecting against delayed neuronal cell death following acute intoxication with the OP diisopropylfluorophosphate (DFP). Adult male Sprague Dawley rats were pretreated with pyridostigmine (0.1 mg/kg BW, i.m.) and atropine methylnitrate (20 mg/kg BW, i.m.) prior to DFP (9 mg/kg BW, i.p.) intoxication to increase survival and reduce peripheral signs of cholinergic toxicity but not prevent DFP-induced seizures or delayed neuronal injury. Pretreatment with NRG-1 did not protect against seizures in rats exposed to DFP. However, neuronal injury was significantly reduced in most brain regions by pretreatment with NRG-1 isoforms NRG-EGF (3.2 μg/kg BW, i.a) or NRG-GGF2 (48 μg/kg BW, i.a.) as determined by FluroJade-B labeling in multiple brain regions at 24 h post-DFP injection. NRG-1 also blocked apoptosis and oxidative stress-mediated protein damage in the brains of DFP-intoxicated rats. Administration of NRG-1 at 1 h after DFP injection similarly provided significant neuroprotection against delayed neuronal injury. These findings identify NRG-1 as a promising adjuvant therapy to current medical countermeasures for enhancing neuroprotection against acute OP intoxication. PMID:22583949

P7C3 neuroprotective chemicals block axonal degeneration and preserve function after traumatic brain injury.

PubMed

Yin, Terry C; Britt, Jeremiah K; De Jesús-Cortés, Héctor; Lu, Yuan; Genova, Rachel M; Khan, Michael Z; Voorhees, Jaymie R; Shao, Jianqiang; Katzman, Aaron C; Huntington, Paula J; Wassink, Cassie; McDaniel, Latisha; Newell, Elizabeth A; Dutca, Laura M; Naidoo, Jacinth; Cui, Huxing; Bassuk, Alexander G; Harper, Matthew M; McKnight, Steven L; Ready, Joseph M; Pieper, Andrew A

2014-09-25

The P7C3 class of neuroprotective aminopropyl carbazoles has been shown to block neuronal cell death in models of neurodegeneration. We now show that P7C3 molecules additionally preserve axonal integrity after injury, before neuronal cell death occurs, in a rodent model of blast-mediated traumatic brain injury (TBI). This protective quality may be linked to the ability of P7C3 molecules to activate nicotinamide phosphoribosyltransferase, the rate-limiting enzyme in nicotinamide adenine dinucleotide salvage. Initiation of daily treatment with our recently reported lead agent, P7C3-S243, 1 day after blast-mediated TBI blocks axonal degeneration and preserves normal synaptic activity, learning and memory, and motor coordination in mice. We additionally report persistent neurologic deficits and acquisition of an anxiety-like phenotype in untreated animals 8 months after blast exposure. Optimized variants of P7C3 thus offer hope for identifying neuroprotective agents for conditions involving axonal damage, neuronal cell death, or both, such as occurs in TBI. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Phloretin ameliorates 2-chlorohexadecanal-mediated brain microvascular endothelial cell dysfunction in vitro.

PubMed

Ullen, Andreas; Fauler, Günter; Bernhart, Eva; Nusshold, Christoph; Reicher, Helga; Leis, Hans-Jörg; Malle, Ernst; Sattler, Wolfgang

2012-11-01

2-Chlorohexadecanal (2-ClHDA), a chlorinated fatty aldehyde, is formed via attack on ether-phospholipids by hypochlorous acid (HOCl) that is generated by the myeloperoxidase-hydrogen peroxide-chloride system of activated leukocytes. 2-ClHDA levels are elevated in atherosclerotic lesions, myocardial infarction, and neuroinflammation. Neuroinflammatory conditions are accompanied by accumulation of neutrophils (an ample source of myeloperoxidase) in the brain. Microvessel damage by inflammatory mediators and/or reactive oxidants can induce blood-brain barrier (BBB) dysfunction, a pathological condition leading to cerebral edema, brain hemorrhage, and neuronal death. In this in vitro study we investigated the impact of 2-ClHDA on brain microvascular endothelial cells (BMVEC), which constitute the morphological basis of the BBB. We show that exogenously added 2-ClHDA is subject to rapid uptake and metabolism by BMVEC. Using C16 structural analogues of 2-ClHDA we found that the cytotoxic potential decreases in the following order: 2-ClHDA>hexadecanal>palmitic acid>2-ClHDA-dimethylacetal. 2-ClHDA induces loss of barrier function, mitochondrial dysfunction, apoptosis via activation of caspase 3, and altered intracellular redox balance. Finally we investigated potential protective effects of several natural polyphenols on in vitro BBB function. Of the compounds tested, phloretin almost completely abrogated 2-ClHDA-induced BMVEC barrier dysfunction and cell death. These data suggest that 2-ClHDA has the potential to induce BBB breakdown under inflammatory conditions and that phloretin confers protection in this experimental setting. Copyright © 2012 Elsevier Inc. All rights reserved.

S. aureus-dependent microglial activation is selectively attenuated by the cyclopentenone prostaglandin 15-deoxy-Delta12,14- prostaglandin J2 (15d-PGJ2).

PubMed

Kielian, Tammy; McMahon, Meredith; Bearden, Edward D; Baldwin, Aaron C; Drew, Paul D; Esen, Nilufer

2004-09-01

Microglial activation is a hallmark of brain abscess. The continual release of proinflammatory mediators by microglia following bacterial challenge may contribute, in part, to the destruction of surrounding normal tissue characteristic of brain abscess. Therefore, attenuating chronic microglial activation during the course of CNS bacterial infections may have therapeutic benefits. The purpose of this study was to evaluate the ability of the natural peroxisome proliferator-activated receptor (PPAR)-gamma agonist 15-deoxy-Delta12,14- prostaglandin J2 (15d-PGJ2) to modulate microglial activation in response to Staphylococcus aureus, one of the main etiologic agents of brain abscess in humans. 15d-PGJ2 was a potent inhibitor of proinflammatory cytokine (IL-1beta, TNF-alpha, IL-12 p40) and CC chemokine (MIP-1beta, MCP-1) production in primary microglia, but had no effect upon the expression of select CXC chemokines (MIP-2, KC). 15d-PGJ2 also selectively inhibited the S. aureus-dependent increase in microglial TLR2, CD14, MHC class II, and CD40 expression, whereas it had no effect on the co-stimulatory molecules CD80 and CD86. Microarray analysis revealed additional inflammatory mediators modulated by 15d-PGJ2 in primary microglia following S. aureus exposure, the majority of which were chemokines. These results suggest that suppressing microglial activation through the use of 15d-PGJ2 may lead to the sparing of damage to normal brain parenchyma that often results from brain abscess. Copyright 2004 International Society for Neurochemistry

Antioxidant and prooxidant effects of polyphenol compounds on copper-mediated DNA damage.

PubMed

Perron, Nathan R; García, Carla R; Pinzón, Julio R; Chaur, Manuel N; Brumaghim, Julia L

2011-05-01

Inhibition of copper-mediated DNA damage has been determined for several polyphenol compounds. The 50% inhibition concentration values (IC(50)) for most of the tested polyphenols are between 8 and 480 μM for copper-mediated DNA damage prevention. Although most tested polyphenols were antioxidants under these conditions, they generally inhibited Cu(I)-mediated DNA damage less effectively than Fe(II)-mediated damage, and some polyphenols also displayed prooxidant activity. Because semiquinone radicals and hydroxyl radical adducts were detected by EPR spectroscopy in solutions of polyphenols, Cu(I), and H(2)O(2), it is likely that weak polyphenol-Cu(I) interactions permit a redox-cycling mechanism, whereby the necessary reactants to cause DNA damage (Cu(I), H(2)O(2), and reducing agents) are regenerated. The polyphenol compounds that prevent copper-mediated DNA damage likely follow a radical scavenging pathway as determined by EPR spectroscopy. Copyright © 2011 Elsevier Inc. All rights reserved.

Hydroxysafflor Yellow A Attenuates Neuron Damage by Suppressing the Lipopolysaccharide-Induced TLR4 Pathway in Activated Microglial Cells.

PubMed

Lv, Yanni; Qian, Yisong; Ou-Yang, Aijun; Fu, Longsheng

2016-11-01

Microglia activation initiates a neurological deficit cascade that contributes to substantial neuronal damage and impairment following ischemia stroke. Toll-like receptor 4 (TLR4) has been demonstrated to play a critical role in this cascade. In the current study, we tested the hypothesis that hydroxysafflor yellow A (HSYA), an active ingredient extracted from Flos Carthami tinctorii, alleviated inflammatory damage, and mediated neurotrophic effects in neurons by inducing the TLR4 pathway in microglia. A non-contact Transwell co-culture system comprised microglia and neurons was treated with HSYA followed by a 1 mg/mL lipopolysaccharide (LPS) stimulation. The microglia were activated prior to neuronal apoptosis, which were induced by increasing TLR4 expression in the activated microglia. However, HSYA suppressed TLR4 expression in the activated microglia, resulting in less neuronal damage at the early stage of LPS stimulation. Western blot analysis and immunofluorescence indicated that dose-dependently HSYA down-regulated TLR4-induced downstream effectors myeloid differentiation factor 88 (MyD88), nuclear factor kappa b (NF-κB), and the mitogen-activated protein kinases (MAPK)-regulated proteins c-Jun NH2-terminal protein kinase (JNK), protein kinase (ERK) 1/2 (ERK1/2), p38 MAPK (p38), as well as the LPS-induced inflammatory cytokine release. However, HSYA up-regulated brain-derived neurotrophic factor (BDNF) expression. Our data suggest that HSYA could exert neurotrophic and anti-inflammatory functions in response to LPS stimulation by inhibiting TLR4 pathway-mediated signaling.

New therapeutic options for the metabolic syndrome: what's next?

PubMed

Flordellis, Christodoulos S; Ilias, Ioannis; Papavassiliou, Athanasios G

2005-08-01

The metabolic syndrome (MSX), characterized by obesity, insulin resistance, dyslipidemia and hypertension, increases the risk of cardiovascular morbidity and mortality. It has recently been hypothesized that MSX and type 2 diabetes are caused by triglyceride and long-chain fatty acid accumulation in liver, muscle, pancreatic islets and selected brain areas. This lipocentric approach is integrated with analysis of inflammation associated with end-organ damage, including the vascular wall. Genes and proteins contributing to insulin resistance, beta cell dysfunction and vascular wall damage have been identified. Transcription factors and coactivators, including peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1 are crucial in mediating insulin resistance and accelerating vascular wall inflammation, and represent promising therapeutic targets. New pharmacological strategies include dual PPARalpha/gamma agonists, drugs with pleiotropic effects or combination therapies.

Expression Profile of DNA Damage Signaling Genes in Proton Exposed Mouse Brain

NASA Astrophysics Data System (ADS)

Ramesh, Govindarajan; Wu, Honglu

Exposure of living systems to radiation results in a wide assortment of lesions, the most signif-icant of is damage to genomic DNA which induce several cellular functions such as cell cycle arrest, repair, apoptosis etc. The radiation induced DNA damage investigation is one of the im-portant area in biology, but still the information available regarding the effects of proton is very limited. In this report, we investigated the differential gene expression pattern of DNA damage signaling genes particularly, damaged DNA binding, repair, cell cycle arrest, checkpoints and apoptosis using quantitative real-time RT-PCR array in proton exposed mouse brain tissues. The expression profiles showed significant changes in DNA damage related genes in 2Gy proton exposed mouse brain tissues as compared with control brain tissues. Furthermore, we also show that significantly increased levels of apoptotic related genes, caspase-3 and 8 activities in these cells, suggesting that in addition to differential expression of DNA damage genes, the alteration of apoptosis related genes may also contribute to the radiation induced DNA damage followed by programmed cell death. In summary, our findings suggest that proton exposed brain tissue undergo severe DNA damage which in turn destabilize the chromatin stability.

Protective and pathological immunity during CNS infections

PubMed Central

Klein, Robyn S.; Hunter, Christopher A.

2017-01-01

The concept of immune privilege of the central nervous system (CNS) has dominated the study of inflammatory processes in the brain. However, clinically relevant models have highlighted the innate pathways that limit pathogen invasion of the CNS and that adaptive immunity mediates control of many neural infections. Because protective responses can result in bystander damage there are regulatory mechanisms that balance protective and pathological inflammation but which may also allow microbial persistence. The focus of this review is to consider the host-pathogen interactions that influence neurotropic infections and to highlight advances in understanding of innate and adaptive mechanisms of resistance as key determinants of the outcome of CNS infection. Advances in these areas have broadened our comprehension of how the immune system functions in the brain and can readily overcome immune privilege. PMID:28636958

Abulia following penetrating brain injury during endoscopic sinus surgery with disruption of the anterior cingulate circuit: Case report

PubMed Central

Grunsfeld, Alexander A; Login, Ivan S

2006-01-01

Background It is common knowledge that the frontal lobes mediate complex human behavior and that damage to these regions can cause executive dysfunction, apathy, disinhibition and personality changes. However, it is less well known that subcortical structures such as the caudate and thalamus are part of functionally segregated fronto-subcortical circuits, that can also alter behavior after injury. Case presentation We present a 57 year old woman who suffered penetrating brain injury during endoscopic sinus surgery causing right basal ganglia injury which resulted in an abulic syndrome. Conclusion Abulia does not result solely from cortical injury but can occur after disruption anywhere in the anterior cingulate circuit – in the case of our patient, most prominently at the right caudate. PMID:16430769

Neurological Disease in Lupus: Toward a Personalized Medicine Approach.

PubMed

McGlasson, Sarah; Wiseman, Stewart; Wardlaw, Joanna; Dhaun, Neeraj; Hunt, David P J

2018-01-01

The brain and nervous system are important targets for immune-mediated damage in systemic lupus erythematosus (SLE), resulting in a complex spectrum of neurological syndromes. Defining nervous system disease in lupus poses significant challenges. Among the difficulties to be addressed are a diversity of clinical manifestations and a lack of understanding of their mechanistic basis. However, despite these challenges, progress has been made in the identification of pathways which contribute to neurological disease in SLE. Understanding the molecular pathogenesis of neurological disease in lupus will inform both classification and approaches to clinical trials.

Patterns of Post-Stroke Brain Damage that Predict Speech Production Errors in Apraxia of Speech and Aphasia Dissociate

PubMed Central

Basilakos, Alexandra; Rorden, Chris; Bonilha, Leonardo; Moser, Dana; Fridriksson, Julius

2015-01-01

Background and Purpose Acquired apraxia of speech (AOS) is a motor speech disorder caused by brain damage. AOS often co-occurs with aphasia, a language disorder in which patients may also demonstrate speech production errors. The overlap of speech production deficits in both disorders has raised questions regarding if AOS emerges from a unique pattern of brain damage or as a sub-element of the aphasic syndrome. The purpose of this study was to determine whether speech production errors in AOS and aphasia are associated with distinctive patterns of brain injury. Methods Forty-three patients with history of a single left-hemisphere stroke underwent comprehensive speech and language testing. The Apraxia of Speech Rating Scale was used to rate speech errors specific to AOS versus speech errors that can also be associated with AOS and/or aphasia. Localized brain damage was identified using structural MRI, and voxel-based lesion-impairment mapping was used to evaluate the relationship between speech errors specific to AOS, those that can occur in AOS and/or aphasia, and brain damage. Results The pattern of brain damage associated with AOS was most strongly associated with damage to cortical motor regions, with additional involvement of somatosensory areas. Speech production deficits that could be attributed to AOS and/or aphasia were associated with damage to the temporal lobe and the inferior pre-central frontal regions. Conclusion AOS likely occurs in conjunction with aphasia due to the proximity of the brain areas supporting speech and language, but the neurobiological substrate for each disorder differs. PMID:25908457

Patterns of poststroke brain damage that predict speech production errors in apraxia of speech and aphasia dissociate.

PubMed

Basilakos, Alexandra; Rorden, Chris; Bonilha, Leonardo; Moser, Dana; Fridriksson, Julius

2015-06-01

Acquired apraxia of speech (AOS) is a motor speech disorder caused by brain damage. AOS often co-occurs with aphasia, a language disorder in which patients may also demonstrate speech production errors. The overlap of speech production deficits in both disorders has raised questions on whether AOS emerges from a unique pattern of brain damage or as a subelement of the aphasic syndrome. The purpose of this study was to determine whether speech production errors in AOS and aphasia are associated with distinctive patterns of brain injury. Forty-three patients with history of a single left-hemisphere stroke underwent comprehensive speech and language testing. The AOS Rating Scale was used to rate speech errors specific to AOS versus speech errors that can also be associated with both AOS and aphasia. Localized brain damage was identified using structural magnetic resonance imaging, and voxel-based lesion-impairment mapping was used to evaluate the relationship between speech errors specific to AOS, those that can occur in AOS or aphasia, and brain damage. The pattern of brain damage associated with AOS was most strongly associated with damage to cortical motor regions, with additional involvement of somatosensory areas. Speech production deficits that could be attributed to AOS or aphasia were associated with damage to the temporal lobe and the inferior precentral frontal regions. AOS likely occurs in conjunction with aphasia because of the proximity of the brain areas supporting speech and language, but the neurobiological substrate for each disorder differs. © 2015 American Heart Association, Inc.

Postconditioning with repeated mild hypoxia protects neonatal hypoxia-ischemic rats against brain damage and promotes rehabilitation of brain function.

PubMed

Deng, Qingqing; Chang, Yanqun; Cheng, Xiaomao; Luo, Xingang; Zhang, Jing; Tang, Xiaoyuan

2018-05-01

Mild hypoxia conditioning induced by repeated episodes of transient ischemia is a clinically applicable method for protecting the brain against injury after hypoxia-ischemic brain damage. To assess the effect of repeated mild hypoxia postconditioning on brain damage and long-term neural functional recovery after hypoxia-ischemic brain damage. Rats received different protocols of repeated mild hypoxia postconditioning. Seven-day-old rats with hypoxia ischemic brain damage (HIBD) from the left carotid ligation procedure plus 2 h hypoxic stress (8% O 2 at 37 °C) were further receiving repeated mild hypoxia intermittently. The gross anatomy, functional analyses, hypoxia inducible factor 1 alpha (HIF-1a) expression, and neuronal apoptosis of the rat brains were subsequently examined. Compared to the HIBD group, rats postconditioned with mild hypoxia had elevated HIF-1a expression, more Nissl-stain positive cells in their brain tissue and their brains functioned better in behavioral analyses. The recovery of the brain function may be directly linked to the inhibitory effect of HIF-1α on neuronal apoptosis. Furthermore, there were significantly less neuronal apoptosis in the hippocampal CA1 region of the rats postconditioned with mild hypoxia, which might also be related to the higher HIF-1a expression and better brain performance. Overall, these results suggested that postconditioning of neonatal rats after HIBD with mild hypoxia increased HIF-1a expression, exerted a neuroprotective effect and promoted neural functional recovery. Repeated mild hypoxia postconditioning protects neonatal rats with HIBD against brain damage and improves neural functional recovery. Our results may have clinical implications for treating infants with HIBD. Copyright © 2018 Elsevier Inc. All rights reserved.

Brain and Bone Damage in KARAP/DAP12 Loss-of-Function Mice Correlate with Alterations in Microglia and Osteoclast Lineages

PubMed Central

Nataf, Serge; Anginot, Adrienne; Vuaillat, Carine; Malaval, Luc; Fodil, Nassima; Chereul¶, Emmanuel; Langlois¶, Jean-Baptiste; Dumontel, Christiane; Cavillon, Gaelle; Confavreux, Christian; Mazzorana, Marlène; Vico, Laurence; Belin, Marie-Franaçoise; Vivier, Eric; Tomasello, Elena; Jurdic, Pierre

2005-01-01

Human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy, also known as Nasu-Hakola disease, has been described to be associated with mutations affecting the immunoreceptor tyrosine-based activation motif-bearing KARAP/DAP12 immunoreceptor gene. Patients present bone fragilities and severe neurological alterations leading to presenile dementia. Here we investigated whether the absence of KARAP/DAP12-mediated signals in loss-of-function (KΔ75) mice also leads to bone and central nervous system pathological features. Histological analysis of adult KΔ75 mice brains revealed a diffuse hypomyelination predominating in anterior brain regions. As this was not accompanied by oligodendrocyte degeneration or microglial cell activation it suggests a developmental defect of myelin formation. Interestingly, in postnatal KΔ75 mice, we observed a dramatic reduction in microglial cell numbers similar to in vitro microglial cell differentiation impairment. Our results raise the intriguing possibility that defective microglial cell differentiation might be responsible for abnormal myelin development. Histomorphometry revealed that bone remodeling is also altered, because of a resorption defect, associated with a severe block of in vitro osteoclast differentiation. In addition, we show that, among monocytic lineages, KARAP/DAP12 specifically controls microglial and osteoclast differentiation. Our results confirm that KARAP/DAP12-mediated signals play an important role in the regulation of both brain and bone homeostasis. Yet, important differences exist between the symptoms observed in Nasu-Hakola patients and KΔ75 mice. PMID:15632019

Schooling mediates brain reserve in Alzheimer's disease: findings of fluoro-deoxy-glucose-positron emission tomography.

PubMed

Perneczky, R; Drzezga, A; Diehl-Schmid, J; Schmid, G; Wohlschläger, A; Kars, S; Grimmer, T; Wagenpfeil, S; Monsch, A; Kurz, A

2006-09-01

Functional imaging studies report that higher education is associated with more severe pathology in patients with Alzheimer's disease, controlling for disease severity. Therefore, schooling seems to provide brain reserve against neurodegeneration. To provide further evidence for brain reserve in a large sample, using a sensitive technique for the indirect assessment of brain abnormality (18F-fluoro-deoxy-glucose-positron emission tomography (FDG-PET)), a comprehensive measure of global cognitive impairment to control for disease severity (total score of the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery) and an approach unbiased by predefined regions of interest for the statistical analysis (statistical parametric mapping (SPM)). 93 patients with mild Alzheimer's disease and 16 healthy controls underwent 18F-FDG-PET imaging of the brain. A linear regression analysis with education as independent and glucose utilisation as dependent variables, adjusted for global cognitive status and demographic variables, was conducted in SPM2. The regression analysis showed a marked inverse association between years of schooling and glucose metabolism in the posterior temporo-occipital association cortex and the precuneus in the left hemisphere. In line with previous reports, the findings suggest that education is associated with brain reserve and that people with higher education can cope with brain damage for a longer time.

Sex Differences in the Effects of Unilateral Brain Damage on Intelligence

NASA Astrophysics Data System (ADS)

Inglis, James; Lawson, J. S.

1981-05-01

A sexual dimorphism in the functional asymmetry of the damaged human brain is reflected in a test-specific laterality effect in male but not in female patients. This sex difference explains some contradictions concerning the effects of unilateral brain damage on intelligence in studies in which the influence of sex was overlooked.

The interleukins-1 alpha, -1 beta, and -2 do not acutely disrupt the murine blood-brain barrier.

PubMed

Banks, W A; Kastin, A J

1992-05-01

Previous studies have suggested that some of the central nervous system (CNS) effects of interleukin-2 (IL-2) and perhaps other cytokines might be mediated through disruption of the blood-brain barrier (BBB). We investigated the ability of human IL-2 and, in selected studies, human IL-1 alpha and human IL-1 beta to disrupt the BBB to radioiodinated bovine serum albumin (RISA) after intravenous (i.v.) and intracerebroventricular (i.c.v.) injection. No disruption of the BBB occurred for up to 2 h after the i.v. injection of 2 micrograms/mouse of IL-2 (10(5) U/kg of body weight), 2 micrograms of IL-1 alpha (10(7) U/kg), or 2 micrograms of IL-1 beta (10(7) U/kg). This dose of i.v. IL-2 also did not affect BBB permeability to RISA in the brain to blood direction. Damage to the BBB induced by hypertension elicited by i.v. epinephrine was not enhanced or prolonged by IL-2. When given directly into the CNS by the i.c.v. route, 100 ng of IL-2 (2.2 x 10(5) U/kg of brain), 100 ng of IL-1 alpha (2.2 x 10(7) U/kg of brain), or 100 ng of IL-1 beta (2.2 x 10(7) U/kg of brain) had no effect on BBB integrity in either the blood to brain or the brain to blood direction. We conclude that the effects of IL-1 alpha, IL-1 beta, and IL-2 on the CNS, as studied under these conditions, are not due to disruption of the BBB but are mediated by other mechanisms including the ability of some interleukins to cross the BBB by a saturable transport system described previously.

Brain damage in fatal non-missile head injury without high intracranial pressure.

PubMed Central

Graham, D I; Lawrence, A E; Adams, J H; Doyle, D; McLellan, D R

1988-01-01

As part of a comprehensive study of brain damage in 635 fatal non-missile head injuries, the type and prevalence of brain damage occurring in the absence of high intracranial pressure were analysed. Of 71 such cases, 53 sustained their injury as a result of a road traffic accident; only 25 experienced a lucid interval. Thirty eight had a fractured skull, a mean total contusion index of 12.9 and diffuse axonal injury in 29: severe to moderate ischaemic damage was present in the cerebral cortex in 25, brain swelling in 13, and acute bacterial meningitis in nine. The prevalence and range of brain damage that may occur in the absence of high intracranial pressure are important to forensic pathologists in the medicolegal interpretation of cases of fatal head injury. PMID:3343378

The impact of unilateral brain damage on anticipatory grip force scaling when lifting everyday objects.

PubMed

Eidenmüller, S; Randerath, J; Goldenberg, G; Li, Y; Hermsdörfer, J

2014-08-01

The scaling of our finger forces according to the properties of manipulated objects is an elementary prerequisite of skilled motor behavior. Lesions of the motor-dominant left brain may impair several aspects of motor planning. For example, limb-apraxia, a tool-use disorder after left brain damage is thought to be caused by deficient recall or integration of tool-use knowledge into an action plan. The aim of the present study was to investigate whether left brain damage affects anticipatory force scaling when lifting everyday objects. We examined 26 stroke patients with unilateral brain damage (16 with left brain damage, ten with right brain damage) and 21 healthy control subjects. Limb apraxia was assessed by testing pantomime of familiar tool-use and imitation of meaningless hand postures. Participants grasped and lifted twelve randomly presented everyday objects. Grip force was measured with help of sensors fixed on thumb, index and middle-finger. The maximum rate of grip force was determined to quantify the precision of anticipation of object properties. Regression analysis yielded clear deficits of anticipation in the group of patients with left brain damage, while the comparison of patient with right brain damage with their respective control group did not reveal comparable deficits. Lesion-analyses indicate that brain structures typically associated with a tool-use network in the left hemisphere play an essential role for anticipatory grip force scaling, especially the left inferior frontal gyrus (IFG) and the premotor cortex (PMC). Furthermore, significant correlations of impaired anticipation with limb apraxia scores suggest shared representations. However, the presence of dissociations, implicates also independent processes. Overall, our findings suggest that the left hemisphere is engaged in anticipatory grip force scaling for lifting everyday objects. The underlying neural substrate is not restricted to a single region or stream; instead it may rely on the intact functioning of a left hemisphere network that may overlap with the left hemisphere dominant tool-use network. Copyright © 2014 Elsevier Ltd. All rights reserved.

BrainPhys® increases neurofilament levels in CNS cultures, and facilitates investigation of axonal damage after a mechanical stretch-injury in vitro.

PubMed

Jackson, Travis C; Kotermanski, Shawn E; Jackson, Edwin K; Kochanek, Patrick M

2018-02-01

Neurobasal®/B27 is a gold standard culture media used to study primary neurons in vitro. An alternative media (BrainPhys®/SM1) was recently developed which robustly enhances neuronal activity vs. Neurobasal® or DMEM. To the best of our knowledge BrainPhys® has not been explored in the setting of neuronal injury. Here we characterized the utility of BrainPhys® in a model of in vitro mechanical-stretch injury. Primary rat cortical neurons were maintained in classic Neurobasal®, or sequentially maintained in Neurocult® followed by BrainPhys® (hereafter simply referred to as "BrainPhys® maintained neurons"). The levels of axonal markers and proteins involved in neurotransmission were compared on day in vitro 10 (DIV10). BrainPhys® maintained neurons had higher levels of GluN2B, GluR1, Neurofilament light/heavy chain (NF-L & NF-H), and protein phosphatase 2 A (PP2A) vs. neurons in Neurobasal®. Mechanical stretch-injury (50ms/54% biaxial stretch) to BrainPhys® maintained neurons modestly (albeit significantly) increased 24h lactate dehydrogenase (LDH) levels but markedly decreased axonal NF-L levels post-injury vs. uninjured controls or neurons given a milder 38% stretch-injury. Furthermore, two 54% stretch-injuries (in tandem) exacerbated 24h LDH release, increased α-spectrin breakdown products (SBDPs), and decreased Tau levels. Also, BrainPhys® maintained cultures had decreased markers of cell damage 24h after a single 54% stretch-injury vs. neurons in Neurobasal®. Finally, we tested the hypothesis that lentivirus mediated overexpression of the pro-death protein RBM5 exacerbates neuronal and/or axonal injury in primary CNS cultures. RBM5 overexpression vs. empty-vector controls increased 24h LDH release, and SBDP levels, after a single 54% stretch-injury but did not affect NF-L levels or Tau. BrainPhys® is a promising new reagent which facilities the investigation of molecular targets involved in axonal and/or neuronal injury in vitro. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Increased brain edema following 5-aminolevulinic acid mediated photodynamic in normal and tumor bearing rats

NASA Astrophysics Data System (ADS)

Hirschberg, Henry; Angell-Petersen, Even; Spetalen, Signe; Mathews, Marlon; Madsen, Steen J.

2007-02-01

Introduction: Failure of treatment for high grade gliomas is usually due to local recurrence at the site of surgical resection indicating that a more aggressive form of local therapy, such as PDT, could be of benefit. PDT causes damage to both tumor cells as well as cerebral blood vessels leading to degradation of the blood brain barrier with subsequent increase of brain edema. The increase in brain edema following ALA-PDT was evaluated in terms of animal survival, histopatological changes in normal brain and tumor tissue and MRI scanning. The effect of steroid treatment, to reduce post-treatment PDT induced edema, was also examined. Methods:Tumors were established in the brains of inbred BD-IX and Fisher rats. At various times following tumor induction the animals were injected with ALA ip. and four hours later light treatment at escalating fluences and fluence rates were given. Nontumor bearing control animals were also exposed to ALA-PDT in a similar manner to evaluate damage to normal brain and degree of blood brain barrier (BBB) disruption. Results: Despite a very low level of PpIX production in normal brain, with a 200:1 tumor to normal tissue selectivity ratio measured at a distance of 2 mm from the tumor border, many animals succumbed shortly after treatment. A total radiant energy of 54 J to non-tumor bearing animals resulted in 50% mortality within 5 days of treatment. Treatment of tumor bearing animals with moderate fluence levels produced similar brain edema compared to higher fluence levels. ALA PDT in nontumor bearing animals produced edema that was light dose dependent. PDT appeared to open the BBB for a period of 24-48 hrs after which it was restored. The addition of post operative steroid treatment reduced the incident of post treatment morbidity and mortality. Conclusions: T2 and contrast enhanced T1 MRI scanning proved to be a highly effective and non-evasive modality in following the development of the edema reaction and the degree and time course of BBB dysfunction thus allowing the use of fewer animals.

Narrative discourse in children with early focal brain injury.

PubMed

Reilly, J S; Bates, E A; Marchman, V A

1998-02-15

Children with early brain damage, unlike adult stroke victims, often go on to develop nearly normal language. However, the route and extent of their linguistic development are still unclear, as is the relationship between lesion site and patterns of delay and recovery. Here we address these questions by examining narratives from children with early brain damage. Thirty children (ages 3:7-10:10) with pre- or perinatal unilateral focal brain damage and their matched controls participated in a storytelling task. Analyses focused on linguistic proficiency and narrative competence. Overall, children with brain damage scored significantly lower than their age-matched controls on both linguistic (morphological and syntactic) indices and those targeting broader narrative qualities. Rather than indicating that children with brain damage fully catch up, these data suggest that deficits in linguistic abilities reassert themselves as children face new linguistic challenges. Interestingly, after age 5, site of lesion does not appear to be a significant factor and the delays we have witnessed do not map onto the lesion profiles observed in adults with analogous brain injuries.

Lacunar infarction and small vessel disease: pathology and pathophysiology.

PubMed

Caplan, Louis R

2015-01-01

Two major vascular pathologies underlie brain damage in patients with disease of small size penetrating brain arteries and arterioles; 1) thickening of the arterial media and 2) obstruction of the origins of penetrating arteries by parent artery intimal plaques. The media of these small vessels may be thickened by fibrinoid deposition and hypertrophy of smooth muscle and other connective tissue elements that accompanies degenerative changes in patients with hypertension and or diabetes or can contain foreign deposits as in amyloid angiopathy and genetically mediated conditions such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. These pathological changes lead to 2 different pathophysiologies: 1) brain ischemia in regions supplied by the affected arteries. The resultant lesions are deep small infarcts, most often involving the basal ganglia, pons, thalami and cerebral white matter. And 2) leakage of fluid causing edema and later gliosis in white matter tracts. The changes in the media and adventitia effect metalloproteinases and other substances within the matrix of the vessels and lead to abnormal blood/brain barriers in these small vessels. and chronic gliosis and atrophy of cerebral white matter.

Diet and cognition: interplay between cell metabolism and neuronal plasticity.

PubMed

Gomez-Pinilla, Fernando; Tyagi, Ethika

2013-11-01

To discuss studies in humans and animals revealing the ability of foods to benefit the brain: new information with regards to mechanisms of action and the treatment of neurological and psychiatric disorders. Dietary factors exert their effects on the brain by affecting molecular events related to the management of energy metabolism and synaptic plasticity. Energy metabolism influences neuronal function, neuronal signaling, and synaptic plasticity, ultimately affecting mental health. Epigenetic regulation of neuronal plasticity appears as an important mechanism by which foods can prolong their effects on long-term neuronal plasticity. The prime focus of the discussion is to emphasize the role of cell metabolism as a mediator for the action of foods on the brain. Oxidative stress promotes damage to phospholipids present in the plasma membrane such as the omega-3 fatty acid docosahexenoic acid, disrupting neuronal signaling. Thus, dietary docosahexenoic acid seems crucial for supporting plasma membrane function, interneuronal signaling, and cognition. The dual action of brain-derived neurotrophic factor in neuronal metabolism and synaptic plasticity is crucial for activating signaling cascades under the action of diet and other environmental factors, using mechanisms of epigenetic regulation.

Lactate transport and receptor actions in cerebral malaria

PubMed Central

Mariga, Shelton T.; Kolko, Miriam; Gjedde, Albert; Bergersen, Linda H.

2014-01-01

Cerebral malaria (CM), caused by Plasmodium falciparum infection, is a prevalent neurological disorder in the tropics. Most of the patients are children, typically with intractable seizures and high mortality. Current treatment is unsatisfactory. Understanding the pathogenesis of CM is required in order to identify therapeutic targets. Here, we argue that cerebral energy metabolic defects are probable etiological factors in CM pathogenesis, because malaria parasites consume large amounts of glucose metabolized mostly to lactate. Monocarboxylate transporters (MCTs) mediate facilitated transfer, which serves to equalize lactate concentrations across cell membranes in the direction of the concentration gradient. The equalizing action of MCTs is the basis for lactate’s role as a volume transmitter of metabolic signals in the brain. Lactate binds to the lactate receptor GPR81, recently discovered on brain cells and cerebral blood vessels, causing inhibition of adenylyl cyclase. High levels of lactate delivered by the parasite at the vascular endothelium may damage the blood–brain barrier, disrupt lactate homeostasis in the brain, and imply MCTs and the lactate receptor as novel therapeutic targets in CM. PMID:24904266

Blockade of P2X7 receptors or pannexin-1 channels similarly attenuates postischemic damage.

PubMed

Cisneros-Mejorado, Abraham; Gottlieb, Miroslav; Cavaliere, Fabio; Magnus, Tim; Koch-Nolte, Friederich; Scemes, Eliana; Pérez-Samartín, Alberto; Matute, Carlos

2015-05-01

The role of P2X7 receptors and pannexin-1 channels in ischemic damage remains controversial. Here, we analyzed their contribution to postanoxic depolarization after ischemia in cultured neurons and in brain slices. We observed that pharmacological blockade of P2X7 receptors or pannexin-1 channels delayed the onset of postanoxic currents and reduced their slope, and that simultaneous inhibition did not further enhance the effects of blocking either one. These results were confirmed in acute cortical slices from P2X7 and pannexin-1 knockout mice. Oxygen-glucose deprivation in cortical organotypic cultures caused neuronal death that was reduced with P2X7 and pannexin-1 blockers as well as in organotypic cultures derived from mice lacking P2X7 and pannexin 1. Subsequently, we used transient middle cerebral artery occlusion to monitor the neuroprotective effect of those drugs in vivo. We found that P2X7 and pannexin-1 antagonists, and their ablation in knockout mice, substantially attenuated the motor symptoms and reduced the infarct volume to ~50% of that in vehicle-treated or wild-type animals. These results show that P2X7 receptors and pannexin-1 channels are major mediators of postanoxic depolarization in neurons and of brain damage after ischemia, and that they operate in the same deleterious signaling cascade leading to neuronal and tissue demise.

Neglect severity after left and right brain damage.

PubMed

Suchan, Julia; Rorden, Chris; Karnath, Hans-Otto

2012-05-01

While unilateral spatial neglect after left brain damage is undoubtedly less common than spatial neglect after a right hemisphere lesion, it is also assumed to be less severe. Here we directly test this latter hypothesis using a continuous measure of neglect severity: the so-called Center of Cancellation (CoC). Rorden and Karnath (2010) recently validated this index for right brain damaged neglect patients. A first aim of the present study was to evaluate this new measure for spatial neglect after left brain damage. In a group of 48 left-sided stroke patients with and without neglect, a score greater than -0.086 on the Bells Test and greater than -0.024 on the Letter Cancellation Task turned out to indicate neglect behavior for acute left brain damaged patients. A second aim was to directly compare the severity of spatial neglect after left versus right brain injury by using the new CoC measure. While neglect is less frequent following left than right hemisphere injury, we found that when this symptom occurs it is of similar severity in acute left brain injury as in patients after acute right brain injury. Copyright © 2012 Elsevier Ltd. All rights reserved.

BRAIN DAMAGE IN CHILDREN, THE BIOLOGICAL AND SOCIAL ASPECTS.

ERIC Educational Resources Information Center

BIRCH, HERBERT G., ED.

PAPERS AND DISCUSSION SUMMARIES ARE PRESENTED FROM A CONFERENCE ON THE BIOLOGICAL AND SOCIAL PROBLEMS OF CHILDHOOD BRAIN DAMAGE, HELD AT THE CHILDREN'S HOSPITAL OF PHILADELPHIA IN NOVEMBER 1962. A VARIETY OF DISCIPLINES IS REPRESENTED, AND THE FOLLOWING TOPICS ARE CONSIDERED--(1) "THE PROBLEM OF 'BRAIN DAMAGE' IN CHILDREN" BY HERBERT G. BIRCH, (2)…

Brain and Cognitive-Behavioural Development after Asphyxia at Term Birth

ERIC Educational Resources Information Center

de Haan, Michelle; Wyatt, John S.; Roth, Simon; Vargha-Khadem, Faraneh; Gadian, David; Mishkin, Mortimer

2006-01-01

Perinatal asphyxia occurs in approximately 1-6 per 1000 live full-term births. Different patterns of brain damage can result, though the relation of these patterns to long-term cognitive-behavioural outcome remains under investigation. The hippocampus is one brain region that can be damaged (typically not in isolation), and this site of damage has…

Dexamethasone Alleviates Tumor-Associated Brain Damage and Angiogenesis

PubMed Central

Fan, Zheng; Sehm, Tina; Rauh, Manfred; Buchfelder, Michael

2014-01-01

Children and adults with the most aggressive form of brain cancer, malignant gliomas or glioblastoma, often develop cerebral edema as a life-threatening complication. This complication is routinely treated with dexamethasone (DEXA), a steroidal anti-inflammatory drug with pleiotropic action profile. Here we show that dexamethasone reduces murine and rodent glioma tumor growth in a concentration-dependent manner. Low concentrations of DEXA are already capable of inhibiting glioma cell proliferation and at higher levels induce cell death. Further, the expression of the glutamate antiporter xCT (system Xc −; SLC7a11) and VEGFA is up-regulated after DEXA treatment indicating early cellular stress responses. However, in human gliomas DEXA exerts differential cytotoxic effects, with some human glioma cells (U251, T98G) resistant to DEXA, a finding corroborated by clinical data of dexamethasone non-responders. Moreover, DEXA-resistant gliomas did not show any xCT alterations, indicating that these gene expressions are associated with DEXA-induced cellular stress. Hence, siRNA-mediated xCT knockdown in glioma cells increased the susceptibility to DEXA. Interestingly, cell viability of primary human astrocytes and primary rodent neurons is not affected by DEXA. We further tested the pharmacological effects of DEXA on brain tissue and showed that DEXA reduces tumor-induced disturbances of the microenvironment such as neuronal cell death and tumor-induced angiogenesis. In conclusion, we demonstrate that DEXA inhibits glioma cell growth in a concentration and species-dependent manner. Further, DEXA executes neuroprotective effects in brains and reduces tumor-induced angiogenesis. Thus, our investigations reveal that DEXA acts pleiotropically and impacts tumor growth, tumor vasculature and tumor-associated brain damage. PMID:24714627

n-3 Polyunsaturated Fatty Acids Reduce Neonatal Hypoxic/Ischemic Brain Injury by Promoting Phosphatidylserine Formation and Akt Signaling.

PubMed

Zhang, Wenting; Liu, Jia; Hu, Xiaoming; Li, Peiying; Leak, Rehana K; Gao, Yanqin; Chen, Jun

2015-10-01

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) attenuate neonatal hypoxic/ischemic (H/I) brain damage, but the underlying mechanisms are not fully understood. This study tested the hypothesis that n-3 PUFAs enhance Akt-dependent prosurvival signaling by promoting the biosynthesis of phosphatidylserine in neuronal cell membranes. Dietary n-3 PUFA supplementation was initiated on the second day of pregnancy in dams. H/I was induced in 7-day-old rat pups by ipsilateral common carotid artery occlusion followed by hypoxia (8% oxygen for 2.5 hours). Neurological outcomes, brain tissue loss, cell death, and the activation of signaling events were assessed after H/I. The effects of n-3 PUFAs (docosahexaenoic acid and eicosapentaenoic acid) on oxygen-glucose deprivation-induced cell death and the underlying mechanism of protection were also examined in primary cortical neuron cultures. n-3 PUFAs reduced brain tissue loss at 7 days after H/I and improved neurological outcomes, whereas inhibition of PI3K/Akt signaling by LY294002 partially abrogated this neuroprotective effect. Docosahexaenoic acid/eicosapentaenoic acid also prevented ischemic neuronal death through the Akt prosurvival pathway in vitro. Furthermore, docosahexaenoic acid/eicosapentaenoic acid increased the production of phosphatidylserine, the major membrane-bound phospholipids, after ischemia both in vitro and in vivo. A reduction in membrane phosphatidylserine by shRNA-mediated knockdown of phosphatidylserine synthetase-1 attenuated Akt activation and neuronal survival after docosahexaenoic acid/eicosapentaenoic acid treatment in the oxygen-glucose deprivation model. n-3 PUFAs robustly protect against H/I-induced brain damage in neonates by activating Akt prosurvival pathway in compromised neurons. In addition, n-3 PUFAs promote the formation of membrane phosphatidylserine, thereby promoting Akt activity and improving cellular survival. © 2015 American Heart Association, Inc.

Neuregulin-1 is neuroprotective in a rat model of organophosphate-induced delayed neuronal injury

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

Li, Yonggang; Lein, Pamela J.; Liu, Cuimei

2012-07-15

Current medical countermeasures against organophosphate (OP) nerve agents are effective in reducing mortality, but do not sufficiently protect the CNS from delayed brain damage and persistent neurological symptoms. In this study, we examined the efficacy of neuregulin-1 (NRG-1) in protecting against delayed neuronal cell death following acute intoxication with the OP diisopropylflurophosphate (DFP). Adult male Sprague–Dawley rats were pretreated with pyridostigmine (0.1 mg/kg BW, i.m.) and atropine methylnitrate (20 mg/kg BW, i.m.) prior to DFP (9 mg/kg BW, i.p.) intoxication to increase survival and reduce peripheral signs of cholinergic toxicity but not prevent DFP-induced seizures or delayed neuronal injury. Pretreatmentmore » with NRG-1 did not protect against seizures in rats exposed to DFP. However, neuronal injury was significantly reduced in most brain regions by pretreatment with NRG-1 isoforms NRG-EGF (3.2 μg/kg BW, i.a) or NRG-GGF2 (48 μg/kg BW, i.a.) as determined by FluroJade-B labeling in multiple brain regions at 24 h post-DFP injection. NRG-1 also blocked apoptosis and oxidative stress-mediated protein damage in the brains of DFP-intoxicated rats. Administration of NRG-1 at 1 h after DFP injection similarly provided significant neuroprotection against delayed neuronal injury. These findings identify NRG-1 as a promising adjuvant therapy to current medical countermeasures for enhancing neuroprotection against acute OP intoxication. -- Highlights: ► NRG-1 blocked DFP induced neuronal injury. ► NRG-1 did not protect against seizures in rats exposed to DFP. ► NRG-1 blocked apoptosis and oxidative stress in the brains of DFP-intoxicated rats. ► Administration of NRG-1 at 1 h after DFP injection prevented delayed neuronal injury.« less

The Beneficial Effect of Cape Gooseberry Juice on Carbon Tetrachloride- Induced Neuronal Damage.

PubMed

Al-Olayan, Ebtesam M; El-Khadragy, Manal F; Omer, Sawsan A; Shata, Mohamed T M; Kassab, Rami B; Abdel Moneim, Ahmed E

2016-01-01

Cape gooseberry (Physalis peruviana L.) belongs to the Solanaceae family. Physalis has many medicinal properties however, the beneficial effect of physalis in protecting against neurotoxins has not yet been evaluated. This experimental study investigated the protective effect of physalis juice against the oxidative damage induced by carbon tetrachloride (CCl4) in the rat brain. The degrees of protection by physalis in brain tissues were evaluated by determining the brain levels of lipid peroxidation, nitric oxide, glutathione content and antioxidant enzyme activities (superoxide dismutase, catalase, glutathione-S-transferase, glutathione peroxidase and glutathione reductase), after CCl4) induction in the presence or absence of physalis. Adult male albino Wistar rats were divided into 4 groups, Group I served as the control group, Group II was intraperitoneally treated with 2 ml CCl4)/kg bwt for 12 weeks, Group III was supplemented with physalis juice via the drinking water for 12 weeks, Group IV was supplemented with physalis juice and was intraperitoneally injected weekly with CCl4). Treatment with CCl4) was significantly associated with a disturbance in the oxidative status in the brain tissues; this was marked by a significant (p<0.05) elevation in the lipid peroxidation and nitric oxide levels with a concomitant reduction in glutathione content compared to the control, along with a remarkable reduction in antioxidant enzymes. The administration of physalis along with CCl4) juice significantly (p<0.05) alleviated the changes in enzymatic antioxidant activity when compared to the CCl4) treated group. Furthermore, physalis juice supplemention inhibited apoptosis, as indicated by the increase of Bcl-2 immunoreactivity in brain tissue. Our results suggest that physalis juice could be effective in preventing neurotoxicity and the neuroprotective effect of physalis might be mediated via antioxidant and anti-apoptosis activities.

Diabetic aggravation of stroke and animal models

PubMed Central

Rehni, Ashish K.; Liu, Allen; Perez-Pinzon, Miguel A.; Dave, Kunjan R.

2017-01-01

Cerebral ischemia in diabetics results in severe brain damage. Different animal models of cerebral ischemia have been used to study the aggravation of ischemic brain damage in the diabetic condition. Since different disease conditions such as diabetes differently affect outcome following cerebral ischemia, the Stroke Therapy Academic Industry Roundtable (STAIR) guidelines recommends use of diseased animals for evaluating neuroprotective therapies targeted to reduce cerebral ischemic damage. The goal of this review is to discuss the technicalities and pros/cons of various animal models of cerebral ischemia currently being employed to study diabetes-related ischemic brain damage. The rational use of such animal systems in studying the disease condition may better help evaluate novel therapeutic approaches for diabetes related exacerbation of ischemic brain damage. PMID:28274862

Categorization skills and recall in brain damaged children: a multiple case study.

PubMed

Mello, Claudia Berlim de; Muszkat, Mauro; Xavier, Gilberto Fernando; Bueno, Orlando Francisco Amodeo

2009-09-01

During development, children become capable of categorically associating stimuli and of using these relationships for memory recall. Brain damage in childhood can interfere with this development. This study investigated categorical association of stimuli and recall in four children with brain damages. The etiology, topography and timing of the lesions were diverse. Tasks included naming and immediate recall of 30 perceptually and semantically related figures, free sorting, delayed recall, and cued recall of the same material. Traditional neuropsychological tests were also employed. Two children with brain damage sustained in middle childhood relied on perceptual rather than on categorical associations in making associations between figures and showed deficits in delayed or cued recall, in contrast to those with perinatal lesions. One child exhibited normal performance in recall despite categorical association deficits. The present results suggest that brain damaged children show deficits in categorization and recall that are not usually identified in traditional neuropsychological tests.

A combination of experimental measurement, constitutive damage model, and diffusion tensor imaging to characterize the mechanical properties of the human brain.

PubMed

Karimi, Alireza; Rahmati, Seyed Mohammadali; Razaghi, Reza

2017-09-01

Understanding the mechanical properties of the human brain is deemed important as it may subject to various types of complex loadings during the Traumatic Brain Injury (TBI). Although many studies so far have been conducted to quantify the mechanical properties of the brain, there is a paucity of knowledge on the mechanical properties of the human brain tissue and the damage of its axon fibers under the various types of complex loadings during the Traumatic Brain Injury (TBI). Although many studies so far have been conducted to quantify the mechanical properties of the brain, there is a paucity of knowledge on the mechanical properties of the human brain tissue and the damage of its axon fibers under the frontal lobe of the human brain. The constrained nonlinear minimization method was employed to identify the brain coefficients according to the axial and transversal compressive data. The pseudo-elastic damage model data was also well compared with that of the experimental data and it not only up to the primary loading but also the discontinuous softening could well address the mechanical behavior of the brain tissue.

Impact of TLR4 on behavioral and cognitive dysfunctions associated with alcohol-induced neuroinflammatory damage.

PubMed

Pascual, María; Baliño, Pablo; Alfonso-Loeches, Silvia; Aragón, Carlos M G; Guerri, Consuelo

2011-06-01

Toll-like receptors (TLRs) play an important role in the innate immune response, and emerging evidence indicates their role in brain injury and neurodegeneration. Our recent results have demonstrated that ethanol is capable of activating glial TLR4 receptors and that the elimination of these receptors in mice protects against ethanol-induced glial activation, induction of inflammatory mediators and apoptosis. This study was designed to assess whether ethanol-induced inflammatory damage causes behavioral and cognitive consequences, and if behavioral alterations are dependent of TLR4 functions. Here we show in mice drinking alcohol for 5months, followed by a 15-day withdrawal period, that activation of the astroglial and microglial cells in frontal cortex and striatum is maintained and that these events are associated with cognitive and anxiety-related behavioral impairments in wild-type (WT) mice, as demonstrated by testing the animals with object memory recognition, conditioned taste aversion and dark and light box anxiety tasks. Mice lacking TLR4 receptors are protected against ethanol-induced inflammatory damage, and behavioral associated effects. We further assess the possibility of the epigenetic modifications participating in short- or long-term behavioral effects associated with neuroinflammatory damage. We show that chronic alcohol treatment decreases H4 histone acetylation and histone acetyltransferases activity in frontal cortex, striatum and hippocampus of WT mice. Alterations in chromatin structure were not observed in TLR4(-/-) mice. These results provide the first evidence of the role that TLR4 functions play in the behavioral consequences of alcohol-induced inflammatory damage and suggest that the epigenetic modifications mediated by TLR4 could contribute to short- or long-term alcohol-induced behavioral or cognitive dysfunctions. Copyright © 2011 Elsevier Inc. All rights reserved.

Horticultural therapy: the 'healing garden'and gardening in rehabilitation measures at Danderyd Hospital Rehabilitation Clinic, Sweden.

PubMed

Söderback, Ingrid; Söderström, Marianne; Schälander, Elisabeth

2004-01-01

Objectives were to review the literature on horticultural therapy and describe the Danderyd Hospital Horticultural Therapy Garden and its associated horticultural therapy programme. The literature review is based on the search words 'gardening', 'healing garden' and 'horticultural therapy'. The description is based on the second author's personal knowledge and popular-scientific articles initiated by her. The material has been integrated with acknowledged occupational therapy literature. The setting was the Danderyd Hospital Rehabilitation Clinic, Sweden, Horticultural Therapy Garden. Forty-six patients with brain damage participated in group horticultural therapy. Horticulture therapy included the following forms: imagining nature, viewing nature, visiting a hospital healing garden and, most important, actual gardening. It was expected to influence healing, alleviate stress, increase well-being and promote participation in social life and re-employment for people with mental or physical illness. The Horticultural Therapy Garden was described regarding the design of the outdoor environment, adaptations of garden tools, cultivation methods and plant material. This therapy programme for mediating mental healing, recreation, social interaction, sensory stimulation, cognitive re-organization and training of sensory motor function is outlined and pre-vocational skills and the teaching of ergonomical body positions are assessed. This study gives a broad historic survey and a systematic description of horticultural therapy with emphasis on its use in rehabilitation following brain damage. Horticulture therapy mediates emotional, cognitive and/or sensory motor functional improvement, increased social participation, health, well-being and life satisfaction. However, the effectiveness, especially of the interacting and acting forms, needs investigation.

Novel neuroprotective and hepatoprotective effects of citric acid in acute malathion intoxication.

PubMed

Abdel-Salam, Omar M E; Youness, Eman R; Mohammed, Nadia A; Yassen, Noha N; Khadrawy, Yasser A; El-Toukhy, Safinaz Ebrahim; Sleem, Amany A

2016-12-01

To study the effect of citric acid given alone or combined with atropine on brain oxidative stress, neuronal injury, liver damage, and DNA damage of peripheral blood lymphocytes induced in the rat by acute malathion exposure. Rats were received intraperitoneal (i.p.) injection of malathion 150 mg/kg along with citric acid (200 or 400 mg/kg, orally), atropine (1 mg/kg, i.p.) or citric acid 200 mg/kg + atropine 1 mg/kg and euthanized 4 h later. Malathion resulted in increased lipid peroxidation (malondialdehyde) and nitric oxide concentrations accompanied with a decrease in brain reduced glutathione, glutathione peroxidase (GPx) activity, total antioxidant capacity (TAC) and glucose concentrations. Paraoxonase-1, acetylcholinesterase (AChE) and butyrylcholinesterase activities decreased in brain as well. Liver aspartate aminotransferase and alanine aminotransferase activities were raised. The comet assay showed increased DNA damage of peripheral blood lymphocytes. Histological damage and increased expression of inducible nitric oxide synthase (iNOS) were observed in brain and liver. Citric acid resulted in decreased brain lipid peroxidation and nitric oxide. Meanwhile, glutathione, GPx activity, TAC capacity and brain glucose level increased. Brain AChE increased but PON1 and butyrylcholinesterase activities decreased by citric acid. Liver enzymes, the percentage of damaged blood lymphocytes, histopathological alterations and iNOS expression in brain and liver was decreased by citric acid. Meanwhile, rats treated with atropine showed decreased brain MDA, nitrite but increased GPx activity, TAC, AChE and glucose. The drug also decreased DNA damage of peripheral blood lymphocytes, histopathological alterations and iNOS expression in brain and liver. The study demonstrates a beneficial effect for citric acid upon brain oxidative stress, neuronal injury, liver and DNA damage due to acute malathion exposure. Copyright © 2016 Hainan Medical University. Production and hosting by Elsevier B.V. All rights reserved.

Antioxidant gene therapy against neuronal cell death

PubMed Central

Navarro-Yepes, Juliana; Zavala-Flores, Laura; Annadurai, Anandhan; Wang, Fang; Skotak, Maciej; Chandra, Namas; Li, Ming; Pappa, Aglaia; Martinez-Fong, Daniel; Razo, Luz Maria Del; Quintanilla-Vega, Betzabet; Franco, Rodrigo

2014-01-01

Oxidative stress is a common hallmark of neuronal cell death associated with neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, as well as brain stroke/ischemia and traumatic brain injury. Increased accumulation of reactive species of both oxygen (ROS) and nitrogen (RNS) has been implicated in mitochondrial dysfunction, energy impairment, alterations in metal homeostasis and accumulation of aggregated proteins observed in neurodegenerative disorders, which lead to the activation/modulation of cell death mechanisms that include apoptotic, necrotic and autophagic pathways. Thus, the design of novel antioxidant strategies to selectively target oxidative stress and redox imbalance might represent important therapeutic approaches against neurological disorders. This work reviews the evidence demonstrating the ability of genetically encoded antioxidant systems to selectively counteract neuronal cell loss in neurodegenerative diseases and ischemic brain damage. Because gene therapy approaches to treat inherited and acquired disorders offer many unique advantages over conventional therapeutic approaches, we discussed basic research/clinical evidence and the potential of virus-mediated gene delivery techniques for antioxidant gene therapy. PMID:24333264

Chickenpox encephalitis and encephalopathy: evidence for differing pathogenesis.

PubMed Central

Shope, T. C.

1982-01-01

Retrospective assessment of hepatic and central nervous system involvement associated with chickenpox cases at a large metropolitan medical center reveals that 28 of 58 patients had biochemical, but not inflammatory, evidence of liver involvement. An additional 18 patients had biochemical liver abnormalities along with non-inflammatory encephalopathy (Reye syndrome) and 12 had clear evidence of central nervous system inflammatory involvement (encephalitis). There were no cases of solitary inflammatory liver involvement. Reviewed evidence suggests that the pathogenesis of hepatopathy and hepatoencephalopathy (Reye syndrome) is not caused by replication of virus in the involved organs, but instead is mediated through a cytotoxic mechanism and that the inflammatory brain disease is also not caused by viral replication in brain tissue, but appears to be tissue damage associated with immune cell responses (post-infectious encephalitis). The concept put forth in this essay is that a virus replicating in one organ (skin) could affect the macromolecular function of cells in another organ (liver, brain) bringing about both hepatopathy and hepatoencephalopathy. PMID:6295009

Role of NMDA Receptor-Mediated Glutamatergic Signaling in Chronic and Acute Neuropathologies

PubMed Central

2016-01-01

N-Methyl-D-aspartate receptors (NMDARs) have two opposing roles in the brain. On the one hand, NMDARs control critical events in the formation and development of synaptic organization and synaptic plasticity. On the other hand, the overactivation of NMDARs can promote neuronal death in neuropathological conditions. Ca2+ influx acts as a primary modulator after NMDAR channel activation. An imbalance in Ca2+ homeostasis is associated with several neurological diseases including schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These chronic conditions have a lengthy progression depending on internal and external factors. External factors such as acute episodes of brain damage are associated with an earlier onset of several of these chronic mental conditions. Here, we will review some of the current evidence of how traumatic brain injury can hasten the onset of several neurological conditions, focusing on the role of NMDAR distribution and the functional consequences in calcium homeostasis associated with synaptic dysfunction and neuronal death present in this group of chronic diseases. PMID:27630777

Hippocampal protection in mice with an attenuated inflammatory monocyte response to acute CNS picornavirus infection

PubMed Central

Howe, Charles L.; LaFrance-Corey, Reghann G.; Sundsbak, Rhianna S.; Sauer, Brian M.; LaFrance, Stephanie J.; Buenz, Eric J.; Schmalstieg, William F.

2012-01-01

Neuronal injury during acute viral infection of the brain is associated with the development of persistent cognitive deficits and seizures in humans. In C57BL/6 mice acutely infected with the Theiler's murine encephalomyelitis virus, hippocampal CA1 neurons are injured by a rapid innate immune response, resulting in profound memory deficits. In contrast, infected SJL and B6xSJL F1 hybrid mice exhibit essentially complete hippocampal and memory preservation. Analysis of brain-infiltrating leukocytes revealed that SJL mice mount a sharply attenuated inflammatory monocyte response as compared to B6 mice. Bone marrow transplantation experiments isolated the attenuation to the SJL immune system. Adoptive transfer of B6 inflammatory monocytes into acutely infected B6xSJL hosts converted these mice to a hippocampal damage phenotype and induced a cognitive deficit marked by failure to recognize a novel object. These findings show that inflammatory monocytes are the critical cellular mediator of hippocampal injury during acute picornavirus infection of the brain. PMID:22848791

Neuroprotective effect of combined ultrasound and microbubbles in a rat model of middle cerebral artery infarction

NASA Astrophysics Data System (ADS)

Fatar, M.; Griebe, M.; Stroick, M.; Kern, R.; Hennerici, M.; Meairs, S.

2005-03-01

Ultrasound-mediated microbubble thrombolysis (UMT) was performed in a middle cerebral artery occlusion model in rats to evaluate possible effects upon brain infarct volume, apoptosis, IL-6 and TNF-alpha levels, and disruption of the blood-brain barrier (BBB). The results show that infarct volume was significantly reduced (p<0.04) in the microbubble + ultrasound (MB + US) group as compared to control animals. The levels of IL-6 and TNF-alpha concentrations, as markers of tissue damage, were not significantly different. In trypan blue treated animals, no additional BBB disruption was observed for the UMT group. Likewise, there was no increase in apoptotic cell death outside the infarction area in animals treated with MB + US. The results demonstrate that UMT does not have a harmful effect upon ischemic stroke in a middle cerebral artery occlusion model of the rat. The significant reduction in brain infarction following insonation with ultrasound and microbubbles suggests a novel neuroprotective effect in ischemic stroke.

New insights into coupling and uncoupling of cerebral blood flow and metabolism in the brain

PubMed Central

Venkat, Poornima; Chopp, Michael; Chen, Jieli

2016-01-01

The brain has high metabolic and energy needs and requires continuous cerebral blood flow (CBF), which is facilitated by a tight coupling between neuronal activity, CBF, and metabolism. Upon neuronal activation, there is an increase in energy demand, which is then met by a hemodynamic response that increases CBF. Such regional CBF increase in response to neuronal activation is observed using neuroimaging techniques such as functional magnetic resonance imaging and positron emission tomography. The mechanisms and mediators (eg, nitric oxide, astrocytes, and ion channels) that regulate CBF-metabolism coupling have been extensively studied. The neurovascular unit is a conceptual model encompassing the anatomical and metabolic interactions between the neurons, vascular components, and glial cells in the brain. It is compromised under disease states such as stroke, diabetes, hypertension, dementias, and with aging, all of which trigger a cascade of inflammatory responses that exacerbate brain damage. Hence, tight regulation and maintenance of neurovascular coupling is central for brain homeostasis. This review article also discusses the waste clearance pathways in the brain such as the glymphatic system. The glymphatic system is a functional waste clearance pathway that removes metabolic wastes and neurotoxins from the brain along paravascular channels. Disruption of the glymphatic system burdens the brain with accumulating waste and has been reported in aging as well as several neurological diseases. PMID:27374823

New insights into coupling and uncoupling of cerebral blood flow and metabolism in the brain.

PubMed

Venkat, Poornima; Chopp, Michael; Chen, Jieli

2016-06-30

The brain has high metabolic and energy needs and requires continuous cerebral blood flow (CBF), which is facilitated by a tight coupling between neuronal activity, CBF, and metabolism. Upon neuronal activation, there is an increase in energy demand, which is then met by a hemodynamic response that increases CBF. Such regional CBF increase in response to neuronal activation is observed using neuroimaging techniques such as functional magnetic resonance imaging and positron emission tomography. The mechanisms and mediators (eg, nitric oxide, astrocytes, and ion channels) that regulate CBF-metabolism coupling have been extensively studied. The neurovascular unit is a conceptual model encompassing the anatomical and metabolic interactions between the neurons, vascular components, and glial cells in the brain. It is compromised under disease states such as stroke, diabetes, hypertension, dementias, and with aging, all of which trigger a cascade of inflammatory responses that exacerbate brain damage. Hence, tight regulation and maintenance of neurovascular coupling is central for brain homeostasis. This review article also discusses the waste clearance pathways in the brain such as the glymphatic system. The glymphatic system is a functional waste clearance pathway that removes metabolic wastes and neurotoxins from the brain along paravascular channels. Disruption of the glymphatic system burdens the brain with accumulating waste and has been reported in aging as well as several neurological diseases.

Structural white-matter connections mediating distinct behavioral components of spatial neglect in right brain-damaged patients.

PubMed

Vaessen, Maarten J; Saj, Arnaud; Lovblad, Karl-Olof; Gschwind, Markus; Vuilleumier, Patrik

2016-04-01

Spatial neglect is a neuropsychological syndrome in which patients fail to perceive and orient to stimuli located in the space contralateral to the lesioned hemisphere. It is characterized by a wide heterogeneity in clinical symptoms which can be grouped into distinct behavioral components correlating with different lesion sites. Moreover, damage to white-matter (WM) fiber tracts has been suggested to disconnect brain networks that mediate different functions associated with spatial cognition and attention. However, it remains unclear what WM pathways are associated with functionally dissociable neglect components. In this study we examined nine patients with a focal right hemisphere stroke using a series of neuropsychological tests and diffusion tensor imaging (DTI) in order to disentangle the role of specific WM pathways in neglect symptoms. First, following previous work, the behavioral test scores of patients were factorized into three independent components reflecting perceptual, exploratory, and object-centered deficits in spatial awareness. We then examined the structural neural substrates of these components by correlating indices of WM integrity (fractional anisotropy) with the severity of deficits along each profile. Several locations in the right parietal and frontal WM correlated with neuropsychological scores. Fiber tracts projecting from these locations indicated that posterior parts of the superior longitudinal fasciculus (SLF), as well as nearby callosal fibers connecting ipsilateral and contralateral parietal areas, were associated with perceptual spatial deficits, whereas more anterior parts of SLF and inferior fronto-occipital fasciculus (IFOF) were predominantly associated with object-centered deficits. In addition, connections between frontal areas and superior colliculus were found to be associated with the exploratory deficits. Our results provide novel support to the view that neglect may result from disconnection lesions in distributed brain networks, but also extend these notions by highlighting the role of dissociable circuits in different functional components of the neglect syndrome. However these preliminary findings require replication with larger samples of patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

Ablation of the sphenopalatine ganglion does not attenuate the infarct reducing effect of vagus nerve stimulation

PubMed Central

Ay, Ilknur; Ay, Hakan

2013-01-01

Electrical stimulation of the cervical vagus nerve reduces infarct size by approximately 50% after cerebral ischemia in rats. The mechanism of ischemic protection by vagus nerve stimulation (VNS) is not known. In this study, we investigated whether the infarct reducing effect of VNS was mediated by activation of the parasympathetic vasodilator fibers that originate from the sphenopalatine ganglion (SPG) and innervate the anterior cerebral circulation. We examined the effects of electrical stimulation of the cervical vagus nerve in two groups of rats: one with and one without SPG ablation. Electrical stimulation was initiated 30 min after induction of ischemia, and lasted for 1h. Measurement of infarct size 24h later revealed that the volume of ischemic damage was smaller in those animals that received VNS treatment (41.32 ± 2.07% vs. 24.19 ± 2.62% of the contralateral hemispheric volume, n=6 in both; p<0.05). SPG ablation did not abolish this effect; the reduction in infarct volume following VNS was 58% in SPG-damaged animals, 41% in SPG-intact animals (p>0.05). In both SPG-intact and SPG-damaged animals VNS treatment resulted in better motor outcome (p<0.05 vs. corresponding controls for both). Our findings show that VNS can protect the brain against acute ischemic injury, and that this effect is not mediated by SPG projections. PMID:23273773

Prevention of dopaminergic neurotoxicity by targeting nitric oxide and peroxynitrite: implications for the prevention of methamphetamine-induced neurotoxic damage.

PubMed

Imam, S Z; Islam, F; Itzhak, Y; Slikker, W; Ali, S F

2000-09-01

Methamphetamine (METH) is a neurotoxic psychostimulant that produces catecholaminergic brain damage by producing oxidative stress and free radical generation. The role of oxygen and nitrogen radicals is well documented as a cause of METH-induced neurotoxic damage. In this study, we have obtained evidence that METH-induced neurotoxicity is the resultant of interaction between oxygen and nitrogen radicals, and it is mediated by the production of peroxynitrite. We have also assessed the effects of inhibitors of neuronal nitric oxide synthase (nNOS) as well as scavenger of nitric oxide and a peroxynitrite decomposition catalyst. Significant protective effects were observed with the inhibitor of nNOS, 7-nitroindazole (7-NI), as well as by the selective peroxynitrite scavenger or decomposition catalyst, 5,10,15,20-tetrakis(2,4,6-trimethyl-3,5-sulfonatophenyl)porphyrinato iron III (FeTPPS). However, the use of a nitric oxide scavenger, 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO), did not provide any significant protection against METH-induced hyperthermia or peroxynitrite generation and the resulting dopaminergic neurotoxicity. In particular, treatment with FeTPPS completely prevented METH-induced hyperthermia, peroxynitrite production, and METH-induced dopaminergic depletion. Together, these data demonstrate that METH-induced dopaminergic neurotoxicity is mediated by the generation of peroxynitrite, which can be selectively protected by nNOS inhibitors or peroxynitrite scavenger or decomposition catalysts.

Processing of Basic Speech Acts Following Localized Brain Damage: A New Light on the Neuroanatomy of Language

ERIC Educational Resources Information Center

Soroker, N.; Kasher, A.; Giora, R.; Batori, G.; Corn, C.; Gil, M.; Zaidel, E.

2005-01-01

We examined the effect of localized brain lesions on processing of the basic speech acts (BSAs) of question, assertion, request, and command. Both left and right cerebral damage produced significant deficits relative to normal controls, and left brain damaged patients performed worse than patients with right-sided lesions. This finding argues…

Functional vision in children with perinatal brain damage.

PubMed

Alimović, Sonja; Jurić, Nikolina; Bošnjak, Vlatka Mejaški

2014-09-01

Many authors have discussed the effects of visual stimulations on visual functions, but there is no research about the effects on using vision in everyday activities (i.e. functional vision). Children with perinatal brain damage can develop cerebral visual impairment with preserved visual functions (e.g. visual acuity, contrast sensitivity) but poor functional vision. Our aim was to discuss the importance of assessing and stimulating functional vision in children with perinatal brain damage. We assessed visual functions (grating visual acuity, contrast sensitivity) and functional vision (the ability of maintaining visual attention and using vision in communication) in 99 children with perinatal brain damage and visual impairment. All children were assessed before and after the visual stimulation program. Our first assessment results showed that children with perinatal brain damage had significantly more problems in functional vision than in basic visual functions. During the visual stimulation program both variables of functional vision and contrast sensitivity improved significantly, while grating acuity improved only in 2.7% of children. We also found that improvement of visual attention significantly correlated to improvement on all other functions describing vision. Therefore, functional vision assessment, especially assessment of visual attention is indispensable in early monitoring of child with perinatal brain damage.

Subjective cognitive dysfunction in rehabilitation outpatients with musculoskeletal disorders or chronic pain.

PubMed

Schrier, Ernst; Geertzen, Jan H; Dijkstra, Pieter U

2017-08-01

Rehabilitation patients, without brain damage, sometimes complain about poor concentration and problems with their memory. The magnitude and associations, of this cognitive dysfunction, with different factors is unclear. To determine the magnitude of cognitive dysfunction in rehabilitation outpatient and to explore its associations with patient characteristics, diagnosis, surgery, pain, stress, anxiety and depression. Cross-sectional. Rehabilitation outpatients. Between July 2009 and January 2012, 274 rehabilitation outpatients were included and divided in 8 different groups through diagnosis. Cognitive functioning was assessed using the cognitive failure questionnaire and compared with the general Dutch population. Associations of gender, age, diagnosis, recent surgery, pain and stress coping ability with cognitive function was explored. Mediation of depression and anxiety was explored. The rehabilitation patients had a significantly higher score on the CFQ (mean 35.9±13.4) when compared to the general Dutch population (mean 31.8±11.1). Mean difference is 4.1, 95% confidence interval 2.60 to 5.60. In the stepwise linear regression analysis only gender, diagnosis and stress coping ability were significantly associated. A significant mediation effect was found of anxiety (P≤0.001) and depression (P≤0.005) between stress coping ability and cognitive function. Rehabilitation outpatients experience more cognitive problems in comparison to the general Dutch population. Reported dysfunction of cognition in rehabilitation outpatients are associated with stress coping ability and for a small amount to gender and diagnosis. The association of stress coping ability and cognitive dysfunction is mediated by depression and anxiety. Women tend to report more dysfunctional cognition compared to men. Patient characteristics, surgery and experienced pain have no significant influence on the experienced cognitive dysfunction. Cognitive problems reported by patients should be addressed by adapting the rehabilitation program, for instance write down instructions, repeat explanations and take more time for instructions. Cognitive problems in rehabilitation patients without brain damage is probably a stress coping problem and can be addressed by boosting resilience. Targeting depression or anxiety is another option of treatment cognition if those are mediating between stress coping and cognitive problems.

Curcumin attenuates acute inflammatory injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway in experimental traumatic brain injury

PubMed Central

2014-01-01

Background Traumatic brain injury (TBI) initiates a neuroinflammatory cascade that contributes to substantial neuronal damage and behavioral impairment, and Toll-like receptor 4 (TLR4) is an important mediator of thiscascade. In the current study, we tested the hypothesis that curcumin, a phytochemical compound with potent anti-inflammatory properties that is extracted from the rhizome Curcuma longa, alleviates acute inflammatory injury mediated by TLR4 following TBI. Methods Neurological function, brain water content and cytokine levels were tested in TLR4-/- mice subjected to weight-drop contusion injury. Wild-type (WT) mice were injected intraperitoneally with different concentrations of curcumin or vehicle 15 minutes after TBI. At 24 hours post-injury, the activation of microglia/macrophages and TLR4 was detected by immunohistochemistry; neuronal apoptosis was measured by FJB and TUNEL staining; cytokines were assayed by ELISA; and TLR4, MyD88 and NF-κB levels were measured by Western blotting. In vitro, a co-culture system comprised of microglia and neurons was treated with curcumin following lipopolysaccharide (LPS) stimulation. TLR4 expression and morphological activation in microglia and morphological damage to neurons were detected by immunohistochemistry 24 hours post-stimulation. Results The protein expression of TLR4 in pericontusional tissue reached a maximum at 24 hours post-TBI. Compared with WT mice, TLR4-/- mice showed attenuated functional impairment, brain edema and cytokine release post-TBI. In addition to improvement in the above aspects, 100 mg/kg curcumin treatment post-TBI significantly reduced the number of TLR4-positive microglia/macrophages as well as inflammatory mediator release and neuronal apoptosis in WT mice. Furthermore, Western blot analysis indicated that the levels of TLR4 and its known downstream effectors (MyD88, and NF-κB) were also decreased after curcumin treatment. Similar outcomes were observed in the microglia and neuron co-culture following treatment with curcumin after LPS stimulation. LPS increased TLR4 immunoreactivity and morphological activation in microglia and increased neuronal apoptosis, whereas curcumin normalized this upregulation. The increased protein levels of TLR4, MyD88 and NF-κB in microglia were attenuated by curcumin treatment. Conclusions Our results suggest that post-injury, curcumin administration may improve patient outcome by reducing acute activation of microglia/macrophages and neuronal apoptosis through a mechanism involving the TLR4/MyD88/NF-κB signaling pathway in microglia/macrophages in TBI. PMID:24669820

A new rabbit model for the study of early brain injury after subarachnoid hemorrhage.

PubMed

Marbacher, Serge; Andereggen, Lukas; Neuschmelting, Volker; Widmer, Hans Rudolf; von Gunten, Michael; Takala, Jukka; Jakob, Stephan M; Fandino, Javier

2012-07-15

Pathophysiological disturbances during subarachnoid hemorrhage (SAH) and within the first few days thereafter are responsible for significant brain damage. Early brain injury (EBI) after SAH has become the focus of current research activities. The purpose of the present study was to evaluate whether a novel rabbit SAH model provokes EBI by means of neuronal degeneration, brain tissue death, and apoptosis in cerebral vascular endothelial cells. SAH was performed using an extra-intracranial blood shunt. Intracranial pressure (ICP), cerebral perfusion pressure (CPP), and bilateral regional cerebral blood flow (rCBF) were continuously measured. Apoptosis and neurodegeneration were detected 24h post-SAH in basilar artery endothelial cells, bilateral basal cortex, and hippocampus (CA1 and CA3) using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and Fluoro-jade B (FJB), respectively. ICP increase caused a CPP decrease to almost zero (8±5mmHg) and decreases in left and right rCBF to 23±8% and 19±9% of their baseline values. TUNEL- and FJB-stained sections revealed significant apoptosis and neurodegeneration in both basal cortex and hippocampal regions compared to sham-operated animals. The apoptotic index in basilar artery endothelial cells was 74%±11%. The blood shunt rabbit SAH model elicits acute physiological dearrangements and provokes marked and consistent early damage to the hippocampus, basal cortex, and cerebral vasculature 24h thereafter. These findings make the model a valid tool for investigation of pre-vasospasm pathophysiological mechanisms and novel treatment modalities. Copyright © 2012 Elsevier B.V. All rights reserved.

SVCT2 Expression and Function in Reactive Astrocytes Is a Common Event in Different Brain Pathologies.

PubMed

Salazar, Katterine; Martínez, Fernando; Pérez-Martín, Margarita; Cifuentes, Manuel; Trigueros, Laura; Ferrada, Luciano; Espinoza, Francisca; Saldivia, Natalia; Bertinat, Romina; Forman, Katherine; Oviedo, María José; López-Gambero, Antonio J; Bonansco, Christian; Bongarzone, Ernesto R; Nualart, Francisco

2017-09-23

Ascorbic acid (AA), the reduced form of vitamin C, acts as a neuroprotector by eliminating free radicals in the brain. Sodium/vitamin C co-transporter isoform 2 (SVCT2) mediates uptake of AA by neurons. It has been reported that SVCT2 mRNA is induced in astrocytes under ischemic damage, suggesting that its expression is enhanced in pathological conditions. However, it remains to be established if SVCT expression is altered in the presence of reactive astrogliosis generated by different brain pathologies. In the present work, we demonstrate that SVCT2 expression is increased in astrocytes present at sites of neuroinflammation induced by intracerebroventricular injection of a GFP-adenovirus or the microbial enzyme, neuraminidase. A similar result was observed at 5 and 10 days after damage in a model of traumatic injury and in the hippocampus and cerebral cortex in the in vivo kindling model of epilepsy. Furthermore, we defined that cortical astrocytes maintained in culture for long periods acquire markers of reactive gliosis and express SVCT2, in a similar way as previously observed in situ. Finally, by means of second harmonic generation and 2-photon fluorescence imaging, we analyzed brain necropsied material from patients with Alzheimer's disease (AD), which presented with an accumulation of amyloid plaques. Strikingly, although AD is characterized by focalized astrogliosis surrounding amyloid plaques, SVCT2 expression at the astroglial level was not detected. We conclude that SVCT2 is heterogeneously induced in reactive astrogliosis generated in different pathologies affecting the central nervous system (CNS).

The mitochondria-targeted antioxidants and remote kidney preconditioning ameliorate brain damage through kidney-to-brain cross-talk.

PubMed

Silachev, Denis N; Isaev, Nikolay K; Pevzner, Irina B; Zorova, Ljubava D; Stelmashook, Elena V; Novikova, Svetlana V; Plotnikov, Egor Y; Skulachev, Vladimir P; Zorov, Dmitry B

2012-01-01

Many ischemia-induced neurological pathologies including stroke are associated with high oxidative stress. Mitochondria-targeted antioxidants could rescue the ischemic organ by providing specific delivery of antioxidant molecules to the mitochondrion, which potentially suffers from oxidative stress more than non-mitochondrial cellular compartments. Besides direct antioxidative activity, these compounds are believed to activate numerous protective pathways. Endogenous anti-ischemic defense may involve the very powerful neuroprotective agent erythropoietin, which is mainly produced by the kidney in a redox-dependent manner, indicating an important role of the kidney in regulation of brain ischemic damage. The goal of this study is to track the relations between the kidney and the brain in terms of the amplification of defense mechanisms during SkQR1 treatment and remote renal preconditioning and provide evidence that the kidney can generate signals inducing a tolerance to oxidative stress-associated brain pathologies. We used the cationic plastoquinone derivative, SkQR1, as a mitochondria-targeted antioxidant to alleviate the deleterious consequences of stroke. A single injection of SkQR1 before cerebral ischemia in a dose-dependent manner reduces infarction and improves functional recovery. Concomitantly, an increase in the levels of erythropoietin in urine and phosphorylated glycogen synthase kinase-3β (GSK-3β) in the brain was detected 24 h after SkQR1 injection. However, protective effects of SkQR1 were not observed in rats with bilateral nephrectomy and in those treated with the nephrotoxic antibiotic gentamicin, indicating the protective role of humoral factor(s) which are released from functional kidneys. Renal preconditioning also induced brain protection in rats accompanied by an increased erythropoietin level in urine and kidney tissue and P-GSK-3β in brain. Co-cultivation of SkQR1-treated kidney cells with cortical neurons resulted in enchanced phosphorylation of GSK-3β in neuronal cells. The results indicate that renal preconditioning and SkQR1-induced brain protection may be mediated through the release of EPO from the kidney.

Cigarette smoking induces heat shock protein 70 kDa expression and apoptosis in rat brain: Modulation by bacoside A.

PubMed

Anbarasi, K; Kathirvel, G; Vani, G; Jayaraman, G; Shyamala Devi, C S

2006-01-01

Cigarette smoking is associated with the development of several diseases and antioxidants play a major role in the prevention of smoking-related diseases. Apoptosis is suggested as a possible contributing factor in the pathogenesis of smoking-induced toxicity. Therefore the present study was designed to investigate the influence of chronic cigarette smoke exposure on apoptosis and the modulatory effect of bacoside A (triterpenoid saponin isolated from the plant Bacopa monniera) on smoking-induced apoptosis in rat brain. Adult male albino rats of Wistar strain were exposed to cigarette smoke and simultaneously administered with bacoside A (10 mg/kg b.w./day, orally) for a period of 12 weeks. Expression of brain hsp70 was analyzed by Western blotting. Apoptosis was identified by DNA fragmentation, terminal deoxynucleotidyl transferase-mediated deoxy uridine triphosphate nick end labeling (TUNEL) staining and transmission electron microscopy. The results showed that exposure to cigarette smoke induced hsp70 expression and apoptosis as characterized by DNA laddering, increased TUNEL-positive cells and ultrastructural apoptotic features in the brain. Administration of bacoside A prevented expression of hsp70 and neuronal apoptosis during cigarette smoking. We speculate that apoptosis may be responsible for the smoking-induced brain damage and bacoside A can protect the brain from the toxic effects of cigarette smoking.

Inhibition of Peripheral TNF-α and Downregulation of Microglial Activation by Alpha-Lipoic Acid and Etanercept Protect Rat Brain Against Ischemic Stroke.

PubMed

Wu, Ming-Hsiu; Huang, Chao-Ching; Chio, Chung-Ching; Tsai, Kuen-Jer; Chang, Ching-Ping; Lin, Nan-Kai; Lin, Mao-Tsun

2016-09-01

Ischemic stroke, caused by obstruction of blood flow to the brain, would initiate microglia activation which contributes to neuronal damage. Therefore, inhibition of microglia-mediated neuroinflammation could be a therapeutic strategy for ischemic stroke. This study was aimed to elucidate the anti-inflammatory effects of alpha-lipoic acid and etanercept given either singly or in combination in rats subjected to middle cerebral artery occlusion. Both α-lipoic acid and etanercept markedly reduced cerebral infarct, blood-brain barrier disruption, and neurological motor deficits with the former drug being more effective with the dosage used. Furthermore, when used in combination, the reduction was more substantial. Remarkably, a greater diminution in the serum levels of tumor necrosis factor-alpha as well as the brain levels of microglial activation (e.g., microgliosis, amoeboid microglia, and microglial overexpression of tumor necrosis factor-α) was observed with the combined drug treatment as compared to the drugs given separately. We conclude that inhibition of peripheral tumor necrosis factor-alpha as well as downregulation of brain microglial activation by alpha-lipoic acid or etanercept protect rat brain against ischemic stroke. Moreover, when both drugs were used in combination, the stroke recovery was promoted more extensively.

Decreased mTOR signalling reduces mitochondrial ROS in brain via accumulation of the telomerase protein TERT within mitochondria.

PubMed

Miwa, Satomi; Czapiewski, Rafal; Wan, Tengfei; Bell, Amy; Hill, Kirsten N; von Zglinicki, Thomas; Saretzki, Gabriele

2016-10-22

Telomerase in its canonical function maintains telomeres in dividing cells. In addition, the telomerase protein TERT has non-telomeric functions such as shuttling to mitochondria resulting in a decreased oxidative stress, DNA damage and apoptosis. TERT protein persists in adult neurons and can co-localise to mitochondria under various stress conditions. We show here that TERT expression decreased in mouse brain during aging while release of reactive oxygen species (ROS) from the mitochondrial electron transport chain increased. Dietary restriction (DR) caused accumulation of TERT protein in mouse brain mitochondria correlating to decreased ROS release and improved learning and spatial short-term memory. Decreased mTOR signalling is a mediator of DR. Accordingly, feeding mice with rapamycin increased brain mitochondrial TERT and reduced ROS release. Importantly, the beneficial effects of rapamycin on mitochondrial function were absent in brains and fibroblasts from first generation TERT -/- mice, and when TERT shuttling was inhibited by the Src kinase inhibitor bosutinib. Taken together, our data suggests that the mTOR signalling pathway impinges on the mitochondrial localisation of TERT protein, which might in turn contribute to the protection of the brain by DR or rapamycin against age-associated mitochondrial ROS increase and cognitive decline.

Ammonia Induces Autophagy through Dopamine Receptor D3 and MTOR

PubMed Central

Li, Zhiyuan; Ji, Xinmiao; Wang, Wenchao; Liu, Juanjuan; Liang, Xiaofei; Wu, Hong; Liu, Jing; Eggert, Ulrike S.; Liu, Qingsong

2016-01-01

Hyperammonemia is frequently seen in tumor microenvironments as well as in liver diseases where it can lead to severe brain damage or death. Ammonia induces autophagy, a mechanism that tumor cells may use to protect themselves from external stresses. However, how cells sense ammonia has been unclear. Here we show that culture medium alone containing Glutamine can generate milimolar of ammonia at 37 degrees in the absence of cells. In addition, we reveal that ammonia acts through the G protein-coupled receptor DRD3 (Dopamine receptor D3) to induce autophagy. At the same time, ammonia induces DRD3 degradation, which involves PIK3C3/VPS34-dependent pathways. Ammonia inhibits MTOR (mechanistic target of Rapamycin) activity and localization in cells, which is mediated by DRD3. Therefore, ammonia has dual roles in autophagy: one to induce autophagy through DRD3 and MTOR, the other to increase autophagosomal pH to inhibit autophagic flux. Our study not only adds a new sensing and output pathway for DRD3 that bridges ammonia sensing and autophagy induction, but also provides potential mechanisms for the clinical consequences of hyperammonemia in brain damage, neurodegenerative diseases and tumors. PMID:27077655

Reducing excessive GABAergic tonic inhibition promotes post-stroke functional recovery

PubMed Central

Clarkson, Andrew N.; Huang, Ben S.; MacIsaac, Sarah E.; Mody, Istvan; Carmichael, S. Thomas

2010-01-01

Stroke is a leading cause of disability; but no pharmacological therapy is currently available for promoting recovery. The brain region adjacent to stroke damage, the peri-infarct zone, is critical for rehabilitation, as it exhibits heightened neuroplasticity, allowing sensorimotor functions to re-map from damaged areas1–3. Thus, understanding the neuronal properties constraining this plasticity is important to developing new treatments. Here we show that after a stroke in mice, tonic neuronal inhibition is increased in the peri-infarct zone. This increased tonic inhibition is mediated by extrasynaptic GABAA receptors (GABAARs) and is caused by an impairment in GABA transporter (GAT-3/4) function. To counteract the heightened inhibition, we administered in vivo a benzodiazepine inverse agonist specific for the α5-subunit-containing extrasynaptic GABAARs at a delay after stroke. This treatment produced an early and sustained recovery of motor function. Genetically lowering the number of α5 or δ-subunit-containing GABAARs responsible for tonic inhibition also proved beneficial for post-stroke recovery, consistent with the therapeutic potential of diminishing extrasynaptic GABAAR function. Together, our results identify new pharmacological targets and provide the rationale for a novel strategy to promote recovery after stroke and possibly other brain injuries. PMID:21048709

PEA and luteolin synergistically reduce mast cell-mediated toxicity and elicit neuroprotection in cell-based models of brain ischemia.

PubMed

Parrella, Edoardo; Porrini, Vanessa; Iorio, Rosa; Benarese, Marina; Lanzillotta, Annamaria; Mota, Mariana; Fusco, Mariella; Tonin, Paolo; Spano, PierFranco; Pizzi, Marina

2016-10-01

The combination of palmitoylethanolamide (PEA), an endogenous fatty acid amide belonging to the family of the N-acylethanolamines, and the flavonoid luteolin has been found to exert neuroprotective activities in a variety of mouse models of neurological disorders, including brain ischemia. Indirect findings suggest that the two molecules can reduce the activation of mastocytes in brain ischemia, thus modulating crucial cells that trigger the inflammatory cascade. Though, no evidence exists about a direct effect of PEA and luteolin on mast cells in experimental models of brain ischemia, either used separately or in combination. In order to fill this gap, we developed a novel cell-based model of severe brain ischemia consisting of primary mouse cortical neurons and cloned mast cells derived from mouse fetal liver (MC/9 cells) subjected to oxygen and glucose deprivation (OGD). OGD exposure promoted both mast cell degranulation and the release of lactate dehydrogenase (LDH) in a time-dependent fashion. MC/9 cells exacerbated neuronal damage in neuron-mast cells co-cultures exposed to OGD. Likewise, the conditioned medium derived from OGD-exposed MC/9 cells induced significant neurotoxicity in control primary neurons. PEA and luteolin pre-treatment synergistically prevented the OGD-induced degranulation of mast cells and reduced the neurotoxic potential of MC/9 cells conditioned medium. Finally, the association of the two drugs promoted a direct synergistic neuroprotection even in pure cortical neurons exposed to OGD. In summary, our results indicate that mast cells release neurotoxic factors upon OGD-induced activation. The association PEA-luteolin actively reduces mast cell-mediated neurotoxicity as well as pure neurons susceptibility to OGD. Copyright © 2016 Elsevier B.V. All rights reserved.

Titanium oxide (TiO2) nanoparticles in induction of apoptosis and inflammatory response in brain

NASA Astrophysics Data System (ADS)

Meena, Ramovatar; Kumar, Sumit; Paulraj, R.

2015-01-01

The ever increasing applications of engineered nanoparticles in 21st century cause serious concern about its potential health risks on living being. Regulatory health risk assessment of such particles has become mandatory for the safe use of nanomaterials in consumer products and medicines. In order to study the mechanism underlying the effects of nano-TiO2 (TiO2 nanoparticles) on the brain, wistar rats were administrated intravenously with various doses of nano-TiO2 (21 nm) through the caudal vein, once a week for 4 weeks and different parameters such as bioaccumulation of nano-TiO2, oxidative stress-mediated response, level of inflammatory markers such as NF-κB (p65), HSP 60, p38, nitric oxide, IFN-γ and TNF-α, and level of neurochemicals in brain as well as DNA damage and expression of apoptosis markers (p53, Bax, Bcl-2, and cyto c) were evaluated. Results show that the concentration of nano-TiO2 in the brain increased with increasing the doses of nano-TiO2. Oxidative stress and injury of the brain occurred as nano-TiO2 appeared to trigger a cascade of reactions such as inflammation, lipid peroxidation, decreases the activities of antioxidative enzymes and melatonin level, the reduction of glutamic acid, downregulated levels of acetylcholinesterase activities, and the increase in caspase-3 activity (a biomarker of apoptosis), DNA fragmentation, and apoptosis. It may be concluded that nano-TiO2 induces oxidative stress that leads to activation of inflammatory cytokines and an alteration in the level of neurotransmitters resulted in the induction of mitochondrial-mediated apoptosis.

T-cell- and macrophage-mediated axon damage in the absence of a CNS-specific immune response: involvement of metalloproteinases.

PubMed

Newman, T A; Woolley, S T; Hughes, P M; Sibson, N R; Anthony, D C; Perry, V H

2001-11-01

Recent evidence has highlighted the fact that axon injury is an important component of multiple sclerosis pathology. The issue of whether a CNS antigen-specific immune response is required to produce axon injury remains unresolved. We investigated the extent and time course of axon injury in a rodent model of a delayed-type hypersensitivity (DTH) reaction directed against the mycobacterium bacille Calmette-Guérin (BCG). Using MRI, we determined whether the ongoing axon injury is restricted to the period during which the blood-brain barrier is compromised. DTH lesions were initiated in adult rats by intracerebral injection of heat-killed BCG followed by a peripheral challenge with BCG. Our findings demonstrate that a DTH reaction to a non-CNS antigen within a CNS white matter tract leads to axon injury. Ongoing axon injury persisted throughout the 3-month period studied and was not restricted to the period of blood-brain barrier breakdown, as detected by MRI enhancing lesions. We have previously demonstrated that matrix metalloproteinases (MMPs) are upregulated in multiple sclerosis plaques and DTH lesions. In this study we demonstrated that microinjection of activated MMPs into the cortical white matter results in axon injury. Our results show that axon injury, possibly mediated by MMPs, is immunologically non-specific and may continue behind an intact blood-brain barrier.

Beyond erythropoiesis: novel applications for recombinant human erythropoietin.

PubMed

Cerami, A

2001-07-01

Erythropoietin (EPO) primarily is produced in the kidney and acts as a principal mediator of the physiologic response to hypoxia by increasing red blood cell production. Astrocytes and neurons in the central nervous system (CNS) also are known to produce EPO in response to hypoxia/ischemia. EPO appears to play a neuroprotective role based on preclinical data demonstrating the ability of recombinant human erythropoietin (r-HuEPO) to shield neurons from hypoxic/ischemic stress when administered intracerebraventricularly. In CNS models, systemically administered r-HuEPO has not been intensely investigated because large glycosylated molecules generally were deemed incapable of crossing the blood-brain barrier (BBB). A collaborative research effort identified expression of EPO receptors on human brain capillaries and a specific receptor-mediated transport of r-HuEPO across the BBB after a single intraperitoneal (IP) injection in rodents, with subsequent protection against various types of neuronal damage. For example, administration of r-HuEPO 24 hours before or up to 6 hours after focal ischemic stroke significantly reduced the extent of infarction. r-HuEPO also attenuated concussive brain injury, kainate-induced seizure activity, and autoimmune encephalomyelitis. These preclinical findings suggest that r-HuEPO may have therapeutic potential for stroke, head trauma, and epilepsy; additional studies are needed to confirm and extend these encouraging observations in animal models. Copyright 2001 by W.B. Saunders Company.

The influence of victim characteristics on potential jurors' perceptions of brain damage in mild traumatic brain injury.

PubMed

Guilmette, T J; Temple, R O; Kennedy, M L; Weiler, M D; Ruffolo, L F; Dufresne, E

2005-11-01

To determine the influence of victim/plaintiff sex, occupation and intoxication status at the time of injury on potential jurors' judgement about the presence of brain damage in mild traumatic brain injury (MTBI). Survey. One of eight scenarios describing a MTBI from a motor vehicle accident was presented to 460 participants at a Department of Motor Vehicles. Victim sex, occupation (accountant or cafeteria worker) and alcohol intoxication status at the time of injury (sober or intoxicated) were manipulated across eight scenarios. Participants rated whether the victim's complaints at 6 months post-injury were the result of brain damage. Ratings were influenced by victim occupation and intoxication status (chi2>5.3, p<0.03), but not the sex of the victim. The occupational and intoxication status of MTBI victims may influence potential jurors' decision about the presence of brain damage.

Protective and Pathological Immunity during Central Nervous System Infections.

PubMed

Klein, Robyn S; Hunter, Christopher A

2017-06-20

The concept of immune privilege of the central nervous system (CNS) has dominated the study of inflammatory processes in the brain. However, clinically relevant models have highlighted that innate pathways limit pathogen invasion of the CNS and adaptive immunity mediates control of many neural infections. As protective responses can result in bystander damage, there are regulatory mechanisms that balance protective and pathological inflammation, but these mechanisms might also allow microbial persistence. The focus of this review is to consider the host-pathogen interactions that influence neurotropic infections and to highlight advances in our understanding of innate and adaptive mechanisms of resistance as key determinants of the outcome of CNS infection. Advances in these areas have broadened our comprehension of how the immune system functions in the brain and can readily overcome immune privilege. Copyright © 2017. Published by Elsevier Inc.

Didehydro-Cortistatin A inhibits HIV-1 Tat mediated neuroinflammation and prevents potentiation of cocaine reward in Tat transgenic mice

PubMed Central

Mediouni, Sonia; Jablonski, Joseph; Paris, Jason J.; Clementz, Mark A.; Thenin-Houssier, Suzie; McLaughlin, Jay P.; Valente, Susana T.

2015-01-01

HIV-1 Tat protein has been shown to have a crucial role in HIV-1-associated neurocognitive disorders (HAND), which includes a group of syndromes ranging from undetectable neurocognitive impairment to dementia. The abuse of psychostimulants, such as cocaine, by HIV infected individuals, may accelerate and intensify neurological damage. On the other hand, exposure to Tat potentiates cocaine-mediated reward mechanisms, which further promotes HAND. Here, we show that didehydro-Cortistatin A (dCA), an analog of a natural steroidal alkaloid, crosses the blood-brain barrier, cross-neutralizes Tat activity from several HIV-1 clades and decreases Tat uptake by glial cell lines. In addition, dCA potently inhibits Tat mediated dysregulation of IL-1β, TNF-α and MCP-1, key neuroinflammatory signaling proteins. Importantly, using a mouse model where doxycycline induces Tat expression, we demonstrate that dCA reverses the potentiation of cocaine-mediated reward. Our results suggest that adding a Tat inhibitor, such as dCA, to current antiretroviral therapy may reduce HIV-1-related neuropathogenesis. PMID:25613133

Angiotensin II Causes Neuronal Damage in Stretch-Injured Neurons: Protective Effects of Losartan, an Angiotensin T1 Receptor Blocker.

PubMed

Abdul-Muneer, P M; Bhowmick, Saurav; Briski, Nicholas

2017-11-08

Angiotensin II (Ang II) is a mediator of oxidative stress via activation/induction of reactive oxygen and nitrogen species-generating enzymes, NADPH oxidase (NOX) and inducible nitric oxide synthase (iNOS). We investigated the hypothesis that overproduction of Ang II during traumatic brain injury (TBI) induces the activation of the oxidative stress, which triggers neuroinflammation and cell apoptosis in a cell culture model of neuronal stretch injury. We first established that stretch injury causes a rapid increase in the level of Ang II, which causes the release of pro-inflammatory cytokines, IL-1β and TNF-α, via the induction of oxidative stress. Since angiotensin-converting enzyme (ACE) mediates the production of Ang II via the conversion of Ang I into Ang II, we analyzed the expression of ACE by western blotting. Further, we analyzed caspase-3-mediated apoptosis by TUNEL staining and annexin V western blotting. Angiotensin type I (AT 1 ) receptor antagonist losartan attenuated Ang II-induced oxidative stress and associated neuroinflammation and cell death in cultured neurons. Remarkably, we noticed that the expression of Ang II type 1 receptor (AngT 1 R) upregulated in neuronal stretch injury; losartan mitigates this upregulation. Findings from this study significantly extend our understanding of the pathophysiology of TBI and may have significant implications for developing therapeutic strategies for TBI-associated brain dysfunctions.

C-fiber-related EEG-oscillations induced by laser radiant heat stimulation of capsaicin-treated skin

PubMed Central

Domnick, Claudia; Hauck, Michael; Casey, Kenneth L; Engel, Andreas K; Lorenz, Jürgen

2009-01-01

Nociceptive input reaches the brain via two different types of nerve fibers, moderately fast A-delta and slowly conducting C-fibers, respectively. To explore their distinct roles in normal and inflammatory pain we used laser stimulation of normal and capsaicin treated skin at proximal and distal arm sites in combination with time frequency transformation of electroencephalography (EEG) data. Comparison of phase-locked (evoked) and non-phase-locked (total) EEG to laser stimuli revealed three significant pain-related oscillatory responses. First, an evoked response in the delta-theta band, mediated by A-fibers, was reduced by topical capsaicin treatment. Second, a decrease of total power in the alpha-to-gamma band reflected both an A- and C-nociceptor-mediated response with only the latter being reduced by capsaicin treatment. Finally, an enhancement of total power in the upper beta band was mediated exclusively by C-nociceptors and appeared strongly augmented by capsaicin treatment. These findings suggest that phase-locking of brain activity to stimulus onset is a critical feature of A-delta nociceptive input, allowing rapid orientation to salient and potentially threatening events. In contrast, the subsequent C-nociceptive input exhibits clearly less phase coupling to the stimulus. It may primarily signal the tissue status allowing more long-term behavioral adaptations during ongoing inflammatory events that accompany tissue damage. PMID:21197293

Traumatic Brain Injury as a Cause of Behavior Disorders.

ERIC Educational Resources Information Center

Nordlund, Marcia R.

There is increasing evidence that many children and adolescents who display behavior disorders have sustained a traumatic brain injury. Traumatic brain injury can take the following forms: closed head trauma in which the brain usually suffers diffuse damage; open head injury which usually results in specific focal damage; or internal trauma (e.g.,…

Experience-Dependent Neural Plasticity in the Adult Damaged Brain

ERIC Educational Resources Information Center

Kerr, Abigail L.; Cheng, Shao-Ying; Jones, Theresa A.

2011-01-01

Behavioral experience is at work modifying the structure and function of the brain throughout the lifespan, but it has a particularly dramatic influence after brain injury. This review summarizes recent findings on the role of experience in reorganizing the adult damaged brain, with a focus on findings from rodent stroke models of chronic upper…

Methamphetamine-induced neurotoxicity and microglial activation are not mediated by fractalkine receptor signaling

PubMed Central

Thomas, David M.; Francescutti-Verbeem, Dina M.; Kuhn, Donald M.

2009-01-01

Methamphetamine (METH) damages dopamine (DA) nerve endings by a process that has been linked to microglial activation but the signaling pathways that mediate this response have not yet been delineated. Cardona et al. [Nat. Neurosci. 9 (2006), 917] recently identified the microglial-specific fractalkine receptor (CX3CR1) as an important mediator of MPTP-induced neurodegeneration of DA neurons. Because the CNS damage caused by METH and MPTP is highly selective for the DA neuronal system in mouse models of neurotoxicity, we hypothesized that the CX3CR1 plays a role in METH-induced neurotoxicity and microglial activation. Mice in which the CX3CR1 gene has been deleted and replaced with a cDNA encoding enhanced green fluorescent protein (eGFP) were treated with METH and examined for striatal neurotoxicity. METH depleted DA, caused microglial activation, and increased body temperature in CX3CR1 knockout mice to the same extent and over the same time course seen in wild-type controls. The effects of METH in CX3CR1 knockout mice were not gender-dependent and did not extend beyond the striatum. Striatal microglia expressing eGFP constitutively show morphological changes after METH that are characteristic of activation. This response was restricted to the striatum and contrasted sharply with unresponsive eGFP-microglia in surrounding brain areas that are not damaged by METH. We conclude from these studies that CX3CR1 signaling does not modulate METH neurotoxicity or microglial activation. Furthermore, it appears that striatal-resident microglia respond to METH with an activation cascade and then return to a surveying state without undergoing apoptosis or migration. PMID:18410508

Methamphetamine-induced neurotoxicity and microglial activation are not mediated by fractalkine receptor signaling.

PubMed

Thomas, David M; Francescutti-Verbeem, Dina M; Kuhn, Donald M

2008-07-01

Methamphetamine (METH) damages dopamine (DA) nerve endings by a process that has been linked to microglial activation but the signaling pathways that mediate this response have not yet been delineated. Cardona et al. [Nat. Neurosci. 9 (2006), 917] recently identified the microglial-specific fractalkine receptor (CX3CR1) as an important mediator of MPTP-induced neurodegeneration of DA neurons. Because the CNS damage caused by METH and MPTP is highly selective for the DA neuronal system in mouse models of neurotoxicity, we hypothesized that the CX3CR1 plays a role in METH-induced neurotoxicity and microglial activation. Mice in which the CX3CR1 gene has been deleted and replaced with a cDNA encoding enhanced green fluorescent protein (eGFP) were treated with METH and examined for striatal neurotoxicity. METH depleted DA, caused microglial activation, and increased body temperature in CX3CR1 knockout mice to the same extent and over the same time course seen in wild-type controls. The effects of METH in CX3CR1 knockout mice were not gender-dependent and did not extend beyond the striatum. Striatal microglia expressing eGFP constitutively show morphological changes after METH that are characteristic of activation. This response was restricted to the striatum and contrasted sharply with unresponsive eGFP-microglia in surrounding brain areas that are not damaged by METH. We conclude from these studies that CX3CR1 signaling does not modulate METH neurotoxicity or microglial activation. Furthermore, it appears that striatal-resident microglia respond to METH with an activation cascade and then return to a surveying state without undergoing apoptosis or migration.

Recombinant AAV8-mediated intrastriatal gene delivery of CDNF protects rats against methamphetamine neurotoxicity

PubMed Central

Wang, Lizheng; Wang, Zixuan; Xu, Xiaoyu; Zhu, Rui; Bi, Jinpeng; Liu, Wenmo; Feng, Xinyao; Wu, Hui; Zhang, Haihong; Wu, Jiaxin; Kong, Wei; Yu, Bin; Yu, Xianghui

2017-01-01

Methamphetamine (METH) exerts significant neurotoxicity in experimental animals and humans when taken at high doses or abused chronically. Long-term abusers have decreased dopamine levels, and they are more likely to develop Parkinson's disease (PD). To date, few medications are available to treat the METH-induced damage of neurons. Glial cell line-derived neurotrophic factor (GDNF) has been previously shown to reduce the dopamine-depleting effects of neurotoxic doses of METH. However, the effect of cerebral dopamine neurotrophic factor (CDNF), which has been reported to be more specific and efficient than GDNF in protecting dopaminergic neurons against 6-OHDA toxicity, in attenuating METH neurotoxicity has not been determined. Thus, the present study aimed to evaluate the neuroprotective effect of CDNF against METH-induced damage to the dopaminergic system in vitro and in vivo. In vitro, CDNF protein increased the survival rate and reduced the tyrosine hydroxylase (TH) loss of METH-treated PC12 cells. In vivo, METH was administered to rats following human CDNF overexpression mediated by the recombinant adeno-associated virus. Results demonstrated that CDNF overexpression in the brain could attenuate the METH-induced dopamine and TH loss in the striatum but could not lower METH-induced hyperthermia. PMID:28553166

Peptidylarginine Deiminases as Drug Targets in Neonatal Hypoxic–Ischemic Encephalopathy

PubMed Central

Lange, Sigrun

2016-01-01

Oxygen deprivation and infection are major causes of perinatal brain injury leading to cerebral palsy and other neurological disabilities. The identification of novel key factors mediating white and gray matter damage are crucial to allow better understanding of the specific contribution of different cell types to the injury processes and pathways for clinical intervention. Recent studies in the Rice–Vannucci mouse model of neonatal hypoxic ischemia (HI) have highlighted novel roles for calcium-regulated peptidylarginine deiminases (PADs) and demonstrated neuroprotective effects of pharmacological PAD inhibition following HI and synergistic infection mimicked by lipopolysaccharide stimulation. PMID:26941709

Neurological Disease in Lupus: Toward a Personalized Medicine Approach

PubMed Central

McGlasson, Sarah; Wiseman, Stewart; Wardlaw, Joanna; Dhaun, Neeraj; Hunt, David P. J.

2018-01-01

The brain and nervous system are important targets for immune-mediated damage in systemic lupus erythematosus (SLE), resulting in a complex spectrum of neurological syndromes. Defining nervous system disease in lupus poses significant challenges. Among the difficulties to be addressed are a diversity of clinical manifestations and a lack of understanding of their mechanistic basis. However, despite these challenges, progress has been made in the identification of pathways which contribute to neurological disease in SLE. Understanding the molecular pathogenesis of neurological disease in lupus will inform both classification and approaches to clinical trials. PMID:29928273

Macrophages and depression - a misalliance or well-arranged marriage?

PubMed

Roman, Adam; Kreiner, Grzegorz; Nalepa, Irena

2013-01-01

Depression is a severe medical condition with multiple manifestations and diverse, largely unknown etiologies. The immune system, particularly macrophages, plays an important role in the pathology of the illness. Macrophages represent a heterogeneous population of immune cells that is dispersed throughout the body. The central nervous system is populated by several types of macrophages, including microglia, perivascular cells, meningeal and choroid plexus macrophages and pericytes. These cells occupy different brain compartments and have various functions. Under basal conditions, brain macrophages support the proper function of neural cells, organize and preserve the neuronal network and maintain homeostasis. As cells of the innate immune system, they recognize and react to any disturbances in homeostasis, eliminating pathogens or damaged cells, terminating inflammation and proceeding to initiate tissue reconstruction. Disturbances in these processes result in diverse pathologies. In particular, tissue stress or malfunction, both in the brain and in the periphery, produce sustained inflammatory states, which may cause depression. Excessive release of proinflammatory mediators is responsible for alterations of neurotransmitter systems and the occurrence of depressive symptoms. Almost all antidepressive drugs target monoamine or serotonin neurotransmission and also have anti-inflammatory or immunosuppressive properties. In addition, non-pharmacological treatments, such as electroconvulsive shock, can also exert anti-inflammatory effects. Recent studies have shown that antidepressive therapies can affect the functional properties of peripheral and brain macrophages and skew them toward the anti-inflammatory M2 phenotype. Because macrophages can affect outcome of inflammatory diseases, alleviate sickness behavior and improve cognitive function, it is possible that the effects of antidepressive treatments may be, at least in part, mediated by changes in macrophage activity.

Clearance of amyloid-β peptide across the choroid plexus in Alzheimer's disease.

PubMed

Alvira-Botero, Ximena; Carro, Eva M

2010-12-01

Aging and several neurodegenerative diseases bring about changes in the anatomy and physiology of the choroid plexus. The identification of specific membrane receptors that bind and internalize extracellular ligands has revolutionized the traditional roles of this tissue. Amyloid beta peptide (Aβ), the major constituent of the amyloid core of senile plaques in patients with Alzheimer's disease (AD) is known to contribute to disease neuropathology and progression. Recent emphasis on comorbidity of AD and a deficient clearance of Aβ across the blood-brain barrier and blood-cerebrospinal fluid barrier have highlighted the importance of brain Aβ clearance in AD. The megalin receptor has also been implicated in the pathogenesis of AD. Faulty Aβ clearance from the brain across the choroid plexus epithelium by megalin appears to mediate focal Aβ accumulation in AD. Patients with AD have reduced levels of megalin at the choroid plexus, which in turn seem to increase brain levels of Aβ through a decreased efflux of brain Aβ. Therapies that increase megalin expression at the choroid plexus could potentially control accumulation of brain Aβ. This review covers in depth the anatomy and function of the choroid plexus, focusing on the brain barrier at the choroid plexus, as it actively participates in Aβ clearance. In addition, we describe the role of the choroid plexus in brain functions, aging and AD, as well as the role of megalin in the process of Aβ clearance. Finally, we present current data on the use of choroid plexus cells to repair the damaged brain.

Pathological correlations between traumatic brain injury and chronic neurodegenerative diseases.

PubMed

Cruz-Haces, Marcela; Tang, Jonathan; Acosta, Glen; Fernandez, Joseph; Shi, Riyi

2017-01-01

Traumatic brain injury is among the most common causes of death and disability in youth and young adults. In addition to the acute risk of morbidity with moderate to severe injuries, traumatic brain injury is associated with a number of chronic neurological and neuropsychiatric sequelae including neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. However, despite the high incidence of traumatic brain injuries and the established clinical correlation with neurodegeneration, the causative factors linking these processes have not yet been fully elucidated. Apart from removal from activity, few, if any prophylactic treatments against post-traumatic brain injury neurodegeneration exist. Therefore, it is imperative to understand the pathophysiological mechanisms of traumatic brain injury and neurodegeneration in order to identify potential factors that initiate neurodegenerative processes. Oxidative stress, neuroinflammation, and glutamatergic excitotoxicity have previously been implicated in both secondary brain injury and neurodegeneration. In particular, reactive oxygen species appear to be key in mediating molecular insult in neuroinflammation and excitotoxicity. As such, it is likely that post injury oxidative stress is a key mechanism which links traumatic brain injury to increased risk of neurodegeneration. Consequently, reactive oxygen species and their subsequent byproducts may serve as novel fluid markers for identification and monitoring of cellular damage. Furthermore, these reactive species may further serve as a suitable therapeutic target to reduce the risk of post-injury neurodegeneration and provide long term quality of life improvements for those suffering from traumatic brain injury.

Brain region and epilepsy-associated differences in inflammatory mediator levels in medically refractory mesial temporal lobe epilepsy.

PubMed

Strauss, Kenneth I; Elisevich, Kost V

2016-10-13

Epilepsy patients have distinct immune/inflammatory cell profiles and inflammatory mediator levels in the blood. Although the neural origin of inflammatory cells and mediators has been implied, few studies have measured these inflammatory components in the human brain itself. This study examines the brain levels of chemokines (8), cytokines (14), and vascular injury mediators (3) suspected of being altered in epilepsy. Soluble protein extracts of fresh frozen resected hippocampus, entorhinal cortex, and temporal cortex from 58 medically refractory mesial temporal lobe epilepsy subjects and 4 nonepileptic neurosurgical subjects were assayed for 25 inflammation-related mediators using ultrasensitive low-density arrays. Brain mediator levels were compared between regions and between epileptic and nonepileptic cases, showing a number of regional and possible epilepsy-associated differences. Eotaxin, interferon-γ, interleukin (IL)-2, IL-4, IL-12 p70, IL-17A, tumor necrosis factor-α, and intercellular adhesion molecule (ICAM)-1 levels were highest in the hippocampus, the presumptive site of epileptogenesis. Surprisingly, IL-1β and IL-1α were lowest in the hippocampus, compared to cortical regions. In the temporal cortex, IL-1β, IL-8, and MIP-1α levels were highest, compared to the entorhinal cortex and the hippocampus. The most pronounced epilepsy-associated differences were decreased levels of eotaxin, IL-1β, C-reactive protein, and vascular cell adhesion molecule (VCAM)-1 and increased IL-12 p70 levels. Caution must be used in interpreting these results, however, because nonepileptic subjects were emergent neurosurgical cases, not a control group. Correlation analyses of each mediator in each brain region yielded valuable insights into the regulation of these mediator levels in the brain. Over 70 % of the associations identified were between different mediators in a single brain region, providing support for local control of mediator levels. Correlations of different mediators in different brain regions suggested more distributed control mechanisms, particularly in the hippocampus. Interestingly, only four mediators showed robust correlations between the brain regions, yet levels in three of these were significantly different between regions, indicating both global and local controls for these mediators. Both brain region-specific and epilepsy-associated changes in inflammation-related mediators were detected. Correlations in mediator levels within and between brain regions indicated local and global regulation, respectively. The hippocampus showed the majority of interregional associations, suggesting a focus of inflammatory control between these regions.

Evaluation of endothelin-1 and MMPs-2, -9, -14 in cerebrospinal fluid as indirect indicators of blood-brain barrier dysfunction in chronic canine hypothyroidism.

PubMed

Pancotto, Theresa E; Rossmeisl, John H; Huckle, William R; Inzana, Karen D; Zimmerman, Kurt L

2016-04-01

Chronic canine hypothyroidism is associated with blood-brain barrier (BBB) disruption. We hypothesized that this change is mediated by endothelin-1(ET-1) and matrix metalloproteinases (MMP) -2, -9, and -14, as evidenced by increased concentrations of these proteins in cerebrospinal fluid (CSF) compared to controls. CSF from 18 dogs, 9 controls and 9 with experimentally induced hypothyroidism was collected before and 6, 12, and 18 months after induction of hypothyroidism. Concentrations of ET-1 using an ELISA kit, and for MMP-2, -9, and -14 using gelatinase zymography were measured in CSF. ET-1 was undetectable in CSF of control and hypothyroid dogs at all time-points. Constitutively expressed MMP-2 was detectable in CSF samples in all dogs at all time-points. No other MMPs were detectable in CSF. No differences in CSF concentrations of ET-1 and MMP-2, 9, and 14 were found between hypothyroid and euthyroid dogs. Therefore, ET-1 and MMP-2, 9, and 14 are unlikely to be primary mediators of BBB damage in chronically hypothyroid dogs. Copyright © 2016 Elsevier Ltd. All rights reserved.

AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APP+PS1 mice.

PubMed

Kiyota, T; Ingraham, K L; Swan, R J; Jacobsen, M T; Andrews, S J; Ikezu, T

2012-07-01

Brain inflammation is a double-edged sword. It is required for brain repair in acute damage, whereas chronic inflammation and autoimmune disorders are neuropathogenic. Certain proinflammatory cytokines and chemokines are closely related to cognitive dysfunction and neurodegeneration. Representative anti-inflammatory cytokines, such as interleukin (IL)-10, can suppress neuroinflammation and have significant therapeutic potentials in ameliorating neurodegenerative disorders such as Alzheimer's disease (AD). Here, we show that adeno-associated virus (AAV) serotype 2/1 hybrid-mediated neuronal expression of the mouse IL-10 gene ameliorates cognitive dysfunction in amyloid precursor protein+ presenilin-1 bigenic mice. AAV2/1 infection of hippocampal neurons resulted in sustained expression of IL-10 without its leakage into the blood, reduced astro/microgliosis, enhanced plasma amyloid-β peptide (Aβ) levels and enhanced neurogenesis. Moreover, increased levels of IL-10 improved spatial learning, as determined by the radial arm water maze. Finally, IL-10-stimulated microglia enhanced proliferation but not differentiation of primary neural stem cells in the co-culture system, whereas IL-10 itself had no effect. Our data suggest that IL-10 gene delivery has a therapeutic potential for a non-Aβ-targeted treatment of AD.

Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems.

PubMed

Mattson, Mark P; Wan, Ruiqian

2005-03-01

Intermittent fasting (IF; reduced meal frequency) and caloric restriction (CR) extend lifespan and increase resistance to age-related diseases in rodents and monkeys and improve the health of overweight humans. Both IF and CR enhance cardiovascular and brain functions and improve several risk factors for coronary artery disease and stroke including a reduction in blood pressure and increased insulin sensitivity. Cardiovascular stress adaptation is improved and heart rate variability is increased in rodents maintained on an IF or a CR diet. Moreover, rodents maintained on an IF regimen exhibit increased resistance of heart and brain cells to ischemic injury in experimental models of myocardial infarction and stroke. The beneficial effects of IF and CR result from at least two mechanisms--reduced oxidative damage and increased cellular stress resistance. Recent findings suggest that some of the beneficial effects of IF on both the cardiovascular system and the brain are mediated by brain-derived neurotrophic factor signaling in the brain. Interestingly, cellular and molecular effects of IF and CR on the cardiovascular system and the brain are similar to those of regular physical exercise, suggesting shared mechanisms. A better understanding of the cellular and molecular mechanisms by which IF and CR affect the blood vessels and heart and brain cells will likely lead to novel preventative and therapeutic strategies for extending health span.

Dietary supplementation of grape seed and skin flour mitigates brain oxidative damage induced by a high-fat diet in rat: Gender dependency.

PubMed

Charradi, Kamel; Mahmoudi, Mohamed; Bedhiafi, Takwa; Kadri, Safwen; Elkahoui, Salem; Limam, Ferid; Aouani, Ezzedine

2017-03-01

It is unknown whether gender has an impact on brain injury in obesity, and, if so, whether treatment with grape seed and skin flour could exert a protective effect. Both male and female rats were fed a standard diet (SD) or a high fat diet (HFD) during eight weeks and treated with high dosage grape seed and skin flour (GSSF). Fat-induced oxidative stress was evaluated into the brain with a special emphasis on transition metals determination. HFD induced male-cholesterol overload (+78.12%) and an oxidative stress status characterized by increased lipoperoxidation (+68.97%), carbonylation (+40.28%), decreased antioxidant enzyme activities as glutathione peroxidase (-61.07%) and manganese-superoxide dismutase (-35.47%) but not catalase. Additionally HFD depleted the brain from manganese (-71.31%) and dropped glutamine synthetase activity (-36.16%), without affecting copper nor iron nor their associated enzymes. HFD also altered intracellular mediators as superoxide anion (+36.12%), calcium (+44.41%) and also calpain (+76.54%) a calcium dependent protease. Importantly all these alterations were detected exclusively in male brain and were efficiently corrected upon GSSF treatment. In conclusion, GSSF has the potential to alleviate the deleterious lipotoxic effect of HFD treatment that occurred in male brain and perhaps in post-menauposal female brain. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Regionally distinct responses of microglia and glial progenitor cells to whole brain irradiation in adult and aging rats.

PubMed

Hua, Kun; Schindler, Matthew K; McQuail, Joseph A; Forbes, M Elizabeth; Riddle, David R

2012-01-01

Radiation therapy has proven efficacy for treating brain tumors and metastases. Higher doses and larger treatment fields increase the probability of eliminating neoplasms and preventing reoccurrence, but dose and field are limited by damage to normal tissues. Normal tissue injury is greatest during development and in populations of proliferating cells but also occurs in adults and older individuals and in non-proliferative cell populations. To better understand radiation-induced normal tissue injury and how it may be affected by aging, we exposed young adult, middle-aged, and old rats to 10 Gy of whole brain irradiation and assessed in gray- and white matter the responses of microglia, the primary cellular mediators of radiation-induced neuroinflammation, and oligodendrocyte precursor cells, the largest population of proliferating cells in the adult brain. We found that aging and/or irradiation caused only a few microglia to transition to the classically "activated" phenotype, e.g., enlarged cell body, few processes, and markers of phagocytosis, that is seen following more damaging neural insults. Microglial changes in response to aging and irradiation were relatively modest and three markers of reactivity - morphology, proliferation, and expression of the lysosomal marker CD68- were regulated largely independently within individual cells. Proliferation of oligodendrocyte precursors did not appear to be altered during normal aging but increased following irradiation. The impacts of irradiation and aging on both microglia and oligodendrocyte precursors were heterogeneous between white- and gray matter and among regions of gray matter, indicating that there are regional regulators of the neural response to brain irradiation. By several measures, the CA3 region of the hippocampus appeared to be differentially sensitive to effects of aging and irradiation. The changes assessed here likely contribute to injury following inflammatory challenges like brain irradiation and represent important end-points for analysis in studies of therapeutic strategies to protect patients from neural dysfunction.

Systems approach to the study of brain damage in the very preterm newborn

PubMed Central

Leviton, Alan; Gressens, Pierre; Wolkenhauer, Olaf; Dammann, Olaf

2015-01-01

Background: A systems approach to the study of brain damage in very preterm newborns has been lacking. Methods: In this perspective piece, we offer encephalopathy of prematurity as an example of the complexity and interrelatedness of brain-damaging molecular processes that can be initiated inflammatory phenomena. Results: Using three transcription factors, nuclear factor-kappa B (NF-κB), Notch-1, and nuclear factor erythroid 2 related factor 2 (NRF2), we show the inter-connectedness of signaling pathways activated by some antecedents of encephalopathy of prematurity. Conclusions: We hope that as biomarkers of exposures and processes leading to brain damage in the most immature newborns become more readily available, those who apply a systems approach to the study of neuroscience can be persuaded to study the pathogenesis of brain disorders in the very preterm newborn. PMID:25926780

Brain-Derived Neurotrophic Factor Promotes Vasculature-Associated Migration of Neuronal Precursors toward the Ischemic Striatum

PubMed Central

Grade, Sofia; Weng, Yuan C.; Snapyan, Marina; Kriz, Jasna; Malva, João O.; Saghatelyan, Armen

2013-01-01

Stroke induces the recruitment of neuronal precursors from the subventricular zone (SVZ) into the ischemic striatum. In injured areas, de-routed neuroblasts use blood vessels as a physical scaffold to their migration, in a process that resembles the constitutive migration seen in the rostral migratory stream (RMS). The molecular mechanism underlying injury-induced vasculature-mediated migration of neuroblasts in the post-stroke striatum remains, however, elusive. Using adult mice we now demonstrate that endothelial cells in the ischemic striatum produce brain-derived neurotrophic factor (BDNF), a neurotrophin that promotes the vasculature-mediated migration of neuronal precursors in the RMS, and that recruited neuroblasts maintain expression of p75NTR, a low-affinity receptor for BDNF. Reactive astrocytes, which are widespread throughout the damaged area, ensheath blood vessels and express TrkB, a high-affinity receptor for BDNF. Despite the absence of BDNF mRNA, we observed strong BDNF immunolabeling in astrocytes, suggesting that these glial cells trap extracellular BDNF. Importantly, this pattern of expression is reminiscent of the adult RMS, where TrkB-expressing astrocytes bind and sequester vasculature-derived BDNF, leading to the entry of migrating cells into the stationary phase. Real-time imaging of cell migration in acute brain slices revealed a direct role for BDNF in promoting the migration of neuroblasts to ischemic areas. We also demonstrated that cells migrating in the ischemic striatum display higher exploratory behavior and longer stationary periods than cells migrating in the RMS. Our findings suggest that the mechanisms involved in the injury-induced vasculature-mediated migration of neuroblasts recapitulate, at least partially, those observed during constitutive migration in the RMS. PMID:23383048

Atherogenic diet induced lipid accumulation induced NFκB level in heart, liver and brain of Wistar rat and diosgenin as an anti-inflammatory agent.

PubMed

Binesh, Ambika; Devaraj, Sivasithamparam Niranjali; Halagowder, Devaraj

2018-03-01

Atherogenic Diet (AD) was given to rats to understand the key role of inflammatory mediators in atherosclerotic lesion formation, as a serendipitous study, the diet induced inflammatory mediators in liver and brain, whereas pancreas, kidney and spleen were not affected. The efficacy of diosgenin in ameliorating atherosclerotic progression in heart and suppression of inflammatory mediators in liver and brain of Wistar rat fed on AD diet was investigated. Atherogenic diet triggered inflammatory mediators in heart, liver and brain by upregulating TNF-α, COX-2 and NFkBp65 which are the inflammatory hub, played a key role in pathophysiologic conditions. Endothelial dysfunction, liver tissue with prominent steatosis and the stress evoked in the brain by the atherogenic diet triggered these inflammatory mediators. TNF-α and COX-2 expression was upregulated and its elevation was associated with NFkBp65 activation in heart, liver and brain of atherogenic diet induced rat. Diosgenin downregulated these inflammatory mediators, thereby prevented the atherosclerotic disease progression and concomitant suppression of inflammatory mediators in liver and brain. Copyright © 2018. Published by Elsevier Inc.

Lateralization of Egocentric and Allocentric Spatial Processing after Parietal Brain Lesions

ERIC Educational Resources Information Center

Iachini, Tina; Ruggiero, Gennaro; Conson, Massimiliano; Trojano, Luigi

2009-01-01

The purpose of this paper was to verify whether left and right parietal brain lesions may selectively impair egocentric and allocentric processing of spatial information in near/far spaces. Two Right-Brain-Damaged (RBD), 2 Left-Brain-Damaged (LBD) patients (not affected by neglect or language disturbances) and eight normal controls were submitted…

Mapping connectivity damage in the case of Phineas Gage.

PubMed

Van Horn, John Darrell; Irimia, Andrei; Torgerson, Carinna M; Chambers, Micah C; Kikinis, Ron; Toga, Arthur W

2012-01-01

White matter (WM) mapping of the human brain using neuroimaging techniques has gained considerable interest in the neuroscience community. Using diffusion weighted (DWI) and magnetic resonance imaging (MRI), WM fiber pathways between brain regions may be systematically assessed to make inferences concerning their role in normal brain function, influence on behavior, as well as concerning the consequences of network-level brain damage. In this paper, we investigate the detailed connectomics in a noted example of severe traumatic brain injury (TBI) which has proved important to and controversial in the history of neuroscience. We model the WM damage in the notable case of Phineas P. Gage, in whom a "tamping iron" was accidentally shot through his skull and brain, resulting in profound behavioral changes. The specific effects of this injury on Mr. Gage's WM connectivity have not previously been considered in detail. Using computed tomography (CT) image data of the Gage skull in conjunction with modern anatomical MRI and diffusion imaging data obtained in contemporary right handed male subjects (aged 25-36), we computationally simulate the passage of the iron through the skull on the basis of reported and observed skull fiducial landmarks and assess the extent of cortical gray matter (GM) and WM damage. Specifically, we find that while considerable damage was, indeed, localized to the left frontal cortex, the impact on measures of network connectedness between directly affected and other brain areas was profound, widespread, and a probable contributor to both the reported acute as well as long-term behavioral changes. Yet, while significantly affecting several likely network hubs, damage to Mr. Gage's WM network may not have been more severe than expected from that of a similarly sized "average" brain lesion. These results provide new insight into the remarkable brain injury experienced by this noteworthy patient.

Phospholipid alterations in the brain and heart in a rat model of asphyxia-induced cardiac arrest and cardiopulmonary bypass resuscitation

PubMed Central

Kim, Junhwan; Lampe, Joshua W.; Yin, Tai; Shinozaki, Koichiro; Becker, Lance B.

2015-01-01

Cardiac arrest (CA) induces whole-body ischemia, causing damage to multiple organs. Ischemic damage to the brain is mainly responsible for patient mortality. However, the molecular mechanism responsible for brain damage is not understood. Prior studies have provided evidence that degradation of membrane phospholipids plays key roles in ischemia/reperfusion injury. The aim of this study is to correlate organ damage to phospholipid alterations following 30 min asphyxia-induced CA or CA followed by cardiopulmonary bypass (CPB) resuscitation using a rat model. Following 30 min CA and CPB resuscitation, rats showed no brain function, moderately compromised heart function, and died within a few hours; typical outcomes of severe CA. However, we did not find any significant change in the content or composition of phospholipids in either tissue following 30 min CA or CA followed by CPB resuscitation. We found a moderate increase in lysophosphatidylinositol in both tissues, and a small increase in lysophosphatidylethanolamine and lysophosphatidylcholine only in brain tissue following CA. CPB resuscitation significantly decreased lysophosphatidylinositol but did not alter the other lyso species. These results indicate that a decrease in phospholipids is not a cause of brain damage in CA or a characteristic of brain ischemia. However, a significant increase in lysophosphatidylcholine and lysophosphatidylethanolamine found only in the brain with more damage suggests that impaired phospholipid metabolism may be correlated with the severity of ischemia in CA. In addition, the unique response of lysophosphatidylinositol suggests that phosphatidylinositol metabolism is highly sensitive to cellular conditions altered by ischemia and resuscitation. PMID:26160279

Phospholipid alterations in the brain and heart in a rat model of asphyxia-induced cardiac arrest and cardiopulmonary bypass resuscitation.

PubMed

Kim, Junhwan; Lampe, Joshua W; Yin, Tai; Shinozaki, Koichiro; Becker, Lance B

2015-10-01

Cardiac arrest (CA) induces whole-body ischemia, causing damage to multiple organs. Ischemic damage to the brain is mainly responsible for patient mortality. However, the molecular mechanism responsible for brain damage is not understood. Prior studies have provided evidence that degradation of membrane phospholipids plays key roles in ischemia/reperfusion injury. The aim of this study is to correlate organ damage to phospholipid alterations following 30 min asphyxia-induced CA or CA followed by cardiopulmonary bypass (CPB) resuscitation using a rat model. Following 30 min CA and CPB resuscitation, rats showed no brain function, moderately compromised heart function, and died within a few hours; typical outcomes of severe CA. However, we did not find any significant change in the content or composition of phospholipids in either tissue following 30 min CA or CA followed by CPB resuscitation. We found a substantial increase in lysophosphatidylinositol in both tissues, and a small increase in lysophosphatidylethanolamine and lysophosphatidylcholine only in brain tissue following CA. CPB resuscitation significantly decreased lysophosphatidylinositol but did not alter the other lyso species. These results indicate that a decrease in phospholipids is not a cause of brain damage in CA or a characteristic of brain ischemia. However, a significant increase in lysophosphatidylcholine and lysophosphatidylethanolamine found only in the brain with more damage suggests that impaired phospholipid metabolism may be correlated with the severity of ischemia in CA. In addition, the unique response of lysophosphatidylinositol suggests that phosphatidylinositol metabolism is highly sensitive to cellular conditions altered by ischemia and resuscitation.

Right hemisphere damage: Communication processing in adults evaluated by the Brazilian Protocole MEC - Bateria MAC.

PubMed

Fonseca, Rochele Paz; Fachel, Jandyra Maria Guimarães; Chaves, Márcia Lorena Fagundes; Liedtke, Francéia Veiga; Parente, Maria Alice de Mattos Pimenta

2007-01-01

Right-brain-damaged individuals may present discursive, pragmatic, lexical-semantic and/or prosodic disorders. To verify the effect of right hemisphere damage on communication processing evaluated by the Brazilian version of the Protocole Montréal d'Évaluation de la Communication (Montreal Communication Evaluation Battery) - Bateria Montreal de Avaliação da Comunicação, Bateria MAC, in Portuguese. A clinical group of 29 right-brain-damaged participants and a control group of 58 non-brain-damaged adults formed the sample. A questionnaire on sociocultural and health aspects, together with the Brazilian MAC Battery was administered. Significant differences between the clinical and control groups were observed in the following MAC Battery tasks: conversational discourse, unconstrained, semantic and orthographic verbal fluency, linguistic prosody repetition, emotional prosody comprehension, repetition and production. Moreover, the clinical group was less homogeneous than the control group. A right-brain-damage effect was identified directly, on three communication processes: discursive, lexical-semantic and prosodic processes, and indirectly, on pragmatic process.

Pericyte protection by edaravone after tissue plasminogen activator treatment in rat cerebral ischemia

PubMed Central

Deguchi, Kentaro; Liu, Ning; Liu, Wentao; Omote, Yoshio; Kono, Syoichiro; Yunoki, Taijun; Deguchi, Shoko; Yamashita, Toru; Ikeda, Yoshio; Abe, Koji

2014-01-01

Pericytes play a pivotal role in contraction, mediating inflammation and regulation of blood flow in the brain. In this study, changes of pericytes in the neurovascular unit (NVU) were examined in relation to the effects of exogenous tissue plasminogen activator (tPA) and a free radical scavenger, edaravone. Immunohistochemistry and Western blot analyses showed that the overlap between platelet-derived growth factor receptor β-positive pericytes and N-acetylglucosamine oligomers (NAGO)-positive endothelial cells increased significantly at 4 days after 90 min of transient middle cerebral artery occlusion (tMCAO). The number of pericytes and the overlap with NAGO decreased with tPA but recovered with edaravone 4 days after tMCAO with proliferation. Thus, tPA treatment damaged pericytes, resulting in the detachment from astrocytes and a decrease in glial cell line-derived neurotrophic factor secretion. However, treatment with edaravone greatly improved tPA-induced damage to pericytes. The present study demonstrates that exogenous tPA strongly damages pericytes and destroys the integrity of the NVU, but edaravone treatment can greatly ameliorate such damage after acute cerebral ischemia in rats. © 2014 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc. PMID:24938625

Retinal ganglion cell damage in an experimental rodent model of blast-mediated traumatic brain injury.

PubMed

Mohan, Kabhilan; Kecova, Helga; Hernandez-Merino, Elena; Kardon, Randy H; Harper, Matthew M

2013-05-15

To evaluate retina and optic nerve damage following experimental blast injury. Healthy adult mice were exposed to an overpressure blast wave using a custom-built blast chamber. The effects of blast exposure on retina and optic nerve function and structure were evaluated using the pattern electroretinogram (pERG), spectral domain optical coherence tomography (OCT), and the chromatic pupil light reflex. Assessment of the pupil response to light demonstrated decreased maximum pupil constriction diameter in blast-injured mice using red light or blue light stimuli 24 hours after injury compared with baseline in the eye exposed to direct blast injury. A decrease in the pupil light reflex was not observed chronically following blast exposure. We observed a biphasic pERG decrease with the acute injury recovering by 24 hours postblast and the chronic injury appearing at 4 months postblast injury. Furthermore, at 3 months following injury, a significant decrease in the retinal nerve fiber layer was observed using OCT compared with controls. Histologic analysis of the retina and optic nerve revealed punctate regions of reduced cellularity in the ganglion cell layer and damage to optic nerves. Additionally, a significant upregulation of proteins associated with oxidative stress was observed acutely following blast exposure compared with control mice. Our study demonstrates that decrements in retinal ganglion cell responses can be detected after blast injury using noninvasive functional and structural tests. These objective responses may serve as surrogate tests for higher CNS functions following traumatic brain injury that are difficult to quantify.

Endoplasmic Reticulum Stress Mediates Methamphetamine-Induced Blood–Brain Barrier Damage

PubMed Central

Qie, Xiaojuan; Wen, Di; Guo, Hongyan; Xu, Guanjie; Liu, Shuai; Shen, Qianchao; Liu, Yi; Zhang, Wenfang; Cong, Bin; Ma, Chunling

2017-01-01

Methamphetamine (METH) abuse causes serious health problems worldwide, and long-term use of METH disrupts the blood–brain barrier (BBB). Herein, we explored the potential mechanism of endoplasmic reticulum (ER) stress in METH-induced BBB endothelial cell damage in vitro and the therapeutic potential of endoplasmic reticulum stress inhibitors for METH-induced BBB disruption in C57BL/6J mice. Exposure of immortalized BMVEC (bEnd.3) cells to METH significantly decreased cell viability, induced apoptosis, and diminished the tightness of cell monolayers. METH activated ER stress sensor proteins, including PERK, ATF6, and IRE1, and upregulated the pro-apoptotic protein CHOP. The ER stress inhibitors significantly blocked the upregulation of CHOP. Knockdown of CHOP protected bEnd.3 cells from METH-induced cytotoxicity. Furthermore, METH elevated the production of reactive oxygen species (ROS) and induced the dysfunction of mitochondrial characterized by a Bcl2/Bax ratio decrease, mitochondrial membrane potential collapse, and cytochrome c. ER stress release was partially reversed by ROS inhibition, and cytochrome c release was partially blocked by knockdown of CHOP. Finally, PBA significantly attenuated METH-induced sodium fluorescein (NaFluo) and Evans Blue leakage, as well as tight junction protein loss, in C57BL/6J mice. These data suggest that BBB endothelial cell damage was caused by METH-induced endoplasmic reticulum stress, which further induced mitochondrial dysfunction, and that PBA was an effective treatment for METH-induced BBB disruption. PMID:28959203

Genes that mediate breast cancer metastasis to the brain.

PubMed

Bos, Paula D; Zhang, Xiang H-F; Nadal, Cristina; Shu, Weiping; Gomis, Roger R; Nguyen, Don X; Minn, Andy J; van de Vijver, Marc J; Gerald, William L; Foekens, John A; Massagué, Joan

2009-06-18

The molecular basis for breast cancer metastasis to the brain is largely unknown. Brain relapse typically occurs years after the removal of a breast tumour, suggesting that disseminated cancer cells must acquire specialized functions to take over this organ. Here we show that breast cancer metastasis to the brain involves mediators of extravasation through non-fenestrated capillaries, complemented by specific enhancers of blood-brain barrier crossing and brain colonization. We isolated cells that preferentially infiltrate the brain from patients with advanced disease. Gene expression analysis of these cells and of clinical samples, coupled with functional analysis, identified the cyclooxygenase COX2 (also known as PTGS2), the epidermal growth factor receptor (EGFR) ligand HBEGF, and the alpha2,6-sialyltransferase ST6GALNAC5 as mediators of cancer cell passage through the blood-brain barrier. EGFR ligands and COX2 were previously linked to breast cancer infiltration of the lungs, but not the bones or liver, suggesting a sharing of these mediators in cerebral and pulmonary metastases. In contrast, ST6GALNAC5 specifically mediates brain metastasis. Normally restricted to the brain, the expression of ST6GALNAC5 in breast cancer cells enhances their adhesion to brain endothelial cells and their passage through the blood-brain barrier. This co-option of a brain sialyltransferase highlights the role of cell-surface glycosylation in organ-specific metastatic interactions.

Creatine kinase isoenzyme patterns upon chronic exposure to cigarette smoke: protective effect of Bacoside A.

PubMed

Anbarasi, K; Vani, G; Balakrishna, K; Devi, C S Shyamala

2005-01-01

Cigarette smoking is implicated as a major risk factor in the development of cardiovascular and cerebrovascular diseases. Creatine kinase (CK) and its isoforms (CK-MM, MB, BB) have been advocated as sensitive markers in the assessment of cardiac and cerebral damage. Therefore, in the present study, we report the isoenzyme patterns of CK in rats upon exposure to cigarette smoke and the protective effect of Bacoside A against chronic smoking induced toxicity. Adult male albino rats were exposed to cigarette smoke and simultaneously administered with Bacoside A, the active constituent from the plant Bacopa monniera, for a period of 12 weeks. The activity of CK was assayed in serum, heart and brain, and its isoenzymes in serum were separated electrophoretically. Rats exposed to cigarette smoke showed significant increase in serum CK activity with concomitant decrease in heart and brain. Also cigarette smoke exposure resulted in a marked increase in all the three isoforms in serum. Administration of Bacoside A prevented these alterations induced by cigarette smoking. Cigarette smoking is known to cause free radical mediated lipid peroxidation leading to increased membrane permeability and cellular damage in the heart and brain resulting in the release of CK into the circulation. The protective effect of Bacoside A on the structural and functional integrity of the membrane prevented the leakage of CK from the respective tissues, which could be attributed to its free radical scavenging and anti-lipid peroxidative effect.

Memantine mediates neuroprotection via regulating neurovascular unit in a mouse model of focal cerebral ischemia.

PubMed

Chen, Zheng-Zhen; Yang, Dan-Dan; Zhao, Zhan; Yan, Hui; Ji, Juan; Sun, Xiu-Lan

2016-04-01

Memantine is a low-moderate affinity and uncompetitive N-methyl-d-aspartate receptor (NMDAR) antagonist, which is also a potential neuroprotectant in acute ischemic stroke for its particular action profiles. The present study was to reveal the mechanisms involved in the neuroprotection of memantine. We used a mouse model of permanent focal cerebral ischemia via middle cerebral artery occlusion to verify our hypothesis. 2,3,5-Triphenyltetrazolium chloride staining was used to compare infarct size. The amount of astrocytes and the somal volume of the microglia cell body were analyzed by immunohistochemistry and stereological estimates. Western blotting was used to determine the protein expressions. Memantine prevented cerebral ischemia-induced brain infarct and neuronal injury, and reduced oxygen-glucose deprivation-induced cortical neuronal apoptosis. Moreover, memantine reduced the amount of the damaged astrocytes and over activated microglia after 24h of ischemia. In the early phase of ischemia, higher production of MMP-9 was observed, and thereby collagen IV was dramatically disrupted. Meanwhile, the post-synaptic density protein 95(PSD-95) was also severely cleavaged. Memantine decreased MMP-9 secretion, prevented the degradation of collagen IV in mouse brain. PSD-95 cleavage was also inhibited by memantine. These results suggested that memantine exerted neuroprotection effects in acute ischemic brain damage, partially via improving the functions of neurovascular unit. Taking all these findings together, we consider that memantine might be a promising protective agent against ischemic stroke. Copyright © 2016 Elsevier Inc. All rights reserved.

Brain and Peripheral Atypical Inflammatory Mediators Potentiate Neuroinflammation and Neurodegeneration.

PubMed

Kempuraj, Duraisamy; Thangavel, Ramasamy; Selvakumar, Govindhasamy P; Zaheer, Smita; Ahmed, Mohammad E; Raikwar, Sudhanshu P; Zahoor, Haris; Saeed, Daniyal; Natteru, Prashant A; Iyer, Shankar; Zaheer, Asgar

2017-01-01

Neuroinflammatory response is primarily a protective mechanism in the brain. However, excessive and chronic inflammatory responses can lead to deleterious effects involving immune cells, brain cells and signaling molecules. Neuroinflammation induces and accelerates pathogenesis of Parkinson's disease (PD), Alzheimer's disease (AD) and Multiple sclerosis (MS). Neuroinflammatory pathways are indicated as novel therapeutic targets for these diseases. Mast cells are immune cells of hematopoietic origin that regulate inflammation and upon activation release many proinflammatory mediators in systemic and central nervous system (CNS) inflammatory conditions. In addition, inflammatory mediators released from activated glial cells induce neurodegeneration in the brain. Systemic inflammation-derived proinflammatory cytokines/chemokines and other factors cause a breach in the blood brain-barrier (BBB) thereby allowing for the entry of immune/inflammatory cells including mast cell progenitors, mast cells and proinflammatory cytokines and chemokines into the brain. These peripheral-derived factors and intrinsically generated cytokines/chemokines, α-synuclein, corticotropin-releasing hormone (CRH), substance P (SP), beta amyloid 1-42 (Aβ1-42) peptide and amyloid precursor proteins can activate glial cells, T-cells and mast cells in the brain can induce additional release of inflammatory and neurotoxic molecules contributing to chronic neuroinflammation and neuronal death. The glia maturation factor (GMF), a proinflammatory protein discovered in our laboratory released from glia, activates mast cells to release inflammatory cytokines and chemokines. Chronic increase in the proinflammatory mediators induces neurotoxic Aβ and plaque formation in AD brains and neurodegeneration in PD brains. Glial cells, mast cells and T-cells can reactivate each other in neuroinflammatory conditions in the brain and augment neuroinflammation. Further, inflammatory mediators from the brain can also enter into the peripheral system through defective BBB, recruit immune cells into the brain, and exacerbate neuroinflammation. We suggest that mast cell-associated inflammatory mediators from systemic inflammation and brain could augment neuroinflammation and neurodegeneration in the brain. This review article addresses the role of some atypical inflammatory mediators that are associated with mast cell inflammation and their activation of glial cells to induce neurodegeneration.

Inhibition of cystathionine-gamma-lyase leads to loss of glutathione and aggravation of mitochondrial dysfunction mediated by excitatory amino acid in the CNS.

PubMed

Diwakar, Latha; Ravindranath, Vijayalakshmi

2007-01-01

Oxidative stress has been implicated in the pathogenesis and progression of neurodegenerative disorders and antioxidants potentially have a major role in neuroprotection. Optimum levels of glutathione (gamma-glutamylcysteinyl glycine), an endogenous thiol antioxidant are required for the maintenance of the redox status of cells. Cystathionine gamma-lyase is the rate-limiting enzyme for the synthesis of cysteine from methionine and availability of cysteine is a critical factor in glutathione synthesis. In the present study, we have examined the role of cystathionine gamma-lyase in maintaining the redox homeostasis in brain, particularly with reference to mitochondrial function since the complex I of the electron transport chain is sensitive to redox perturbation. Inhibition of cystathionine gamma-lyase by l-propargylglycine caused loss of glutathione and decrease in complex I activity in the brain although the enzyme activity in mouse brain was 1% of the corresponding hepatic activity. We then examined the effect of this inhibition on the neurotoxicity mediated by the excitatory amino acid, l-beta-oxalyl amino-l-alanine, which is the causative factor of a type of motor neuron disease, neurolathyrism. l-beta-Oxalyl amino-l-alanine toxicity was exacerbated by l-propargylglycine measured as loss of complex I activity indicating the importance of cystathionine gamma-lyase in maintaining glutathione levels and in turn the mitochondrial function during excitotoxicity. Oxidative stress generated by l-beta-oxalyl amino-l-alanine itself inhibited cystathionine gamma-lyase, which could be prevented by prior treatment with thiol antioxidant. Thus, cystathionine gamma-lyase itself is susceptible to inactivation by oxidative stress and this can potentially exacerbate oxidant-induced damage. Cystathionine gamma-lyase is present in neuronal cells in human brain and its activity is several-fold higher compared to mouse brain. It could potentially play an important role in maintaining glutathione and protein thiol homeostasis in brain and hence afford neuroprotection.

Neuropsychological outcome after traumatic temporal lobe damage.

PubMed

Formisano, R; Schmidhuber-Eiler, B; Saltuari, L; Cigany, E; Birbamer, G; Gerstenbrand, F

1991-01-01

The most frequent sequelae after severe brain injury include changes in personality traits, disturbances of emotional behaviour and impairment of cognitive functions. In particular, emotional changes and/or verbal and non verbal dysfunctions were found in patients with bilateral or unilateral temporal lobe lesions. The aim of our study is to correlate the localization of the brain damage after severe brain injury, in particular of the temporal lobe, with the cognitive impairment and the emotional and behavioural changes resulting from these lesions. The patients with right temporal lobe lesions showed significantly better scores in verbal intelligence and verbal memory in comparison with patients with left temporal lobe lesions and those with other focal brain lesions or diffuse brain damage. In contradistinction, study of the personality and the emotional changes (MMPI and FAF) failed to demonstrate pathological scores in the 3 groups with different CT lesions, without any significant difference being found between the groups with temporal lesions and those with other focal brain lesions or diffuse brain damage. The severity of the brain injury and the prolongation of the disturbance of consciousness could, in our patients, account for prevalence of congnitive impairment on personality and emotional changes.

Singing ability after right and left sided brain damage. A research note.

PubMed

Kinsella, G; Prior, M R; Murray, G

1988-03-01

Capacity to sing following brain damage was investigated in a series of 15 right sided and 15 left sided lesioned subjects and 15 normal control subjects. All subjects were asked to sing the same well-known song and performance was judged by independent expert musicians using criteria of ability to pitch the melody, accurately produce the rhythm, and overall quality of the production. There was a lack of support for differential effect of right and left cerebral damage on pitch and rhythm aspects of singing, but a generalized effect of brain damage was found.

Diet-gene interactions underlie metabolic individuality and influence brain development: Implications for clinical practice

PubMed Central

Zeisel, Steven H.

2014-01-01

One of the underlying mechanisms for metabolic individuality is genetic variation. Single nucleotide polymorphisms (SNPs) in genes of metabolic pathways can create metabolic inefficiencies that alter the dietary requirement for, and responses to nutrients. These SNPS can be detected using genetic profiling and the metabolic inefficiencies they cause can be detected using metabolomic profiling. Studies on the human dietary requirement for choline illustrate how useful these new approaches can be, as this requirement is influenced by SNPs in genes of choline and folate metabolism. In adults, these SNPs determine whether people develop fatty liver, liver damage and muscle damage when eating diets low in choline. Because choline is very important for fetal development, these SNPs may identify women who need to eat more choline during pregnancy. Some of the actions of choline are mediated by epigenetic mechanisms that permit “retuning” of metabolic pathways during early life. PMID:22614815

Postconditioning Effectively Prevents Trimethyltin Induced Neuronal Damage in the Rat Brain.

PubMed

Lalkovicova, Maria; Burda, Jozef; Nemethova, Miroslava; Burda, Rastislav; Danielisova, Viera

Trimethyltin (TMT) is a toxic substance formerly used as a catalyst in the production of organic substances, as well as in industry and agriculture. TMT poisoning has caused death or severe injury in many dozens of people. The toxicity of TMT is mediated by dose dependent selective damage to the limbic system in humans and other animals, specifically the degeneration of CA1 neurons in the hippocampus. The typical symptoms include memory loss and decreased learning ability. Using knowledge gained in previous studies of global ischaemia, we used delayed postconditioning after TMT intoxication (8 mg/kg i.p.), consisting of applying a stressor (BR, bradykinin 150 μg/kg i.p.) 24 or 48 hours after the injection of TMT. We found that BR had preventive effects on neurodegenerative changes as well as learning and memory deficits induced by TMT intoxication.

Altered energy production, lowered antioxidant potential, and inflammatory processes mediate CNS damage associated with abuse of the psychostimulants MDMA and methamphetamine

PubMed Central

Downey, Luke A.; Loftis, Jennifer M.

2014-01-01

Central nervous system (CNS) damage associated with psychostimulant dependence may be an ongoing, degenerative process with adverse effects on neuropsychiatric function. However, the molecular mechanisms regarding how altered energy regulation affects immune response in the context of substance use disorders are not fully understood. This review summarizes the current evidence regarding the effects of psychostimulant [particularly 3,4-methylenedioxy-N-methylamphetamine (MDMA) and methamphetamine] exposure on brain energy regulation, immune response, and neuropsychiatric function. Importantly, the neuropsychiatric impairments (e.g., cognitive deficits, depression, and anxiety) that persist following abstinence are associated with poorer treatment outcomes – increased relapse rates, lower treatment retention rates, and reduced daily functioning. Qualifying the molecular changes within the CNS according to the exposure and use patterns of specifically abused substances should inform the development of new therapeutic approaches for addiction treatment. PMID:24485894

Altered energy production, lowered antioxidant potential, and inflammatory processes mediate CNS damage associated with abuse of the psychostimulants MDMA and methamphetamine.

PubMed

Downey, Luke A; Loftis, Jennifer M

2014-03-15

Central nervous system (CNS) damage associated with psychostimulant dependence may be an ongoing, degenerative process with adverse effects on neuropsychiatric function. However, the molecular mechanisms regarding how altered energy regulation affects immune response in the context of substance use disorders are not fully understood. This review summarizes the current evidence regarding the effects of psychostimulant [particularly 3,4-methylenedioxy-N-methylamphetamine (MDMA) and methamphetamine] exposure on brain energy regulation, immune response, and neuropsychiatric function. Importantly, the neuropsychiatric impairments (e.g., cognitive deficits, depression, and anxiety) that persist following abstinence are associated with poorer treatment outcomes - increased relapse rates, lower treatment retention rates, and reduced daily functioning. Qualifying the molecular changes within the CNS according to the exposure and use patterns of specifically abused substances should inform the development of new therapeutic approaches for addiction treatment. Published by Elsevier B.V.

Delayed brain radiation necrosis: pathological review and new molecular targets for treatment.

PubMed

Furuse, Motomasa; Nonoguchi, Naosuke; Kawabata, Shinji; Miyatake, Shin-Ichi; Kuroiwa, Toshihiko

2015-12-01

Delayed radiation necrosis is a well-known adverse event following radiotherapy for brain diseases and has been studied since the 1930s. The primary pathogenesis is thought to be the direct damage to endothelial and glial cells, particularly oligodendrocytes, which causes vascular hyalinization and demyelination. This primary pathology leads to tissue inflammation and ischemia, inducing various tissue protective responses including angiogenesis. Macrophages and lymphocytes then infiltrate the surrounding areas of necrosis, releasing inflammatory cytokines such as interleukin (IL)-1α, IL-6, and tumor necrosis factor (TNF)-α. Microglia also express these inflammatory cytokines. Reactive astrocytes play an important role in angiogenesis, expressing vascular endothelial growth factor (VEGF). Some chemokine networks, like the CXCL12/CXCR4 axis, are upregulated by tissue inflammation. Hypoxia may mediate the cell-cell interactions among reactive astrocytes, macrophages, and microglial cells around the necrotic core. Recently, bevacizumab, an anti-VEGF antibody, has demonstrated promising results as an alternative treatment for radiation necrosis. The importance of VEGF in the pathophysiology of brain radiation necrosis is being recognized. The discovery of new molecular targets could facilitate novel treatments for radiation necrosis. This literature review will focus on recent work characterizing delayed radiation necrosis in the brain.

Bacoside A: Role in Cigarette Smoking Induced Changes in Brain

PubMed Central

Vani, G.; Anbarasi, K.; Shyamaladevi, C. S.

2015-01-01

Cigarette smoking (CS) is a major health hazard that exerts diverse physiologic and biochemical effects mediated by the components present and generated during smoking. Recent experimental studies have shown predisposition to several biological consequences from both active and passive cigarette smoke exposure. In particular, passive smoking is linked to a number of adverse health effects which are equally harmful as active smoking. A pragmatic approach should be considered for designing a pharmacological intervention to combat the adverse effects of passive smoking. This review describes the results from a controlled experimental condition, testing the effect of bacoside A (BA) on the causal role of passive/secondhand smoke exposure that caused pathological and neurological changes in rat brain. Chronic exposure to cigarette smoke induced significant changes in rat brain histologically and at the neurotransmitter level, lipid peroxidation states, mitochondrial functions, membrane alterations, and apoptotic damage in rat brain. Bacoside A is a neuroactive agent isolated from Bacopa monnieri. As a neuroactive agent, BA was effective in combating these changes. Future research should examine the effects of BA at molecular level and assess its functional effects on neurobiological and behavioral processes associated with passive smoke. PMID:26413118

Bacoside A: Role in Cigarette Smoking Induced Changes in Brain.

PubMed

Vani, G; Anbarasi, K; Shyamaladevi, C S

2015-01-01

Cigarette smoking (CS) is a major health hazard that exerts diverse physiologic and biochemical effects mediated by the components present and generated during smoking. Recent experimental studies have shown predisposition to several biological consequences from both active and passive cigarette smoke exposure. In particular, passive smoking is linked to a number of adverse health effects which are equally harmful as active smoking. A pragmatic approach should be considered for designing a pharmacological intervention to combat the adverse effects of passive smoking. This review describes the results from a controlled experimental condition, testing the effect of bacoside A (BA) on the causal role of passive/secondhand smoke exposure that caused pathological and neurological changes in rat brain. Chronic exposure to cigarette smoke induced significant changes in rat brain histologically and at the neurotransmitter level, lipid peroxidation states, mitochondrial functions, membrane alterations, and apoptotic damage in rat brain. Bacoside A is a neuroactive agent isolated from Bacopa monnieri. As a neuroactive agent, BA was effective in combating these changes. Future research should examine the effects of BA at molecular level and assess its functional effects on neurobiological and behavioral processes associated with passive smoke.

YC‑1 reduces inflammatory responses by inhibiting nuclear factor‑κB translocation in mice subjected to transient focal cerebral ischemia.

PubMed

Lee, Wei-Ting; Tai, Shih-Huang; Lin, Yu-Wen; Wu, Tian-Shung; Lee, E-Jian

2018-06-15

3‑(5‑hydroxymethyl‑2‑furyl)‑1‑benzyl‑indazole (YC‑1) is understood to protect against ischemic stroke, but the molecular basis for its neuroprotection remains to be fully characterized. The present study investigated the influence of YC‑1 on inflammatory responses following experimental stroke. Previous studies indicated that nuclear factor (NF)‑κB‑driven signals serve a pivotal role in mediating inflammatory responses following stroke. Ischemic stroke results in activation of NF‑κB to induce gene expression of factors including inducible nitric oxide synthase, interleukin (IL)‑1β, IL‑6 and matrix metalloproteinases (MMPs). The results of the present study demonstrated that YC‑1 effectively reduced brain infarction and brain edema, and improved blood‑brain barrier leakage. Additionally, animals treated with YC‑1 exhibited significant reductions in neutrophil and macrophage infiltration into the ischemic brain. Furthermore, YC‑1 effectively inhibited NF‑κB translocation and binding activity, and the activity and expression of MMP‑9 following ischemic stroke. In conclusion, YC‑1 may effectively attenuate NF‑κB‑induced inflammatory damage following cerebral ischemia‑reperfusion.

Diet and cognition: interplay between cell metabolism and neuronal plasticity

PubMed Central

Gomez-Pinilla, Fernando; Tyagi, Ethika

2014-01-01

Purpose of Study To discuss studies in humans and animals revealing the ability of foods to benefit the brain: new information with regards to mechanisms of action and the treatment of neurological and psychiatric disorders. Recent Findings Dietary factors exert their effects on the brain by affecting molecular events related to the management of energy metabolism and synaptic plasticity. Energy metabolism influences neuronal function, neuronal signaling, and synaptic plasticity, ultimately affecting mental health. Epigenetic regulation of neuronal plasticity appears as an important mechanism by which foods can prolong their effects on long term neuronal plasticity. Summary The prime focus of the discussion is to emphasize the role of cell metabolism as a mediator for the action of foods on the brain. Oxidative stress promotes damage to phospholipids present in the plasma membrane such as the omega-3 fatty acid DHA, disrupting neuronal signaling. Thus, dietary DHA seems crucial for supporting plasma membrane function, interneuronal signaling, and cognition. The dual action of brain-derived neurotrophic factor (BDNF) in neuronal metabolism and synaptic plasticity is crucial for activating signaling cascades under the action of diet and other environmental factors, using mechanisms of epigenetic regulation. PMID:24071781

Roles of microglia in brain development, tissue maintenance and repair

PubMed Central

Michell-Robinson, Mackenzie A.; Touil, Hanane; Healy, Luke M.; Owen, David R.; Durafourt, Bryce A.; Bar-Or, Amit; Antel, Jack P.

2015-01-01

The emerging roles of microglia are currently being investigated in the healthy and diseased brain with a growing interest in their diverse functions. In recent years, it has been demonstrated that microglia are not only immunocentric, but also neurobiological and can impact neural development and the maintenance of neuronal cell function in both healthy and pathological contexts. In the disease context, there is widespread consensus that microglia are dynamic cells with a potential to contribute to both central nervous system damage and repair. Indeed, a number of studies have found that microenvironmental conditions can selectively modify unique microglia phenotypes and functions. One novel mechanism that has garnered interest involves the regulation of microglial function by microRNAs, which has therapeutic implications such as enhancing microglia-mediated suppression of brain injury and promoting repair following inflammatory injury. Furthermore, recently published articles have identified molecular signatures of myeloid cells, suggesting that microglia are a distinct cell population compared to other cells of myeloid lineage that access the central nervous system under pathological conditions. Thus, new opportunities exist to help distinguish microglia in the brain and permit the study of their unique functions in health and disease. PMID:25823474

Cell fusion in the brain: two cells forward, one cell back.

PubMed

Kemp, Kevin; Wilkins, Alastair; Scolding, Neil

2014-11-01

Adult stem cell populations, notably those which reside in the bone marrow, have been shown to contribute to several neuronal cell types in the rodent and human brain. The observation that circulating bone marrow cells can migrate into the central nervous system and fuse with, in particular, cerebellar Purkinje cells has suggested, at least in part, a potential mechanism behind this process. Experimentally, the incidence of cell fusion in the brain is enhanced with age, radiation exposure, inflammation, chemotherapeutic drugs and even selective damage to the neurons themselves. The presence of cell fusion, shown by detection of increased bi-nucleated neurons, has also been described in a variety of human central nervous system diseases, including both multiple sclerosis and Alzheimer's disease. Accumulating evidence is therefore raising new questions into the biological significance of cell fusion, with the possibility that it represents an important means of cell-mediated neuroprotection or rescue of highly complex neurons that cannot be replaced in adult life. Here, we discuss the evidence behind this phenomenon in the rodent and human brain, with a focus on the subsequent research investigating the physiological mechanisms of cell fusion underlying this process. We also highlight how these studies offer new insights into endogenous neuronal repair, opening new exciting avenues for potential therapeutic interventions against neurodegeneration and brain injury.

Roles of microglia in brain development, tissue maintenance and repair.

PubMed

Michell-Robinson, Mackenzie A; Touil, Hanane; Healy, Luke M; Owen, David R; Durafourt, Bryce A; Bar-Or, Amit; Antel, Jack P; Moore, Craig S

2015-05-01

The emerging roles of microglia are currently being investigated in the healthy and diseased brain with a growing interest in their diverse functions. In recent years, it has been demonstrated that microglia are not only immunocentric, but also neurobiological and can impact neural development and the maintenance of neuronal cell function in both healthy and pathological contexts. In the disease context, there is widespread consensus that microglia are dynamic cells with a potential to contribute to both central nervous system damage and repair. Indeed, a number of studies have found that microenvironmental conditions can selectively modify unique microglia phenotypes and functions. One novel mechanism that has garnered interest involves the regulation of microglial function by microRNAs, which has therapeutic implications such as enhancing microglia-mediated suppression of brain injury and promoting repair following inflammatory injury. Furthermore, recently published articles have identified molecular signatures of myeloid cells, suggesting that microglia are a distinct cell population compared to other cells of myeloid lineage that access the central nervous system under pathological conditions. Thus, new opportunities exist to help distinguish microglia in the brain and permit the study of their unique functions in health and disease. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Probiotic attributes, antioxidant, anti-inflammatory and neuromodulatory effects of Enterococcus faecium CFR 3003: in vitro and in vivo evidence.

PubMed

Divyashri, G; Krishna, G; Muralidhara; Prapulla, S G

2015-12-01

Accumulating evidence suggests that probiotic bacteria play a vital role in modulating various aspects integral to the health and well-being of humans. In the present study, probiotic attributes and the antioxidant, anti-inflammatory and neuromodulatory potential of Enterococcus faecium CFR 3003 were investigated by employing suitable model systems. E. faecium exhibited robust resistance to gastrointestinal stress conditions as it could withstand acid stress at pH 1.5, 2 and 3. The bacterium also survived at a bile salt concentration of 0.45 %, and better tolerance was observed towards pepsin and trypsin. E. faecium produced lactic acid as a major metabolic product, followed by butyric acid. Lyophilized cell-free supernatant (LCS) of E. faecium exhibited significant antioxidant capacity evaluated against 1,1-diphenyl-2-picryl-hydrazyl, ascorbate auto-oxidation, oxygen radical absorbance and reducing power. Interestingly, E. faecium, Lactobacillus rhamnosus GG MTCC 1408 and LCS showed a significant anti-inflammatory effect by negatively modulating TNF-α production and upregulating IL-10 levels in LPS-stimulated macrophage cell lines. In an in vivo mice model, the propensity of probiotic supplements to modulate endogenous oxidative markers and redox status in brain regions was assessed. Young mice provided with oral supplements (daily for 28 days) of E. faecium and L. rhamnosus exhibited diminished oxidative markers in the brain and enhanced activities of antioxidant enzymes with a concomitant increase in γ-aminobutyric acid and dopamine levels. Collectively, our findings clearly suggest the propensity of these bacteria to protect against tissue damage mediated through free radicals and inflammatory cytokines. Although the underlying molecular mechanisms need further studies, it is tempting to speculate that probiotics confer a neuroprotective advantage in vivo against oxidative damage-mediated neurodegenerative conditions.

Astaxanthin Inhibits Acetaldehyde-Induced Cytotoxicity in SH-SY5Y Cells by Modulating Akt/CREB and p38MAPK/ERK Signaling Pathways.

PubMed

Yan, Tingting; Zhao, Yan; Zhang, Xia; Lin, Xiaotong

2016-03-10

Excessive alcohol consumption can lead to brain tissue damage and cognitive dysfunction. Acetaldehyde, the most toxic metabolite of ethanol, mediates the brain tissue damage and cognitive dysfunction induced by chronic excessive alcohol consumption. In this study, the effect of astaxanthin, a marine bioactive compound, on acetaldehyde-induced cytotoxicity was investigated in SH-SY5Y cells. It was found that astaxanthin protected cells from apoptosis by ameliorating the effect of acetaldehyde on the expression of Bcl-2 family proteins, preventing the reduction of anti-apoptotic protein Bcl-2 and the increase of pro-apoptotic protein Bak induced by acetaldehyde. Further analyses showed that astaxanthin treatment inhibited acetaldehyde-induced reduction of the levels of activated Akt and cyclic AMP-responsive element binding protein (CREB). Astaxanthin treatment also prevented acetaldehyde-induced increase of the level of activated p38 mitogen-activated protein kinase (MAPK) and decrease of the level of activated extracellular signal-regulated kinases (ERKs). Activation of Akt/CREB pathway promotes cell survival and is involved in the upregulation of Bcl-2 gene. P38MAPK plays a critical role in apoptotic events while ERKs mediates the inhibition of apoptosis. Thus, astaxanthin may inhibit acetaldehyde-induced apoptosis through promoting the activation of Akt/CREB and ERKs and blocking the activation of p38MAPK. In addition, astaxanthin treatment suppressed the oxidative stress induced by acetaldehyde and restored the antioxidative capacity of SH-SY5Y cells. Therefore, astaxanthin may protect cells against acetaldehyde-induced cytotoxicity through maintaining redox balance and modulating apoptotic and survival signals. The results suggest that astaxanthin treatment may be beneficial for preventing neurotoxicity associated with acetaldehyde and excessive alcohol consumption.

Nobiletin improves propofol-induced neuroprotection via regulating Akt/mTOR and TLR 4/NF-κB signaling in ischemic brain injury in rats.

PubMed

Zheng, Yuzhen; Bu, Jinmei; Yu, Liang; Chen, Jun; Liu, Haigen

2017-07-01

Stroke is regarded as one of the main health concerns globally, presenting with high mortality and morbidity rates. Cerebral ischemic damage and infarction are critically associated with stroke. Various mechanisms related to inflammation, oxidative stress and excitotoxicity are found to be involved in ischemic damage. Very short time period for treatment has necessitated in development of more effective neuroprotective agents. Study aimed in investigated the effects of nobiletin on experimentally induced ischemic brain injury and also to assess whether nobiletin potentiated the neuroprotective effects of propofol. Male Sprague-Dawley rats were subjected to ischemia/reperfusion (I/R) injury. Induction of cerebral infarction and I/R was done by middle cerebral artery occlusion (MCAO). Nobiletin (100 or 200mg/kg b.wt.) was intragastrically administered to rats for 9 days before ischemia induction and on the day of induction nobiletin was administered an hour prior. Separate group of rats were post-conditioned with propofol (50mg/kg/h; i.v.) for 30min following 24h of reperfusion. Propofol post-conditioning either with or without administration of nobiletin prior I/R injury attenuated pulmonary edema, neuronal apoptosis and reduced cerebral infarct volume. Overproduction of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) and nitric oxide following I/R were reduced. Propofol either alone or with prior nobiletin treatment had down-regulated TLR4 and TLR4-mediated NF-κB signaling and caused activation of Akt/mTOR cascade. Propofol post-conditioning either with nobiletin prior I/R injury was found to be more effective than propofol alone, suggesting the positive effects of nobiletin on propofol-mediated anti-inflammatory and neuroprotective effects. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Intermittent fasting attenuates inflammasome activity in ischemic stroke.

PubMed

Fann, David Yang-Wei; Santro, Tomislav; Manzanero, Silvia; Widiapradja, Alexander; Cheng, Yi-Lin; Lee, Seung-Yoon; Chunduri, Prasad; Jo, Dong-Gyu; Stranahan, Alexis M; Mattson, Mark P; Arumugam, Thiruma V

2014-07-01

Recent findings have revealed a novel inflammatory mechanism that contributes to tissue injury in cerebral ischemia mediated by multi-protein complexes termed inflammasomes. Intermittent fasting (IF) can decrease the levels of pro-inflammatory cytokines in the periphery and brain. Here we investigated the impact of IF (16h of food deprivation daily) for 4months on NLRP1 and NLRP3 inflammasome activities following cerebral ischemia. Ischemic stroke was induced in C57BL/6J mice by middle cerebral artery occlusion, followed by reperfusion (I/R). IF decreased the activation of NF-κB and MAPK signaling pathways, the expression of NLRP1 and NLRP3 inflammasome proteins, and both IL-1β and IL-18 in the ischemic brain tissue. These findings demonstrate that IF can attenuate the inflammatory response and tissue damage following ischemic stroke by a mechanism involving suppression of NLRP1 and NLRP3 inflammasome activity. Copyright © 2014 Elsevier Inc. All rights reserved.

METHAMPHETAMINE TOXICITY AND MESSENGERS OF DEATH

PubMed Central

Krasnova, Irina N.; Cadet, Jean Lud

2009-01-01

Methamphetamine (METH) is an illicit psychostimulant that is widely abused in the world. Several lines of evidence suggest that chronic METH abuse leads to neurodegenerative changes in the human brain. These include damage to dopamine and serotonin axons, loss of gray matter accompanied by hypertrophy of the white matter and microgliosis in different brain areas. In the present review, we summarize data on the animal models of METH neurotoxicity which include degeneration of monoaminergic terminals and neuronal apoptosis. In addition, we discuss molecular and cellular bases of METH-induced neuropathologies. The accumulated evidence indicates that multiple events, including oxidative stress, excitotoxicity, hyperthermia, neuroinflammatory responses, mitochondrial dysfunction, endoplasmic reticulum stress converge to mediate METH-induced terminal degeneration and neuronal apoptosis. When taken together, these findings suggest that pharmacological strategies geared towards the prevention and treatment of the deleterious effects of this drug will need to attack the various pathways that form the substrates of METH toxicity. PMID:19328213

Brain-Heart Interaction: Cardiac Complications After Stroke.

PubMed

Chen, Zhili; Venkat, Poornima; Seyfried, Don; Chopp, Michael; Yan, Tao; Chen, Jieli

2017-08-04

Neurocardiology is an emerging specialty that addresses the interaction between the brain and the heart, that is, the effects of cardiac injury on the brain and the effects of brain injury on the heart. This review article focuses on cardiac dysfunction in the setting of stroke such as ischemic stroke, brain hemorrhage, and subarachnoid hemorrhage. The majority of post-stroke deaths are attributed to neurological damage, and cardiovascular complications are the second leading cause of post-stroke mortality. Accumulating clinical and experimental evidence suggests a causal relationship between brain damage and heart dysfunction. Thus, it is important to determine whether cardiac dysfunction is triggered by stroke, is an unrelated complication, or is the underlying cause of stroke. Stroke-induced cardiac damage may lead to fatality or potentially lifelong cardiac problems (such as heart failure), or to mild and recoverable damage such as neurogenic stress cardiomyopathy and Takotsubo cardiomyopathy. The role of location and lateralization of brain lesions after stroke in brain-heart interaction; clinical biomarkers and manifestations of cardiac complications; and underlying mechanisms of brain-heart interaction after stroke, such as the hypothalamic-pituitary-adrenal axis; catecholamine surge; sympathetic and parasympathetic regulation; microvesicles; microRNAs; gut microbiome, immunoresponse, and systemic inflammation, are discussed. © 2017 American Heart Association, Inc.

Objective instrumental memory and performance tests for evaluation of patients with brain damage: a search for a behavioral diagnostic tool.

PubMed

Harness, B Z; Bental, E; Carmon, A

1976-03-01

Cognition and performance of patients with localized and diffuse brain damage was evaluated through the application of objective perceptual testing. A series of visual perceptual and verbal tests, memory tests, as well as reaction time tasks were administered to the patients by logic programming equipment. In order to avoid a bias due to communicative disorders, all responses were motor, and achievement was scored in terms of correct identification and latencies of response. Previously established norms based on a large sample of non-brain-damaged hospitalized patients served to standardize the performance of the brain-damaged patient since preliminary results showed that age and educational level constitute an important variable affecting performance of the control group. The achievement of brain-damaged patients, corrected for these factors, was impaired significantly in all tests with respect to both recognition and speed of performance. Lateralized effects of brain damage were not significantly demonstrated. However, when the performance was analyzed with respect to the locus of visual input, it was found that patients with right hemispheric lesions showed impairment mainly on perception of figurative material, and that this deficit was more apparent in the left visual field. Conversely, patients with left hemispheric lesions tended to show impairment on perception of visually presented verbal material when the input was delivered to the right visual field.

Protective effects of Curcuma longa against neurobehavioral and neurochemical damage caused by cerium chloride in mice.

PubMed

Kadri, Yamina; Nciri, Riadh; Brahmi, Noura; Saidi, Saber; Harrath, Abdel Halim; Alwasel, Saleh; Aldahmash, Waleed; El Feki, Abdelfatteh; Allagui, Mohamed Salah

2018-05-07

Cerium chloride (CeCl 3 ) is considered an environmental pollutant and a potent neurotoxic agent. Medicinal plants have many bioactive compounds that provide protection against damage caused by such pollutants. Curcuma longa is a bioactive compound-rich plant with very important antioxidant properties. To study the preventive and healing effects of Curcuma longa on cerium-damaged mouse brains, we intraperitoneally injected cerium chloride (CeCl 3 , 20 mg/kg BW) along with Curcuma longa extract, administrated by gavage (100 mg/kg BW), into mice for 60 days. We then examined mouse behavior, brain tissue damage, and brain oxidative stress parameters. Our results revealed a significant modification in the behavior of the CeCl 3 -treated mice. In addition, CeCl 3 induced a significant increment in lipid peroxidation, carbonyl protein (PCO), and advanced oxidation protein product levels, as well as a significant reduction in superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. Acetylcholinesterase (AChE) activity remarkably increased in the brain of CeCl 3 -treated mice. Histopathological observations confirmed these results. Curcuma longa attenuated CeCl 3 -induced oxidative stress and increased the activities of antioxidant enzymes. It also decreased AChE activity in the CeCl 3 -damaged mouse brain that was confirmed by histopathology. In conclusion, this study suggests that Curcuma longa has a neuroprotective effect against CeCl 3 -induced damage in the brain.

Role of brain cytochrome P450 mono-oxygenases in bilirubin oxidation-specific induction and activity.

PubMed

Gambaro, Sabrina E; Robert, Maria C; Tiribelli, Claudio; Gazzin, Silvia

2016-02-01

In the Crigler-Najjar type I syndrome, the genetic absence of efficient hepatic glucuronidation of unconjugated bilirubin (UCB) by the uridine 5'-diphospho-glucuronosyltransferase1A1 (UGT1A1) enzyme produces the rise of UCB level in blood. Its entry to central nervous system could generate toxicity and neurological damage, and even death. In the past years, a compensatory mechanism to liver glucuronidation has been indicated in the hepatic cytochromes P450 enzymes (Cyps) which are able to oxidize bilirubin. Cyps are expressed also in the central nervous system, the target of bilirubin toxicity, thus making them theoretically important to confer a protective activity toward bilirubin accumulation and neurotoxicity. We therefore investigated the functional induction (mRNA, EROD/MROD) and the ability to oxidize bilirubin of Cyp1A1, 1A2, and 2A3 in primary astrocytes cultures obtained from two rat brain region (cortex: Cx and cerebellum: Cll). We observed that Cyp1A1 was the Cyp isoform more easily induced by beta-naphtoflavone (βNF) in both Cx and Cll astrocytes, but oxidized bilirubin only after uncoupling by 3, 4,3',4'-tetrachlorobiphenyl (TCB). On the contrary, Cyp1A2 was the most active Cyp in bilirubin clearance without uncoupling, but its induction was confined only in Cx cells. Brain Cyp2A3 was not inducible. In conclusion, the exposure of astrocytes to βNF plus TCB significantly enhanced Cyp1A1 mediating bilirubin clearance, improving cell viability in both regions. These results may be a relevant groundwork for the manipulation of brain Cyps as a therapeutic approach in reducing bilirubin-induced neurological damage.

Integrity of normal-appearing white matter: Influence of age, visible lesion burden and hypertension in patients with small-vessel disease.

PubMed

Muñoz Maniega, Susana; Chappell, Francesca M; Valdés Hernández, Maria C; Armitage, Paul A; Makin, Stephen D; Heye, Anna K; Thrippleton, Michael J; Sakka, Eleni; Shuler, Kirsten; Dennis, Martin S; Wardlaw, Joanna M

2017-02-01

White matter hyperintensities accumulate with age and occur in patients with stroke, but their pathogenesis is poorly understood. We measured multiple magnetic resonance imaging biomarkers of tissue integrity in normal-appearing white matter and white matter hyperintensities in patients with mild stroke, to improve understanding of white matter hyperintensities origins. We classified white matter into white matter hyperintensities and normal-appearing white matter and measured fractional anisotropy, mean diffusivity, water content (T1-relaxation time) and blood-brain barrier leakage (signal enhancement slope from dynamic contrast-enhanced magnetic resonance imaging). We studied the effects of age, white matter hyperintensities burden (Fazekas score) and vascular risk factors on each biomarker, in normal-appearing white matter and white matter hyperintensities, and performed receiver-operator characteristic curve analysis. Amongst 204 patients (34.3-90.9 years), all biomarkers differed between normal-appearing white matter and white matter hyperintensities ( P < 0.001). In normal-appearing white matter and white matter hyperintensities, mean diffusivity and T1 increased with age ( P < 0.001), all biomarkers varied with white matter hyperintensities burden ( P < 0.001; P = 0.02 signal enhancement slope), but only signal enhancement slope increased with hypertension ( P = 0.028). Fractional anisotropy showed complex age-white matter hyperintensities-tissue interactions; enhancement slope showed white matter hyperintensities-tissue interactions. Mean diffusivity distinguished white matter hyperintensities from normal-appearing white matter best at all ages. Blood-brain barrier leakage increases with hypertension and white matter hyperintensities burden at all ages in normal-appearing white matter and white matter hyperintensities, whereas water mobility and content increase as tissue damage accrues, suggesting that blood-brain barrier leakage mediates small vessel disease-related brain damage.

Rewarding brain stimulation reverses the disruptive effect of amygdala damage on emotional learning.

PubMed

Kádár, Elisabet; Ramoneda, Marc; Aldavert-Vera, Laura; Huguet, Gemma; Morgado-Bernal, Ignacio; Segura-Torres, Pilar

2014-11-01

Intracranial self-stimulation (SS) in the lateral hypothalamus, a rewarding deep-brain stimulation, is able to improve acquisition and retention of implicit and explicit memory tasks in rats. SS treatment is also able to reverse cognitive deficits associated with aging or with experimental brain injuries and evaluated in a two-way active avoidance (2wAA) task. The main objective of the present study was to explore the potential of the SS treatment to reverse the complete learning and memory impairment caused by bilateral lesion in the lateral amygdala (LA). The effects of post-training SS, administered after each acquisition session, were evaluated on distributed 2wAA acquisition and 10-day retention in rats with electrolytic bilateral LA lesions. SS effect in acetylcholinestaresase (AchE) activity was evaluated by immunohistochemistry in LA-preserved and Central nuclei (Ce) of the amygdala of LA-damaged rats. Results showed that LA lesion over 40% completely impeded 2wAA acquisition and retention. Post-training SS in the LA-lesioned rats improved conditioning and retention compared with both the lesioned but non-SS treated and the non-lesioned control rats. SS treatment also seemed to induce a decrease in AchE activity in the LA-preserved area of the lesioned rats, but no effects were observed in the Ce. This empirical evidence supports the idea that self-administered rewarding stimulation is able to completely counteract the 2wAA acquisition and retention deficits induced by LA lesion. Cholinergic mechanisms in preserved LA and the contribution of other brain memory-related areas activated by SS could mediate the compensatory effect observed. Copyright © 2014 Elsevier B.V. All rights reserved.

Development of a systems-based in situ multiplex biomarker screening approach for the assessment of immunopathology and neural tissue plasticity in male rats after traumatic brain injury.

PubMed

Bogoslovsky, Tanya; Bernstock, Joshua D; Bull, Greg; Gouty, Shawn; Cox, Brian M; Hallenbeck, John M; Maric, Dragan

2018-04-01

Traumatic brain injuries (TBIs) pose a massive burden of disease and continue to be a leading cause of morbidity and mortality throughout the world. A major obstacle in developing effective treatments is the lack of comprehensive understanding of the underlying mechanisms that mediate tissue damage and recovery after TBI. As such, our work aims to highlight the development of a novel experimental platform capable of fully characterizing the underlying pathobiology that unfolds after TBI. This platform encompasses an empirically optimized multiplex immunohistochemistry staining and imaging system customized to screen for a myriad of biomarkers required to comprehensively evaluate the extent of neuroinflammation, neural tissue damage, and repair in response to TBI. Herein, we demonstrate that our multiplex biomarker screening platform is capable of evaluating changes in both the topographical location and functional states of resident and infiltrating cell types that play a role in neuropathology after controlled cortical impact injury to the brain in male Sprague-Dawley rats. Our results demonstrate that our multiplex biomarker screening platform lays the groundwork for the comprehensive characterization of changes that occur within the brain after TBI. Such work may ultimately lead to the understanding of the governing pathobiology of TBI, thereby fostering the development of novel therapeutic interventions tailored to produce optimal tissue protection, repair, and/or regeneration with minimal side effects, and may ultimately find utility in a wide variety of other neurological injuries, diseases, and disorders that share components of TBI pathobiology. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Comprehensive 3D Model of Shock Wave-Brain Interactions in Blast-Induced Traumatic Brain Injuries

DTIC Science & Technology

2009-10-01

waves can cause brain damage by other mechanisms including excess pressure (leading to contusions), excess strain (leading to subdural ... hematomas and/or diffuse axonal injuries), and, in particular, cavitation effects (leading to subcellular damage). This project aims at the development of a

Frequency and Type of Situational Awareness Errors Contributing to Death and Brain Damage: A Closed Claims Analysis.

PubMed

Schulz, Christian M; Burden, Amanda; Posner, Karen L; Mincer, Shawn L; Steadman, Randolph; Wagner, Klaus J; Domino, Karen B

2017-08-01

Situational awareness errors may play an important role in the genesis of patient harm. The authors examined closed anesthesia malpractice claims for death or brain damage to determine the frequency and type of situational awareness errors. Surgical and procedural anesthesia death and brain damage claims in the Anesthesia Closed Claims Project database were analyzed. Situational awareness error was defined as failure to perceive relevant clinical information, failure to comprehend the meaning of available information, or failure to project, anticipate, or plan. Patient and case characteristics, primary damaging events, and anesthesia payments in claims with situational awareness errors were compared to other death and brain damage claims from 2002 to 2013. Anesthesiologist situational awareness errors contributed to death or brain damage in 198 of 266 claims (74%). Respiratory system damaging events were more common in claims with situational awareness errors (56%) than other claims (21%, P < 0.001). The most common specific respiratory events in error claims were inadequate oxygenation or ventilation (24%), difficult intubation (11%), and aspiration (10%). Payments were made in 85% of situational awareness error claims compared to 46% in other claims (P = 0.001), with no significant difference in payment size. Among 198 claims with anesthesia situational awareness error, perception errors were most common (42%), whereas comprehension errors (29%) and projection errors (29%) were relatively less common. Situational awareness error definitions were operationalized for reliable application to real-world anesthesia cases. Situational awareness errors may have contributed to catastrophic outcomes in three quarters of recent anesthesia malpractice claims.Situational awareness errors resulting in death or brain damage remain prevalent causes of malpractice claims in the 21st century.

Impact of Single-Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) and Positron Emission Tomography/Computed Tomography (PET/CT) in the Diagnosis of Traumatic Brain Injury (TBI): Case Report.

PubMed

Molina-Vicenty, Irma L; Santiago-Sánchez, Michelaldemar; Vélez-Miró, Iván; Motta-Valencia, Keryl

2016-09-01

Traumatic brain injury (TBI) is defined as damage to the brain resulting from an external force. TBI, a global leading cause of death and disability, is associated with serious social, economic, and health problems. In cases of mild-to-moderate brain damage, conventional anatomical imaging modalities may or may not detect the cascade of metabolic changes that have occurred or are occurring at the intracellular level. Functional nuclear medicine imaging and neurophysiological parameters can be used to characterize brain damage, as the former provides direct visualization of brain function, even in the absence of overt behavioral manifestations or anatomical findings. We report the case of a 30-year-old Hispanic male veteran who, after 2 traumatic brain injury events, developed cognitive and neuropsychological problems with no clear etiology in the presence of negative computed tomography (CT) findings.

Analysis of brain and spinal cord lesions to occult brain damage in seropositive and seronegative neuromyelitis optica.

PubMed

Sun, Jie; Sun, Xianting; Zhang, Ningnannan; Wang, Qiuhui; Cai, Huanhuan; Qi, Yuan; Li, Ting; Qin, Wen; Yu, Chunshui

2017-09-01

According to aquaporin-4 antibody (AQP4-Ab), neuromyelitis optica (NMO) can be divided into seropositive and seronegative subgroups. The purpose of this study was to a) compare the distribution of spinal cord and brain magnetic resonance imaging (MRI) lesions between seropositive and seronegative NMO patients; b) explore occult brain damage in seropositive and seronegative NMO patients; and c) explore the contribution of visible lesions to occult grey and white matter damage in seropositive and seronegative NMO patients. Twenty-two AQP4-Ab seropositive and 14 seronegative NMO patients and 30 healthy controls were included in the study. Two neuroradiologists independently measured the brain lesion volume (BLV) and the length of spinal cord lesion (LSCL) and recorded the region of brain lesions. The normal-appearing grey matter volume (NAGM-GMV) and white matter fractional anisotropy (NAWM-FA) were calculated for each subject to evaluate occult brain damage. The seropositive patients displayed more extensive damage in the spinal cord than the seronegative patients, and the seronegative group had a higher proportion of patients with brainstem lesions (28.57%) than the seropositive group (4.55%, P=0.064). Both NMO subgroups exhibited reduced NAGM-GMV and NAWM-FA compared with the healthy controls. NAGM-GMV was negatively correlated with LSCL in the seropositive group (r s =-0.444, P=0.044) and with BLV in the seronegative group (r s =-0.768, P=0.002). NAWM-FA was also negatively correlated with BLV in the seropositive group (r s =-0.682, P<0.001). Our findings suggest that the occult brain damage in these two NMO subgroups may be due to different mechanisms, which need to be further clarified. Copyright © 2017 Elsevier B.V. All rights reserved.

The evaluation of oxidative DNA damage in children with brain damage using 8-hydroxydeoxyguanosine levels.

PubMed

Fukuda, Miho; Yamauchi, Hiroshi; Yamamoto, Hitoshi; Aminaka, Masahito; Murakami, Hiroshi; Kamiyama, Noriko; Miyamoto, Yusaku; Koitabashi, Yasushi

2008-02-01

Urinary and cerebrospinal fluid (CSF) levels of 8-hydroxydeoxyguanosine (8-OHdG) were examined to estimate the relevance of oxidative stress in children with brain damage. Urinary 8-OHdG levels were measured in 51 children with various forms of central nervous system (CNS) disorders (status epilepticus [SE], hypoxic-ischemic encephalopathy [HIE], CNS infections and chronic epilepsy) and these levels were compared with those in 51 healthy children. CSF 8-OHdG levels were measured in 25 children with brain damage and in 19 control subjects. In addition, urinary and CSF levels of 8-OHdG were compared between the children with brain damage and healthy children. Finally, the relationship between urinary and CSF levels of 8-OHdG was determined in 12 children that provided both urinary and CSF samples. Our results showed that urinary 8-OHdG levels in children with HIE and CNS infections were higher than those of controls (Steel test; p < 0.05 and p < 0.05, respectively) and that CSF 8-OHdG levels were higher in children with SE, HIE, and CNS infections than in control subjects (Steel test; p < 0.01, 0.05 and 0.05, respectively). In addition, a positive correlation between the levels of urinary and CSF 8-OHdG was noted in the 12 children that provided both CSF and urinary samples (Spearman's rank correlation; rho = 0.82, p < 0.01). Further, we observed changes in the urinary 8-OHdG in a patient with HHV-6 encephalopathy, and found that the changes correlated well with the patient's clinical condition. These results suggest that oxidative stress is strongly related to acute brain damage in children, and that 8-OHdG is a useful marker of brain damage. Therefore, repeated measurements of urinary 8-OHdG may be helpful in estimating the extent of brain damage.

Computational Modeling of Resting-State Activity Demonstrates Markers of Normalcy in Children with Prenatal or Perinatal Stroke

PubMed Central

Raja Beharelle, Anjali; Griffa, Alessandra; Hagmann, Patric; Solodkin, Ana; McIntosh, Anthony R.; Small, Steven L.; Deco, Gustavo

2015-01-01

Children who sustain a prenatal or perinatal brain injury in the form of a stroke develop remarkably normal cognitive functions in certain areas, with a particular strength in language skills. A dominant explanation for this is that brain regions from the contralesional hemisphere “take over” their functions, whereas the damaged areas and other ipsilesional regions play much less of a role. However, it is difficult to tease apart whether changes in neural activity after early brain injury are due to damage caused by the lesion or by processes related to postinjury reorganization. We sought to differentiate between these two causes by investigating the functional connectivity (FC) of brain areas during the resting state in human children with early brain injury using a computational model. We simulated a large-scale network consisting of realistic models of local brain areas coupled through anatomical connectivity information of healthy and injured participants. We then compared the resulting simulated FC values of healthy and injured participants with the empirical ones. We found that the empirical connectivity values, especially of the damaged areas, correlated better with simulated values of a healthy brain than those of an injured brain. This result indicates that the structural damage caused by an early brain injury is unlikely to have an adverse and sustained impact on the functional connections, albeit during the resting state, of damaged areas. Therefore, these areas could continue to play a role in the development of near-normal function in certain domains such as language in these children. PMID:26063923

Regulatory T cells ameliorate tissue plasminogen activator-induced brain haemorrhage after stroke.

PubMed

Mao, Leilei; Li, Peiying; Zhu, Wen; Cai, Wei; Liu, Zongjian; Wang, Yanling; Luo, Wenli; Stetler, Ruth A; Leak, Rehana K; Yu, Weifeng; Gao, Yanqin; Chen, Jun; Chen, Gang; Hu, Xiaoming

2017-07-01

Delayed thrombolytic treatment with recombinant tissue plasminogen activator (tPA) may exacerbate blood-brain barrier breakdown after ischaemic stroke and lead to lethal haemorrhagic transformation. The immune system is a dynamic modulator of stroke response, and excessive immune cell accumulation in the cerebral vasculature is associated with compromised integrity of the blood-brain barrier. We previously reported that regulatory T cells, which function to suppress excessive immune responses, ameliorated blood-brain barrier damage after cerebral ischaemia. This study assessed the impact of regulatory T cells in the context of tPA-induced brain haemorrhage and investigated the underlying mechanisms of action. The number of circulating regulatory T cells in stroke patients was dramatically reduced soon after stroke onset (84 acute ischaemic stroke patients with or without intravenous tPA treatment, compared to 115 age and gender-matched healthy controls). Although stroke patients without tPA treatment gradually repopulated the numbers of circulating regulatory T cells within the first 7 days after stroke, post-ischaemic tPA treatment led to sustained suppression of regulatory T cells in the blood. We then used the murine suture and embolic middle cerebral artery occlusion models of stroke to investigate the therapeutic potential of adoptive regulatory T cell transfer against tPA-induced haemorrhagic transformation. Delayed administration of tPA (10 mg/kg) resulted in haemorrhagic transformation in the ischaemic territory 1 day after ischaemia. When regulatory T cells (2 × 106/mouse) were intravenously administered immediately after delayed tPA treatment in ischaemic mice, haemorrhagic transformation was significantly decreased, and this was associated with improved sensorimotor functions. Blood-brain barrier disruption and tight junction damages were observed in the presence of delayed tPA after stroke, but were mitigated by regulatory T cell transfer. Mechanistic studies demonstrated that regulatory T cells completely abolished the tPA-induced elevation of MMP9 and CCL2 after stroke. Using MMP9 and CCL2 knockout mice, we discovered that both molecules partially contributed to the protective actions of regulatory T cells. In an in vitro endothelial cell-based model of the blood-brain barrier, we confirmed that regulatory T cells inhibited tPA-induced endothelial expression of CCL2 and preserved blood-brain barrier integrity after an ischaemic challenge. Lentivirus-mediated CCL2 knockdown in endothelial cells completely abolished the blood-brain barrier protective effect of regulatory T cells in vitro. Altogether, our studies suggest that regulatory T cell adoptive transfer may alleviate thrombolytic treatment-induced haemorrhage in stroke victims. Furthermore, regulatory T cell-afforded protection in the tPA-treated stroke model is mediated by two inhibitory mechanisms involving CCL2 and MMP9. Thus, regulatory T cell adoptive transfer may be useful as a cell-based therapy to improve the efficacy and safety of thrombolytic treatment for ischaemic stroke. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Zingiber officinale Mitigates Brain Damage and Improves Memory Impairment in Focal Cerebral Ischemic Rat

PubMed Central

Wattanathorn, Jintanaporn; Jittiwat, Jinatta; Tongun, Terdthai; Muchimapura, Supaporn; Ingkaninan, Kornkanok

2011-01-01

Cerebral ischemia is known to produce brain damage and related behavioral deficits including memory. Recently, accumulating lines of evidence showed that dietary enrichment with nutritional antioxidants could reduce brain damage and improve cognitive function. In this study, possible protective effect of Zingiber officinale, a medicinal plant reputed for neuroprotective effect against oxidative stress-related brain damage, on brain damage and memory deficit induced by focal cerebral ischemia was elucidated. Male adult Wistar rats were administrated an alcoholic extract of ginger rhizome orally 14 days before and 21 days after the permanent occlusion of right middle cerebral artery (MCAO). Cognitive function assessment was performed at 7, 14, and 21 days after MCAO using the Morris water maze test. The brain infarct volume and density of neurons in hippocampus were also determined. Furthermore, the level of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in cerebral cortex, striatum, and hippocampus was also quantified at the end of experiment. The results showed that cognitive function and neurons density in hippocampus of rats receiving ginger rhizome extract were improved while the brain infarct volume was decreased. The cognitive enhancing effect and neuroprotective effect occurred partly via the antioxidant activity of the extract. In conclusion, our study demonstrated the beneficial effect of ginger rhizome to protect against focal cerebral ischemia. PMID:21197427

Role of Signal Transducer and Activator of Transcription 3 in Neuronal Survival and Regeneration

PubMed Central

Dziennis, Suzan; Alkayed, Nabil J.

2009-01-01

Synopsis Signal Transducers and Activators of Transcription (STATs) comprise a family of transcription factors that mediate a wide variety of biological functions in the central and peripheral nervous systems. Injury to neural tissue induces STAT activation, and STATs are increasingly recognized for their role in neuronal survival. In this review, we discuss the role of STAT3 during neural development and following ischemic and traumatic injury in brain, spinal cord and peripheral nerves. We focus on STAT3 because of the expanding body of literature that investigates protective and regenerative effects of growth factors, hormones and cytokines that use STAT3 to mediate their effect, in part through transcriptional upregulation of neuroprotective and neurotrophic genes. Defining the endogenous molecular mechanisms that lead to neuroprotection by STAT3 after injury might identify novel therapeutic targets against acute neural tissue damage as well as chronic neurodegenerative disorders. PMID:19145989

A neurologist's reflections on boxing. V. Conclude remarks.

PubMed

Unterharnscheidt, F

1995-01-01

Clinical and morphological publications have shown convincingly, that participation in boxing leads to a severe permanent brain damage. The extent of the brain damage is correlated to the number of bouts fought, which correspondents in a certain way how many blows against his head a boxer received and to his weight class. The intensity of a boxing blow of a heavyweight is much more severe than those achieved by boxers of lighter weight classes. The permanent brain damage in a boxer, the amateur and the professional boxer, manifests itself in several clinical syndromes in which the pyramidal, the extrapyramidal and the cerebellar systems are involved. A traumatic Parkinsonism, in its complete or abortive form, develops as the result of the numerous boxing blows a boxer sustains in his boxing career. Especially lateral parts of the substantia nigra are affected and reveal at macroscopical and microscopical examination a severe loss of pigmented neurons. Melanin pigment is visible free in the tissue and/or is phagozytosed in macrophages and glial cells. The traumatic Parkinson syndrome, often only in an abortive form, is combined in a boxer with additional clinical and morphological findings due to traumatic lesions in other areas of the brain. It is not as pure as in a patient with a Parkinson syndrome sui generis. The permanent brain damage in a boxer is diffuse, involving all areas of the brain. Especially involved are the large neurons of different layers of the cerebral cortex, the neurons of the Ammons horn formation, the Purkinje cells of the cerebellum. In place of destroyed and lost neurons, proliferation of glial elements, especially astroglial cells, has occurred. The defects are first replaced by protoplasmatic astroglial elements, and later by fibrillary astroglia. The destroyed neurons are replaced by glial scar tissue, which cannot perform the functions of the lost neurons. It is a process which is called partial necrosis of brain tissue. There is no reparation or restitution of the destroyed neural tissue of the brain. What is destroyed remains so, a restitution ad integrum does not occur. As the result of the diffuse loss of neurons in the brain a cerebral atrophy exists. The septum pellucidum, which consists of two thin lamellae, and is small or very small in a normal brain, forms a Cavum septi pellucidi, which is considerably enlarged. The walls of this structure, especially in its dorsal parts are considerably thinned; they show fenestrations and are, in dorsal parts no longer detectable, so that a direct connection between the two lateral ventricles exists. The clinically and morphologically existing permanent brain damage is the result of the boxing activity. Diagnostically, processes of another origin, such as alcoholism, luetic processes, other forms of dementia, etc. can undoubtedly be excluded. A permanent brain damage develops in professional and amateur boxers. The objection, which are voiced by members of the different Amateur Boxing Association, that such permanent brain damage in amateur boxers today no longer exists, after stricter protective measurements were introduced, is not tenable. Individuals who represent today the opinion, that a permanent brain damage or punch drunkenness in boxers does not occur, are not familiar with the pertinent medical literature. The argument, the injury quotient in boxing is lower than in all other athletic activities is not sound, since the statistics show only the inconsequential injuries of boxers, as lesions of the skin of the face, injuries of the hand, fractures, etc. but not the much more important and severe permanent brain damage, which is not taken into consideration in these so-called statistics. Besides of the permanent brain damage of former boxers as the result of the repeated and numerous blows against their head, severe permanent damage of the eyes and the hearing organ exists.

Functional neuroimaging in multiple sclerosis with radiolabelled glia markers: preliminary comparative PET studies with [11C]vinpocetine and [11C]PK11195 in patients.

PubMed

Vas, Adám; Shchukin, Yevgeni; Karrenbauer, Virginija D; Cselényi, Zsolt; Kostulas, Kosta; Hillert, Jan; Savic, Ivanka; Takano, Akihiro; Halldin, Christer; Gulyás, Balázs

2008-01-15

With the purpose of demonstrating the use of positron emission tomography (PET) and radiolabelled glia markers to indicate regional cerebral damage, we measured with PET in four young multiplex sclerosis (MS) patients in two consecutive measurements the global and regional brain uptake as well as regional distribution and binding potential (BP) of [(11)C]vinpocetine and [(11)C]PK11195. Both ligands showed increased uptake and BP in the regions of local brain damage. However, regional BP values for [(11)C]vinpocetine were markedly higher than those for [(11)C]PK11195. This feature of the former radioligand may be related to its high brain uptake and marked affinity to the peripheral benzodiazepine receptor binding sites (PBBS), characteristic for glia cells. As local brain traumas entail reactive glia accumulation in and around the site of the damage, the present findings may indicate that [(11)C]vinpocetine marks the place or boundaries of local brain damage by binding to the PBBS present in glia cells, which, in turn, accumulate in the region of the damage. The present findings (i) confirm earlier observations with [(11)C]PK11195 as a potential glia marker in PET studies and (ii) support the working hypothesis that [(11)C]vinpocetine is a potentially useful PET marker of regional and global brain damage resulting in glia accumulation locally or globally in the human brain. The comparative analysis of the two ligands indicate that [(11)C]vinpocetine shows a number of characteristics favourable in comparison with [(11)C]PK11195.

EphA4 Activation of c-Abl Mediates Synaptic Loss and LTP Blockade Caused by Amyloid-β Oligomers

PubMed Central

M. Vargas, Lina; Leal, Nancy; Estrada, Lisbell D.; González, Adrian; Serrano, Felipe; Araya, Katherine; Gysling, Katia; Inestrosa, Nibaldo C.; Pasquale, Elena B.; Alvarez, Alejandra R.

2014-01-01

The early stages of Alzheimer's disease are characterised by impaired synaptic plasticity and synapse loss. Here, we show that amyloid-β oligomers (AβOs) activate the c-Abl kinase in dendritic spines of cultured hippocampal neurons and that c-Abl kinase activity is required for AβOs-induced synaptic loss. We also show that the EphA4 receptor tyrosine kinase is upstream of c-Abl activation by AβOs. EphA4 tyrosine phosphorylation (activation) is increased in cultured neurons and synaptoneurosomes exposed to AβOs, and in Alzheimer-transgenic mice brain. We do not detect c-Abl activation in EphA4-knockout neurons exposed to AβOs. More interestingly, we demonstrate EphA4/c-Abl activation is a key-signalling event that mediates the synaptic damage induced by AβOs. According to this results, the EphA4 antagonistic peptide KYL and c-Abl inhibitor STI prevented i) dendritic spine reduction, ii) the blocking of LTP induction and iii) neuronal apoptosis caused by AβOs. Moreover, EphA4-/- neurons or sh-EphA4-transfected neurons showed reduced synaptotoxicity by AβOs. Our results are consistent with EphA4 being a novel receptor that mediates synaptic damage induced by AβOs. EphA4/c-Abl signalling could be a relevant pathway involved in the early cognitive decline observed in Alzheimer's disease patients. PMID:24658113

Cerebellar Degeneration

MedlinePlus

... cause inflammation in the brain, including the cerebellum multiple sclerosis, in which damage to the insulating membrane (myelin) ... cause inflammation in the brain, including the cerebellum multiple sclerosis, in which damage to the insulating membrane (myelin) ...

The structural basis of moderate disability after traumatic brain damage

PubMed Central

Adams, J; Graham, D; Jennett, B

2001-01-01

The objective was to discover the nature of brain damage in survivors of head injury who are left with moderate disability. Macroscopic and microscopic examination was carried out on the brains of 20 persons who had died long after a head injury that had been treated in a neurosurgical unit. All had become independent but had various disabilities (moderate disability on the Glasgow outcome scale) Most deaths had been sudden, which had led to their referral from forensic pathologists. Post-traumatic epilepsy was a feature in 75%. An intracranial haematoma had been evacuated in 75%, and in 11 of the 15 with epilepsy. Diffuse axonal injury was found in six patients, five of the mildest type (grade 1) and one of grade 2. No patient had diffuse thalamic damage but one had a small focal ischaemic lesion in the thalamus. No patient had severe ischaemic brain damage, but three had moderate lesions which were bilateral in only one. No patient had severe cortical contusions. In conclusion, the dominant lesion was focal damage from an evacuated intracranial haematoma. Severe diffuse damage was not found, with diffuse axonal injury only mild and thalamic damage in only one patient.

 PMID:11561038

Prevention of experimental autoimmune encephalomyelitis by antibodies against α4βl integrin

NASA Astrophysics Data System (ADS)

Yednock, Ted A.; Cannon, Catherine; Fritz, Lawrence C.; Sanchez-Madrid, Francisco; Steinman, Lawrence; Karin, Nathan

1992-03-01

EXPERIMENTAL autoimmune encephalomyelitis (EAE) is an inflammatory condition of the central nervous system with similarities to multiple sclerosis1,2. In both diseases, circulating leukocytes penetrate the blood-brain barrier and damage myelin, resulting in impaired nerve conduction and paralysis3-5. We sought to identify the adhesion receptors that mediate the attachment of circulating leukocytes to inflamed brain endothelium in EAE, because this interaction is the first step in leukocyte entry into the central nervous system. Using an in vitro adhesion assay on tissue sections, we found that lymphocytes and monocytes bound selectively to inflamed EAE brain vessels. Binding was inhibited by antibodies against the integrin molecule α4βl, but not by antibodies against numerous other adhesion receptors. When tested in vivo, anti-α4 integrin effectively prevented the accumulation of leukocytes in the central nervous system and the development of EAE. Thus, therapies designed to interfere with α4βl integrin may be useful in treating inflammatory diseases of the central nervous system, such as multiple sclerosis.

The Emerging Role of Epigenetics in Stroke

PubMed Central

Qureshi, Irfan A.; Mehler, Mark F.

2013-01-01

The transplantation of exogenous stem cells and the activation of endogenous neural stem and progenitor cells (NSPCs) are promising treatments for stroke. These cells can modulate intrinsic responses to ischemic injury and may even integrate directly into damaged neural networks. However, the neuroprotective and neural regenerative effects that can be mediated by these cells are limited and may even be deleterious. Epigenetic reprogramming represents a novel strategy for enhancing the intrinsic potential of the brain to protect and repair itself by modulating pathologic neural gene expression and promoting the recapitulation of seminal neural developmental processes. In fact, recent evidence suggests that emerging epigenetic mechanisms are critical for orchestrating nearly every aspect of neural development and homeostasis, including brain patterning, neural stem cell maintenance, neurogenesis and gliogenesis, neural subtype specification, and synaptic and neural network connectivity and plasticity. In this review, we survey the therapeutic potential of exogenous stem cells and endogenous NSPCs and highlight innovative technological approaches for designing, developing, and delivering epigenetic therapies for targeted reprogramming of endogenous pools of NSPCs, neural cells at risk, and dysfunctional neural networks to rescue and restore neurologic function in the ischemic brain. PMID:21403016

Activity-Dependent NPAS4 Expression and the Regulation of Gene Programs Underlying Plasticity in the Central Nervous System

PubMed Central

2013-01-01

The capability of the brain to change functionally in response to sensory experience is most active during early stages of development but it decreases later in life when major alterations of neuronal network structures no longer take place in response to experience. This view has been recently challenged by experimental strategies based on the enhancement of environmental stimulation levels, genetic manipulations, and pharmacological treatments, which all have demonstrated that the adult brain retains a degree of plasticity that allows for a rewiring of neuronal circuitries over the entire life course. A hot spot in the field of neuronal plasticity centres on gene programs that underlie plastic phenomena in adulthood. Here, I discuss the role of the recently discovered neuronal-specific and activity-dependent transcription factor NPAS4 as a critical mediator of plasticity in the nervous system. A better understanding of how modifications in the connectivity of neuronal networks occur may shed light on the treatment of pathological conditions such as brain damage or disease in adult life, some of which were once considered untreatable. PMID:24024041

Disruption of neurogenesis by hypothalamic inflammation in obesity or aging.

PubMed

Purkayastha, Sudarshana; Cai, Dongsheng

2013-12-01

Adult neural stem cells contribute to neurogenesis and plasticity of the brain which is essential for central regulation of systemic homeostasis. Damage to these homeostatic components, depending on locations in the brain, poses threat to impaired neurogenesis, neurodegeneration, cognitive loss and energy imbalance. Recent research has identified brain metabolic inflammation via proinflammatory IκB kinase-β (IKKβ) and its downstream nuclear transcription factor NF-κB pathway as a non-classical linker of metabolic and neurodegenerative disorders. Chronic activation of the pathway results in impairment of energy balance and nutrient metabolism, impediment of neurogenesis, neural stem cell proliferation and differentiation, collectively converging on metabolic and cognitive decline. Hypothalamic IKKβ/NF-κB via inflammatory crosstalk between microglia and neurons has been discovered to direct systemic aging by inhibiting the production of gonadotropin-releasing hormone (GnRH) and inhibition of inflammation or GnRH therapy could revert aging related degenerative symptoms at least in part. This article reviews the crucial role of hypothalamic inflammation in affecting neural stem cells which mediates the neurodegenerative mechanisms of causing metabolic derangements as well as aging-associated disorders or diseases.

Right hemisphere damage: Communication processing in adults evaluated by the Brazilian Protocole MEC – Bateria MAC

PubMed Central

Fonseca, Rochele Paz; Fachel, Jandyra Maria Guimarães; Chaves, Márcia Lorena Fagundes; Liedtke, Francéia Veiga; Parente, Maria Alice de Mattos Pimenta

2007-01-01

Right-brain-damaged individuals may present discursive, pragmatic, lexical-semantic and/or prosodic disorders. Objective To verify the effect of right hemisphere damage on communication processing evaluated by the Brazilian version of the Protocole Montréal d’Évaluation de la Communication (Montreal Communication Evaluation Battery) – Bateria Montreal de Avaliação da Comunicação, Bateria MAC, in Portuguese. Methods A clinical group of 29 right-brain-damaged participants and a control group of 58 non-brain-damaged adults formed the sample. A questionnaire on sociocultural and health aspects, together with the Brazilian MAC Battery was administered. Results Significant differences between the clinical and control groups were observed in the following MAC Battery tasks: conversational discourse, unconstrained, semantic and orthographic verbal fluency, linguistic prosody repetition, emotional prosody comprehension, repetition and production. Moreover, the clinical group was less homogeneous than the control group. Conclusions A right-brain-damage effect was identified directly, on three communication processes: discursive, lexical-semantic and prosodic processes, and indirectly, on pragmatic process. PMID:29213400

Thalamic inflammation after brain trauma is associated with thalamo-cortical white matter damage.

PubMed

Scott, Gregory; Hellyer, Peter J; Ramlackhansingh, Anil F; Brooks, David J; Matthews, Paul M; Sharp, David J

2015-12-01

Traumatic brain injury can trigger chronic neuroinflammation, which may predispose to neurodegeneration. Animal models and human pathological studies demonstrate persistent inflammation in the thalamus associated with axonal injury, but this relationship has never been shown in vivo. Using [(11)C]-PK11195 positron emission tomography, a marker of microglial activation, we previously demonstrated thalamic inflammation up to 17 years after traumatic brain injury. Here, we use diffusion MRI to estimate axonal injury and show that thalamic inflammation is correlated with thalamo-cortical tract damage. These findings support a link between axonal damage and persistent inflammation after brain injury.

Laser treatments of deep-seated brain lesions

NASA Astrophysics Data System (ADS)

Ward, Helen A.

1997-06-01

The five year survival rate of deep-seated malignant brain tumors after surgery/radiotherapy is virtually 100 percent mortality. Special problems include: (1) Lesions often present late. (2) Position: lesion overlies vital structures, so complete surgical/radiotherapy lesion destruction can damage vital brain-stem functions. (3) Difficulty in differentiating normal brain form malignant lesions. This study aimed to use the unique properties of the laser: (a) to minimize damage during surgical removal of deep-seated brain lesions by operating via fine optic fibers; and (b) to employ the propensity of certain lasers for absorption of dyes and absorption and induction of fluorescence in some brain substances, to differentiate borders of malignant and normal brain, for more complete tumor removal. In the method a fine laser endoscopic technique was devised for removal of brain lesions. The results of this technique, were found to minimize and accurately predict the extent of thermal damage and shock waves to within 1-2mm of the surgical laser beam. Thereby it eliminated the 'popcorn' effect.

beta-Citryl-L-glutamate is an endogenous iron chelator that occurs naturally in the developing brain.

PubMed

Hamada-Kanazawa, Michiko; Kouda, Makiko; Odani, Akira; Matsuyama, Kaori; Kanazawa, Kiyoka; Hasegawa, Tatsuya; Narahara, Masanori; Miyake, Masaharu

2010-01-01

The compound beta-citryl-L-glutamate (beta-CG) was initially isolated from developing brains, while it has also been found in high concentrations in testes and eyes. However, its functional roles are unclear. To evaluate its coordination with metal ions, we performed pH titration experiments. The stability constant, logbeta(pqr) for M(p)(beta-CG)(q)H(r) was calculated from pH titration data, which showed that beta-CG forms relatively strong complexes with Fe(III), Cu(II), Fe(II) and Zn(II). beta-CG was also found able to solubilize Fe more effectively from Fe(OH)(2) than from Fe(OH)(3). Therefore, we examined the effects of beta-CG on Fe-dependent reactive oxygen species (ROS)-generating systems, as well as the potential ROS-scavenging activities of beta-CG and metal ion-(beta-CG) complexes. beta-CG inhibited the Fe-dependent degradation of deoxyribose and Fe-dependent damage to DNA or plasmid DNA in a dose-dependent manner, whereas it had no effect on Cu-mediated DNA damage. In addition, thermodynamic data showed that beta-CG in a physiological pH solution is an Fe(II) chelator rather than an Fe(III) chelator. Taken together, these findings suggest that beta-CG is an endogenous low molecular weight Fe chelator.

The continuum of spreading depolarizations in acute cortical lesion development: Examining Leão’s legacy

PubMed Central

Shuttleworth, C William; Kirov, Sergei A; Ayata, Cenk; Hinzman, Jason M; Foreman, Brandon; Andrew, R David; Boutelle, Martyn G; Brennan, KC; Carlson, Andrew P; Dahlem, Markus A; Drenckhahn, Christoph; Dohmen, Christian; Fabricius, Martin; Farkas, Eszter; Feuerstein, Delphine; Graf, Rudolf; Helbok, Raimund; Lauritzen, Martin; Major, Sebastian; Oliveira-Ferreira, Ana I; Richter, Frank; Rosenthal, Eric S; Sakowitz, Oliver W; Sánchez-Porras, Renán; Santos, Edgar; Schöll, Michael; Strong, Anthony J; Urbach, Anja; Westover, M Brandon; Winkler, Maren KL; Witte, Otto W; Woitzik, Johannes; Dreier, Jens P

2016-01-01

A modern understanding of how cerebral cortical lesions develop after acute brain injury is based on Aristides Leão’s historic discoveries of spreading depression and asphyxial/anoxic depolarization. Treated as separate entities for decades, we now appreciate that these events define a continuum of spreading mass depolarizations, a concept that is central to understanding their pathologic effects. Within minutes of acute severe ischemia, the onset of persistent depolarization triggers the breakdown of ion homeostasis and development of cytotoxic edema. These persistent changes are diagnosed as diffusion restriction in magnetic resonance imaging and define the ischemic core. In delayed lesion growth, transient spreading depolarizations arise spontaneously in the ischemic penumbra and induce further persistent depolarization and excitotoxic damage, progressively expanding the ischemic core. The causal role of these waves in lesion development has been proven by real-time monitoring of electrophysiology, blood flow, and cytotoxic edema. The spreading depolarization continuum further applies to other models of acute cortical lesions, suggesting that it is a universal principle of cortical lesion development. These pathophysiologic concepts establish a working hypothesis for translation to human disease, where complex patterns of depolarizations are observed in acute brain injury and appear to mediate and signal ongoing secondary damage. PMID:27328690

The flavonoid fisetin attenuates postischemic immune cell infiltration, activation and infarct size after transient cerebral middle artery occlusion in mice

PubMed Central

Gelderblom, Mathias; Leypoldt, Frank; Lewerenz, Jan; Birkenmayer, Gabriel; Orozco, Denise; Ludewig, Peter; Thundyil, John; Arumugam, Thiruma V; Gerloff, Christian; Tolosa, Eva; Maher, Pamela; Magnus, Tim

2012-01-01

The development of the brain tissue damage in ischemic stroke is composed of an immediate component followed by an inflammatory response with secondary tissue damage after reperfusion. Fisetin, a flavonoid, has multiple biological effects, including neuroprotective and antiinflammatory properties. We analyzed the effects of fisetin on infarct size and the inflammatory response in a mouse model of stroke, temporary middle cerebral artery occlusion, and on the activation of immune cells, murine primary and N9 microglial and Raw264.7 macrophage cells and human macrophages, in an in vitro model of inflammatory immune cell activation by lipopolysaccharide (LPS). Fisetin not only protected brain tissue against ischemic reperfusion injury when given before ischemia but also when applied 3 hours after ischemia. Fisetin also prominently inhibited the infiltration of macrophages and dendritic cells into the ischemic hemisphere and suppressed the intracerebral immune cell activation as measured by intracellular tumor necrosis factor α (TNFα) production. Fisetin also inhibited LPS-induced TNFα production and neurotoxicity of macrophages and microglia in vitro by suppressing nuclear factor κB activation and JNK/Jun phosphorylation. Our findings strongly suggest that the fisetin-mediated inhibition of the inflammatory response after stroke is part of the mechanism through which fisetin is neuroprotective in cerebral ischemia. PMID:22234339

It is the outcome that counts! Damage to the ventromedial prefrontal cortex disrupts the integration of outcome and belief information for moral judgment.

PubMed

Ciaramelli, Elisa; Braghittoni, Davide; di Pellegrino, Giuseppe

2012-11-01

Moral judgment involves considering not only the outcome of an action but also the intention with which it was pursued. Previous functional magnetic resonance imaging (fMRI) research has shown that integrating outcome and belief information for moral judgment relies on a brain network including temporo-parietal, precuneus, and medial prefrontal regions. Here, we investigated whether the ventromedial prefrontal cortex (vmPFC) plays a crucial role in this process. Patients with lesions in vmPFC (vmPFC patients), and brain-damaged and healthy controls considered scenarios in which the protagonist caused intentional harm (negative-outcome, negative-belief), accidental harm (negative-outcome, neutral-belief), attempted harm (neutral-outcome, negative-belief), or no harm (neutral-outcome, neutral-belief), and rated the moral permissibility of the protagonists' behavior. All groups responded similarly to scenarios involving intentional harm and no harm. vmPFC patients, however, judged attempted harm as more permissible, and accidental harm as less permissible, than the control groups. For vmPFC patients, outcome information, rather than belief information, shaped moral judgment. The results indicate that vmPFC is necessary for integrating outcome and belief information during moral reasoning. During moral judgment vmPFC may mediate intentions' understanding, and overriding of prepotent responses to salient outcomes.

Neurodegeneration and adaptation in response to low-dose photon irradiation

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

Limoli, Charles L.

2014-10-27

Neural stem and precursor cells (i.e. multipotent neural cells) are concentrated in the neurogenic regions of the brain (hippocampal dentate gyrus, subventricular zones), and considerable evidence suggests that these cells are important in mediating the stress response of the CNS after damage from ionizing radiation. The capability of these cells to proliferate, migrate and differentiate (i.e. to undergo neurogenesis) suggests they can participate in the repair and maintenance of CNS functions by replacing brain cells damaged or depleted due to irradiation. Importantly, we have shown that multipotent neural cells are markedly sensitive to irradiation and oxidative stress, insults that compromisemore » neurogenesis and hasten the onset and progression of degenerative processes that are likely to have an adverse impact on cognition. Our past and current work has demonstrated that relatively low doses of radiation cause a persistent (weeks-months) oxidative stress in multipotent neural cells that can elicit a range of degenerative sequelae in the CNS. Therefore, our project is focused on determining the extent that endogenous and redox sensitive multipotent neural cells represent important radioresponsive targets for low dose radiation effects. We hypothesize that the activation of redox sensitive signaling can trigger radioadaptive changes in these cells that can be either harmful or beneficial to overall cognitive health.« less

The Use of Computers and Video Games in Brain Damage Therapy.

ERIC Educational Resources Information Center

Lorimer, David

The use of computer assisted therapy (CAT) in the rehabilitation of individuals with brain damage is examined. Hardware considerations are explored, and the variety of software programs available for brain injury rehabilitation is discussed. Structured testing and treatment programs in time measurement, memory, and direction finding are described,…

Neurology of Affective Prosody and Its Functional-Anatomic Organization in Right Hemisphere

ERIC Educational Resources Information Center

Ross, Elliott D.; Monnot, Marilee

2008-01-01

Unlike the aphasic syndromes, the organization of affective prosody in brain has remained controversial because affective-prosodic deficits may occur after left or right brain damage. However, different patterns of deficits are observed following left and right brain damage that suggest affective prosody is a dominant and lateralized function of…

Childhood Aphasia and Brain Damage: Volume II, Differential Diagnosis.

ERIC Educational Resources Information Center

Rappaport, Sheldon R., Ed.

Addressing itself to factors leading to the misdiagnosis of the brain damaged child and the aphasic child, the Pathway School's Second Annual Institute considered the differences between the following: the aphasic and the aphasoid child; the sensory aphasic and the deaf child; the psychotic and the psychotic aphasic child; childhood brain damage…

Should Individuals Who Possess Only One Brain Be Allowed To Box?

ERIC Educational Resources Information Center

Brady, Don

This paper questions the acceptance of injuries obtained while participating in sport and in particular, the relationship between participation in boxing and brain injury/damage identified in boxers. A review of the literature indicates research findings support the tenet that brain damage found in boxers is cumulative and is directly related to…

Inferencing Processes after Right Hemisphere Brain Damage: Effects of Contextual Bias

ERIC Educational Resources Information Center

Blake, Margaret Lehman

2009-01-01

Purpose: Comprehension deficits associated with right hemisphere brain damage (RHD) have been attributed to an inability to use context, but there is little direct evidence to support the claim. This study evaluated the effect of varying contextual bias on predictive inferencing by adults with RHD. Method: Fourteen adults with no brain damage…

Age-dependent loss of cholinergic neurons in learning and memory-related brain regions and impaired learning in SAMP8 mice with trigeminal nerve damage.

PubMed

He, Yifan; Zhu, Jihong; Huang, Fang; Qin, Liu; Fan, Wenguo; He, Hongwen

2014-11-15

The tooth belongs to the trigeminal sensory pathway. Dental damage has been associated with impairments in the central nervous system that may be mediated by injury to the trigeminal nerve. In the present study, we investigated the effects of damage to the inferior alveolar nerve, an important peripheral nerve in the trigeminal sensory pathway, on learning and memory behaviors and structural changes in related brain regions, in a mouse model of Alzheimer's disease. Inferior alveolar nerve transection or sham surgery was performed in middle-aged (4-month-old) or elderly (7-month-old) senescence-accelerated mouse prone 8 (SAMP8) mice. When the middle-aged mice reached 8 months (middle-aged group 1) or 11 months (middle-aged group 2), and the elderly group reached 11 months, step-down passive avoidance and Y-maze tests of learning and memory were performed, and the cholinergic system was examined in the hippocampus (Nissl staining and acetylcholinesterase histochemistry) and basal forebrain (choline acetyltransferase immunohistochemistry). In the elderly group, animals that underwent nerve transection had fewer pyramidal neurons in the hippocampal CA1 and CA3 regions, fewer cholinergic fibers in the CA1 and dentate gyrus, and fewer cholinergic neurons in the medial septal nucleus and vertical limb of the diagonal band, compared with sham-operated animals, as well as showing impairments in learning and memory. Conversely, no significant differences in histology or behavior were observed between middle-aged group 1 or group 2 transected mice and age-matched sham-operated mice. The present findings suggest that trigeminal nerve damage in old age, but not middle age, can induce degeneration of the septal-hippocampal cholinergic system and loss of hippocampal pyramidal neurons, and ultimately impair learning ability. Our results highlight the importance of active treatment of trigeminal nerve damage in elderly patients and those with Alzheimer's disease, and indicate that tooth extraction should be avoided in these populations.

Moderate ethanol preconditioning of rat brain cultures engenders neuroprotection against dementia-inducing neuroinflammatory proteins: possible signaling mechanisms.

PubMed

Collins, Michael A; Neafsey, Edward J; Wang, Kewei; Achille, Nicholas J; Mitchell, Robert M; Sivaswamy, Sreevidya

2010-06-01

There is no question that chronic alcohol (ethanol) abuse, a leading worldwide problem, causes neuronal dysfunction and brain damage. However, various epidemiologic studies in recent years have indicated that in comparisons with abstainers or never-drinkers, light/moderate alcohol consumers have lower risks of age-dependent cognitive decline and/or dementia, including Alzheimer's disease (AD). Such reduced risks have been variously attributed to favorable circulatory and/or cerebrovascular effects of moderate ethanol intake, but they could also involve ethanol "preconditioning" phenomena in brain glia and neurons. Here we summarize our experimental studies showing that moderate ethanol preconditioning (MEP; 20-30 mM ethanol) of rat brain cultures prevents neurodegeneration due to beta-amyloid, an important protein implicated in AD, and to other neuroinflammatory proteins such as gp120, the human immunodeficiency virus 1 envelope protein linked to AIDS dementia. The MEP neuroprotection is associated with suppression of neurotoxic protein-evoked initial increases in [Ca(+2)](i) and proinflammatory mediators--e.g., superoxide anion, arachidonic acid, and glutamate. Applying a sensor --> transducer --> effector model to MEP, we find that onset of neuroprotection correlates temporally with elevations in "effector" heat shock proteins (HSP70, HSP27, and phospho-HSP27). The effector status of HSPs is supported by the fact that inhibiting HSP elevations due to MEP largely restores gp120-induced superoxide potentiation and subsequent neurotoxicity. As upstream mediators, synaptic N-methyl-d-aspartate receptors may be initial prosurvival sensors of ethanol, and protein kinase C epsilon and focal adhesion kinase are likely transducers during MEP that are essential for protective HSP elevations. Regarding human consumption, we speculate that moderate ethanol intake might counter incipient cognitive deterioration during advanced aging or AD by exerting preconditioning-like suppression of ongoing neuroinflammation related to amyloidogenic protein accumulation.

Phosphatidyl-Inositol-3 Kinase Inhibitors Regulate Peptidoglycan-Induced Myeloid Leukocyte Recruitment, Inflammation, and Neurotoxicity in Mouse Brain.

PubMed

Arroyo, Daniela S; Gaviglio, Emilia A; Peralta Ramos, Javier M; Bussi, Claudio; Avalos, Maria P; Cancela, Liliana M; Iribarren, Pablo

2018-01-01

Acute brain injury leads to the recruitment and activation of immune cells including resident microglia and infiltrating peripheral myeloid cells (MC), which contribute to the inflammatory response involved in neuronal damage. We previously reported that TLR2 stimulation by peptidoglycan (PGN) from Staphylococcus aureus, in vitro and in vivo , induced microglial cell activation followed by autophagy induction. In this report, we evaluated if phosphatidyl-inositol-3 kinase (PI3K) pharmacological inhibitors LY294200 and 3-methyladenine (3-MA) can modulate the innate immune response to PGN in the central nervous system. We found that injection of PGN into the mouse brain parenchyma (caudate putamen) triggered an inflammatory reaction, which involved activation of microglial cells, recruitment of infiltrating MC to injection site, production of pro-inflammatory mediators, and neuronal injury. In addition, we observed the accumulation of LC3B + CD45 + cells and colocalization of LC3B and lysosomal-associated membrane protein 1 in brain cells. Besides, we found that pharmacological inhibitors of PI3K, including the classical autophagy inhibitor 3-MA, reduced the recruitment of MC, microglial cell activation, and neurotoxicity induced by brain PGN injection. Collectively, our results suggest that PI3K pathways and autophagic response may participate in the PGN-induced microglial activation and MC recruitment to the brain. Thus, inhibition of these pathways could be therapeutically targeted to control acute brain inflammatory conditions.

Levetiracetam protects against kainic acid-induced toxicity.

PubMed

Marini, Herbert; Costa, Cinzia; Passaniti, Maria; Esposito, Maria; Campo, Giuseppe M; Ientile, Riccardo; Adamo, Elena Bianca; Marini, Rolando; Calabresi, Paolo; Altavilla, Domenica; Minutoli, Letteria; Pisani, Francesco; Squadrito, Francesco

2004-01-23

We investigated the Levetiracetam (LVT) ability to protect the brain against kainic acid (KA) induced neurotoxicity. Brain injury was induced by intraperitoneal administration of KA (10 mg/kg). Sham brain injury rats were used as controls. Animals were randomized to receive either LVT (50 mg/kg) or its vehicle (1 ml/kg) 30 min. before KA administration. Animals were sacrificed 6 hours after KA injection to measure brain malonildialdehyde (MDA), glutathione levels (GSH) and the mRNA for interleukin-1beta (IL-1beta) in the cortex and in the diencephalon. Behavioral changes were also monitored. Intraperitoneal administration of LVT decreased significantly MDA in the cortex (KA + vehicle = 0.25 +/- 0.03 nmol/mg protein; KA + LVT = 0.13 +/- 0.01 nmol/mg protein; P < 0.005), and in the diencephalons (KA + vehicle = 1,01 +/- 0.2 nmol/mg protein; KA + LVT = 0,33 +/- 0,08 nmol/mg protein; P < 0.005), prevented the brain loss of GSH in both cortex (KA + vehicle = 5 +/- 1 micromol/g protein; KA + LVT = 15 +/- 2 micromol/g protein; P < 0.005) and diencephalons (KA + vehicle = 9 +/- 0.8 micromol/g protein; KA + LVT = 13 +/- 0.3 micromol/g protein; P < 0.05), reduced brain IL-1beta mRNA and markedly controlled seizures. Histological analysis showed a reduction of cell damage in LVT treated samples. The present data indicate that LVT displays neuro-protective effects against KA induced brain toxicity and suggest that these effects are mediated, at least in part, by inhibition of lipid peroxidation.

Phosphatidyl-Inositol-3 Kinase Inhibitors Regulate Peptidoglycan-Induced Myeloid Leukocyte Recruitment, Inflammation, and Neurotoxicity in Mouse Brain

PubMed Central

Arroyo, Daniela S.; Gaviglio, Emilia A.; Peralta Ramos, Javier M.; Bussi, Claudio; Avalos, Maria P.; Cancela, Liliana M.; Iribarren, Pablo

2018-01-01

Acute brain injury leads to the recruitment and activation of immune cells including resident microglia and infiltrating peripheral myeloid cells (MC), which contribute to the inflammatory response involved in neuronal damage. We previously reported that TLR2 stimulation by peptidoglycan (PGN) from Staphylococcus aureus, in vitro and in vivo, induced microglial cell activation followed by autophagy induction. In this report, we evaluated if phosphatidyl-inositol-3 kinase (PI3K) pharmacological inhibitors LY294200 and 3-methyladenine (3-MA) can modulate the innate immune response to PGN in the central nervous system. We found that injection of PGN into the mouse brain parenchyma (caudate putamen) triggered an inflammatory reaction, which involved activation of microglial cells, recruitment of infiltrating MC to injection site, production of pro-inflammatory mediators, and neuronal injury. In addition, we observed the accumulation of LC3B+ CD45+ cells and colocalization of LC3B and lysosomal-associated membrane protein 1 in brain cells. Besides, we found that pharmacological inhibitors of PI3K, including the classical autophagy inhibitor 3-MA, reduced the recruitment of MC, microglial cell activation, and neurotoxicity induced by brain PGN injection. Collectively, our results suggest that PI3K pathways and autophagic response may participate in the PGN-induced microglial activation and MC recruitment to the brain. Thus, inhibition of these pathways could be therapeutically targeted to control acute brain inflammatory conditions. PMID:29719536

Brain MRI fiber-tracking reveals white matter alterations in hypertensive patients without damage at conventional neuroimaging.

PubMed

Carnevale, Lorenzo; D'Angelosante, Valentina; Landolfi, Alessandro; Grillea, Giovanni; Selvetella, Giulio; Storto, Marianna; Lembo, Giuseppe; Carnevale, Daniela

2018-06-12

Hypertension is one of the main risk factor for dementia. The subtle damage provoked by chronic high blood pressure in the brain is usually evidenced by conventional magnetic resonance imaging (MRI), in terms of white matter (WM) hyperintensities or cerebral atrophy. However, it is clear that by the time brain damage is visible, it may be too late hampering neurodegeneration. Aim of this study was to characterize a signature of early brain damage induced by hypertension, before the neurodegenerative injury manifests. This work was conducted on hypertensive and normotensive subjects with no sign of structural damage at conventional neuroimaging and no diagnosis of dementia revealed by neuropsychological assessment. All individuals underwent cardiological clinical examination in order to define the hypertensive status and the related target organ damage. Additionally, patients were subjected to DTI-MRI scan to identify microstructural damage of WM by probabilistic fiber-tracking. To gain insights in the neurocognitive profile of patients a specific battery of tests was administered. As primary outcome of the study we aimed at finding any specific signature of fiber-tracts alterations in hypertensive patients, associated with an impairment of the related cognitive functions. Hypertensive patients showed significant alterations in three specific WM fiber-tracts: the anterior thalamic radiation, the superior longitudinal fasciculus and the forceps minor. Hypertensive patients also scored significantly worse in the cognitive domains ascribable to brain regions connected through those WM fiber-tracts, showing decreased performances in executive functions, processing speed, memory, and paired associative learning tasks. Overall, WM fiber-tracking on MRI evidenced an early signature of damage in hypertensive patients when otherwise undetectable by conventional neuroimaging. In perspective, this approach could allow identifying those patients that are in initial stages of brain damage and could benefit of therapies aimed at limiting the transition to dementia and neurodegeneration.

Exposure to 900 MHz electromagnetic fields activates the mkp-1/ERK pathway and causes blood-brain barrier damage and cognitive impairment in rats.

PubMed

Tang, Jun; Zhang, Yuan; Yang, Liming; Chen, Qianwei; Tan, Liang; Zuo, Shilun; Feng, Hua; Chen, Zhi; Zhu, Gang

2015-03-19

With the rapid increase in the number of mobile phone users, the potential adverse effects of the electromagnetic field radiation emitted by a mobile phone has become a serious concern. This study demonstrated, for the first time, the blood-brain barrier and cognitive changes in rats exposed to 900 MHz electromagnetic field (EMF) and aims to elucidate the potential molecular pathway underlying these changes. A total of 108 male Sprague-Dawley rats were exposed to a 900 MHz, 1 mW/cm(2) EMF or sham (unexposed) for 14 or 28 days (3h per day). The specific energy absorption rate (SAR) varied between 0.016 (whole body) and 2 W/kg (locally in the head). In addition, the Morris water maze test was used to examine spatial memory performance determination. Morphological changes were investigated by examining ultrastructural changes in the hippocampus and cortex, and the Evans Blue assay was used to assess blood brain barrier (BBB) damage. Immunostaining was performed to identify heme oxygenase-1 (HO-1)-positive neurons and albumin extravasation detection. Western blot was used to determine HO-1 expression, phosphorylated ERK expression and the upstream mediator, mkp-1 expression. We found that the frequency of crossing platforms and the percentage of time spent in the target quadrant were lower in rats exposed to EMF for 28 days than in rats exposed to EMF for 14 days and unexposed rats. Moreover, 28 days of EMF exposure induced cellular edema and neuronal cell organelle degeneration in the rat. In addition, damaged BBB permeability, which resulted in albumin and HO-1 extravasation were observed in the hippocampus and cortex. Thus, for the first time, we found that EMF exposure for 28 days induced the expression of mkp-1, resulting in ERK dephosphorylation. Taken together, these results demonstrated that exposure to 900 MHz EMF radiation for 28 days can significantly impair spatial memory and damage BBB permeability in rat by activating the mkp-1/ERK pathway. Copyright © 2015 Elsevier B.V. All rights reserved.

Phosphorylated recombinant HSP27 protects the brain and attenuates blood-brain barrier disruption following stroke in mice receiving intravenous tissue-plasminogen activator.

PubMed

Shimada, Yoshiaki; Shimura, Hideki; Tanaka, Ryota; Yamashiro, Kazuo; Koike, Masato; Uchiyama, Yasuo; Urabe, Takao; Hattori, Nobutaka

2018-01-01

Loss of integrity of the blood-brain barrier (BBB) in ischemic stroke victims initiates a devastating cascade of events causing brain damage. Maintaining the BBB is important to preserve brain function in ischemic stroke. Unfortunately, recombinant tissue plasminogen activator (tPA), the only effective fibrinolytic treatment at the acute stage of ischemic stroke, also injures the BBB and increases the risk of brain edema and secondary hemorrhagic transformation. Thus, it is important to identify compounds that maintain BBB integrity in the face of ischemic injury in patients with stroke. We previously demonstrated that intravenously injected phosphorylated recombinant heat shock protein 27 (prHSP27) protects the brains of mice with transient middle cerebral artery occlusion (tMCAO), an animal stroke-model. Here, we determined whether prHSP27, in addition to attenuating brain injury, also decreases BBB damage in hyperglycemic tMCAO mice that had received tPA. After induction of hyperglycemia and tMCAO, we examined 4 treatment groups: 1) bovine serum albumin (BSA), 2) prHSP27, 3) tPA, 4) tPA plus prHSP27. We examined the effects of prHSP27 by comparing the BSA and prHSP27 groups and the tPA and tPA plus prHSP27 groups. Twenty-four hours after injection, prHSP27 reduced infarct volume, brain swelling, neurological deficits, the loss of microvessel proteins and endothelial cell walls, and mortality. It also reduced the rates of hemorrhagic transformation, extravasation of endogenous IgG, and MMP-9 activity, signs of BBB damage. Therefore, prHSP27 injection attenuated brain damage and preserved the BBB in tPA-injected, hyperglycemic tMCAO experimental stroke-model mice, in which the BBB is even more severely damaged than in simple tMCAO mice. The attenuation of brain damage and BBB disruption in the presence of tPA suggests the effectiveness of prHSP27 and tPA as a combination therapy. prHSP27 may be a novel therapeutic agent for ischemic stroke patients whose BBBs are injured following tPA injections.

Clostridium butyricum exerts a neuroprotective effect in a mouse model of traumatic brain injury via the gut-brain axis.

PubMed

Li, H; Sun, J; Du, J; Wang, F; Fang, R; Yu, C; Xiong, J; Chen, W; Lu, Z; Liu, J

2018-05-01

Traumatic brain injury (TBI) is a common occurrence following gastrointestinal dysfunction. Recently, more and more attentions are being focused on gut microbiota in brain and behavior. Glucagon-like peptide-1 (GLP-1) is considered as a mediator that links the gut-brain axis. The aim of this study was to explore the neuroprotective effects of Clostridium butyricum (Cb) on brain damage in a mouse model of TBI. Male C57BL/6 mice were subjected to a model of TBI-induced by weight-drop impact head injury and were treated intragastrically with Cb. The cognitive deficits, brain water content, neuronal death, and blood-brain barrier (BBB) permeability were evaluated. The expression of tight junction (TJ) proteins, Bcl-2, Bax, GLP-1 receptor (GLP-1R), and phosphorylation of Akt (p-Akt) in the brain were also measured. Moreover, the intestinal barrier permeability, the expression of TJ protein and GLP-1, and IL-6 level in the intestine were detected. Cb treatment significantly improved neurological dysfunction, brain edema, neurodegeneration, and BBB impairment. Meanwhile, Cb treatment also significantly increased the expression of TJ proteins (occludin and zonula occluden-1), p-Akt and Bcl-2, but decreased expression of Bax. Moreover, Cb treatment exhibited more prominent effects on decreasing the levels of plasma d-lactate and colonic IL-6, upregulating expression of Occludin, and protecting intestinal barrier integrity. Furthermore, Cb-treated mice showed increased the secretion of intestinal GLP-1 and upregulated expression of cerebral GLP-1R. Our findings demonstrated the neuroprotective effect of Cb in TBI mice and the involved mechanisms were partially attributed to the elevating GLP-1 secretion through the gut-brain axis. © 2017 John Wiley & Sons Ltd.

Long-term prehypertension treatment with losartan effectively prevents brain damage and stroke in stroke-prone spontaneously hypertensive rats.

PubMed

He, De-Hua; Zhang, Liang-Min; Lin, Li-Ming; Ning, Ruo-Bing; Wang, Hua-Jun; Xu, Chang-Sheng; Lin, Jin-Xiu

2014-02-01

Prehypertension has been associated with adverse cerebrovascular events and brain damage. The aims of this study were to investigate ⅰ) whether short‑ and long-term treatments with losartan or amlodipine for prehypertension were able to prevent blood pressure (BP)-linked brain damage, and ⅱ) whether there is a difference in the effectiveness of treatment with losartan and amlodipine in protecting BP-linked brain damage. In the present study, prehypertensive treatment with losartan and amlodipine (6 and 16 weeks treatment with each drug) was performed on 4-week‑old stroke-prone spontaneously hypertensive rats (SHRSP). The results showed that long-term (16 weeks) treatment with losartan is the most effective in lowering systolic blood pressure in the long term (up to 40 weeks follow-up). Additionally, compared with the amlodipine treatment groups, the short‑ and long-term losartan treatments protected SHRSP from stroke and improved their brains structurally and functionally more effectively, with the long-term treatment having more benefits. Mechanistically, the short‑ and long-term treatments with losartan reduced the activity of the local renin-angiotensin-aldosterone system (RAAS) in a time-dependent manner and more effectively than their respective counterpart amlodipine treatment group mainly by decreasing AT1R levels and increasing AT2R levels in the cerebral cortex. By contrast, the amlodipine treatment groups inhibited brain cell apoptosis more effectively as compared with the losartan treatment groups mainly through the suppression of local oxidative stress. Taken together, the results suggest that long-term losartan treatment for prehypertension effectively protects SHRSP from stroke-induced brain damage, and this protection is associated with reduced local RAAS activity than with brain cell apoptosis. Thus, the AT1R receptor blocker losartan is a good candidate drug that may be used in the clinic for long-term treatment on prehypertensive populations in order to prevent BP-linked brain damage.

Pregnancy Complications: Umbilical Cord Abnormalities

MedlinePlus

... before and during delivery, which may contribute to cerebral palsy and other forms of brain damage References Cruikshank, ... before and during delivery, which may contribute to cerebral palsy and other forms of brain damage References Cruikshank, ...

Severe blood-brain barrier disruption and surrounding tissue injury.

PubMed

Chen, Bo; Friedman, Beth; Cheng, Qun; Tsai, Phil; Schim, Erica; Kleinfeld, David; Lyden, Patrick D

2009-12-01

Blood-brain barrier opening during ischemia follows a biphasic time course, may be partially reversible, and allows plasma constituents to enter brain and possibly damage cells. In contrast, severe vascular disruption after ischemia is unlikely to be reversible and allows even further extravasation of potentially harmful plasma constituents. We sought to use simple fluorescent tracers to allow wide-scale visualization of severely damaged vessels and determine whether such vascular disruption colocalized with regions of severe parenchymal injury. Severe vascular disruption and ischemic injury was produced in adult Sprague Dawley rats by transient occlusion of the middle cerebral artery for 1, 2, 4, or 8 hours, followed by 30 minutes of reperfusion. Fluorescein isothiocyanate-dextran (2 MDa) was injected intravenously before occlusion. After perfusion-fixation, brain sections were processed for ultrastructure or fluorescence imaging. We identified early evidence of tissue damage with Fluoro-Jade staining of dying cells. With increasing ischemia duration, greater quantities of high molecular weight dextran-fluorescein isothiocyanate invaded and marked ischemic regions in a characteristic pattern, appearing first in the medial striatum, spreading to the lateral striatum, and finally involving cortex; maximal injury was seen in the mid-parietal areas, consistent with the known ischemic zone in this model. The regional distribution of the severe vascular disruption correlated with the distribution of 24-hour 2,3,5-triphenyltetrazolium chloride pallor (r=0.75; P<0.05) and the cell death marker Fluoro-Jade (r=0.86; P<0.05). Ultrastructural examination showed significantly increased areas of swollen astrocytic foot process and swollen mitochondria in regions of high compared to low leakage, and compared to contralateral homologous regions (ANOVA P<0.01). Dextran extravasation into the basement membrane and surrounding tissue increased significantly from 2 to 8 hours of occlusion duration (Independent samples t test, P<0.05). Severe vascular disruption, as labeled with high-molecular-weight dextran-fluorescein isothiocyanate leakage, is associated with severe tissue injury. This marker of severe vascular disruption may be useful in further studies of the pathoanatomic mechanisms of vascular disruption-mediated tissue injury.

Edaravone attenuates neuronal apoptosis in hypoxic-ischemic brain damage rat model via suppression of TRAIL signaling pathway.

PubMed

Li, Chunyi; Mo, Zhihuai; Lei, Junjie; Li, Huiqing; Fu, Ruying; Huang, Yanxia; Luo, Shijian; Zhang, Lei

2018-06-01

Edaravone is a new type of oxygen free radical scavenger and able to attenuate various brain damage including hypoxic-ischemic brain damage (HIBD). This study was aimed at investigating the neuroprotective mechanism of edaravone in rat hypoxic-ischemic brain damage model and its correlation with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling pathway. 75 seven-day-old Sprague-Dawley neonatal rats were equally divided into three groups: sham-operated group (sham), HIBD group and HIBD rats injected with edaravone (HIBD + EDA) group. Neurological severity and space cognitive ability of rats in each group were evaluated using Longa neurological severity score and Morris water maze testing. TUNEL assay and flow cytometry were used to determine brain cell apoptosis. Western blot was used to estimate the expression level of death receptor-5 (DR5), Fas-associated protein with death domain (FADD), caspase 8, B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax). In addition, immunofluorescence was performed to detect caspase 3. Edaravone reduced neurofunctional damage caused by HIBD and improved the cognitive capability of rats. The above experiment results suggested that edaravone could down-regulate the expression of active caspase 3 protein, thereby relieving neuronal apoptosis. Taken together, edaravone could attenuate neuronal apoptosis in rat hypoxic-ischemic brain damage model via suppression of TRAIL signaling pathway, which also suggested that edaravone might be an effective therapeutic strategy for HIBD clinical treatment. Copyright © 2018 Elsevier Ltd. All rights reserved.

Maternal obesity increases inflammation and exacerbates damage following neonatal hypoxic-ischaemic brain injury in rats.

PubMed

Teo, Jonathan D; Morris, Margaret J; Jones, Nicole M

2017-07-01

In humans, maternal obesity is associated with an increase in the incidence of birth related difficulties. However, the impact of maternal obesity on the severity of brain injury in offspring is not known. Recent studies have found evidence of increased glial response and inflammatory mediators in the brains as a result of obesity in humans and rodents. We hypothesised that hypoxic-ischaemic (HI) brain injury is greater in neonatal offspring from obese rat mothers compared to lean controls. Female Sprague Dawley rats were randomly allocated to high fat (HFD, n=8) or chow (n=4) diet and mated with lean male rats. On postnatal day 7 (P7), male and female pups were randomly assigned to HI injury or control (C) groups. HI injury was induced by occlusion of the right carotid artery followed by 3h exposure to 8% oxygen, at 37°C. Control pups were removed from the mother for the same duration under ambient conditions. Righting behaviour was measured on day 1 and 7 following HI. The extent of brain injury was quantified in brain sections from P14 pups using cresyl violet staining and the difference in volume between brain hemispheres was measured. Before mating, HFD mothers were 11% heavier than Chow mothers (p<0.05, t-test). Righting reflex was delayed in offspring from HFD-fed mothers compared to the Chow mothers. The Chow-HI pups showed a loss in ipsilateral brain tissue, while the HFD-HI group had significantly greater loss. No significant difference was detected in brain volume between the HFD-C and Chow-C pups. When analysed on a per litter basis, the size of the injury was significantly correlated with maternal weight. Similar observations were made with neuronal staining showing a greater loss of neurons in the brain of offspring from HFD-mothers following HI compared to Chow. Astrocytes appeared to more hypertrophic and a greater number of microglia were present in the injured hemisphere in offspring from mothers on HFD. HI caused an increase in the proportion of amoeboid microglia and exposure to maternal HFD exacerbated this response. In the contralateral hemisphere, offspring exposed to maternal HFD displayed a reduced proportion of ramified microglia. Our data clearly demonstrate that maternal obesity can exacerbate the severity of brain damage caused by HI in neonatal offspring. Given that previous studies have shown enhanced inflammatory responses in offspring of obese mothers, these factors including gliosis and microglial infiltration are likely to contribute to enhanced brain injury. Copyright © 2016 Elsevier Inc. All rights reserved.

Recent Advances in the Gastric Mucosal Protection Against Stress-induced Gastric Lesions. Importance of Renin-angiotensin Vasoactive Metabolites, Gaseous Mediators and Appetite Peptides.

PubMed

Brzozowski, Tomasz; Magierowska, Katarzyna; Magierowski, Marcin; Ptak-Belowska, Agata; Pajdo, Robert; Kwiecien, Slawomir; Olszanecki, Rafal; Korbut, Ryszard

2017-01-01

Stress is known to cause severe adverse effects in the human gastrointestinal tract including mucosal microbleedings and erosions or even gastric ulceration but the mechanism of these complications has not been fully elucidated. The pathogenesis of stress-induced gastric damage involves the fall in Gastric Blood Flow (GBF), an increase in gastric acid secretion and gastric motility, enhanced adrenergic and cholinergic nerve activity and the rise in gastric mucosal generation of reactive oxygen species. The gastric mucosal defense mechanisms against the deleterious effect of stress include the activation of the hypothalamic-pituitary-adrenal axis which has been linked with glucocorticoids release capable of counteracting of stress-induced gastric lesions. Here we summarize the novel gastroprotective mechanisms against stress damage exhibited by angiotensin-(1-7), the newly discovered metabolite of Renin-Angiotensin System (RAS), the gaseous mediators such as nitric oxide (NO), hydrogen sulfide (H2S) or Carbon Monoxide (CO), and the food intake controlling peptides ghrelin, nesfatin- 1 and apelin possibly acting via brain-gut axis. These bioactive molecules such as RAS vasoactive metabolite angiotensin-(1-7) and appetite peptides have been shown to afford gastroprotective effect against stressinduced gastric lesions mainly mediated by an increase in gastric microcirculation. Gaseous mediators protect the gastric mucosa against stress lesions by mechanism involving the activation of PG/COX and CO/HO-1 biosynthetic pathways, and their anti-inflammatory and anti-oxidizing properties. Thus, these new components add new mechanistic aspects to the common cooperation of NO/NO-synthase, PG/COX systems and vasoactive sensory neuropeptides including CGRP but their gastroprotective efficacy against experimental stress ulcerogenesis requires the confirmation in human clinical trials. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Auditory Temporal Processing Deficits in Chronic Stroke: A Comparison of Brain Damage Lateralization Effect.

PubMed

Jafari, Zahra; Esmaili, Mahdiye; Delbari, Ahmad; Mehrpour, Masoud; Mohajerani, Majid H

2016-06-01

There have been a few reports about the effects of chronic stroke on auditory temporal processing abilities and no reports regarding the effects of brain damage lateralization on these abilities. Our study was performed on 2 groups of chronic stroke patients to compare the effects of hemispheric lateralization of brain damage and of age on auditory temporal processing. Seventy persons with normal hearing, including 25 normal controls, 25 stroke patients with damage to the right brain, and 20 stroke patients with damage to the left brain, without aphasia and with an age range of 31-71 years were studied. A gap-in-noise (GIN) test and a duration pattern test (DPT) were conducted for each participant. Significant differences were found between the 3 groups for GIN threshold, overall GIN percent score, and DPT percent score in both ears (P ≤ .001). For all stroke patients, performance in both GIN and DPT was poorer in the ear contralateral to the damaged hemisphere, which was significant in DPT and in 2 measures of GIN (P ≤ .046). Advanced age had a negative relationship with temporal processing abilities for all 3 groups. In cases of confirmed left- or right-side stroke involving auditory cerebrum damage, poorer auditory temporal processing is associated with the ear contralateral to the damaged cerebral hemisphere. Replication of our results and the use of GIN and DPT tests for the early diagnosis of auditory processing deficits and for monitoring the effects of aural rehabilitation interventions are recommended. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Perceptual Asymmetry for Chimeric Stimuli in Children with Early Unilateral Brain Damage

ERIC Educational Resources Information Center

Bava, Sunita; Ballantyne, Angela O.; May, Susanne J.; Trauner, Doris A.

2005-01-01

The present study used a chimeric stimuli task to assess the magnitude of the left-hemispace bias in children with congenital unilateral brain damage (n=46) as compared to typically developing matched controls (n=46). As would be expected, controls exhibited a significant left-hemispace bias. In the presence of left hemisphere (LH) damage, the…

Computational modeling of resting-state activity demonstrates markers of normalcy in children with prenatal or perinatal stroke.

PubMed

Adhikari, Mohit H; Raja Beharelle, Anjali; Griffa, Alessandra; Hagmann, Patric; Solodkin, Ana; McIntosh, Anthony R; Small, Steven L; Deco, Gustavo

2015-06-10

Children who sustain a prenatal or perinatal brain injury in the form of a stroke develop remarkably normal cognitive functions in certain areas, with a particular strength in language skills. A dominant explanation for this is that brain regions from the contralesional hemisphere "take over" their functions, whereas the damaged areas and other ipsilesional regions play much less of a role. However, it is difficult to tease apart whether changes in neural activity after early brain injury are due to damage caused by the lesion or by processes related to postinjury reorganization. We sought to differentiate between these two causes by investigating the functional connectivity (FC) of brain areas during the resting state in human children with early brain injury using a computational model. We simulated a large-scale network consisting of realistic models of local brain areas coupled through anatomical connectivity information of healthy and injured participants. We then compared the resulting simulated FC values of healthy and injured participants with the empirical ones. We found that the empirical connectivity values, especially of the damaged areas, correlated better with simulated values of a healthy brain than those of an injured brain. This result indicates that the structural damage caused by an early brain injury is unlikely to have an adverse and sustained impact on the functional connections, albeit during the resting state, of damaged areas. Therefore, these areas could continue to play a role in the development of near-normal function in certain domains such as language in these children. Copyright © 2015 the authors 0270-6474/15/358914-11$15.00/0.

Examination of Physiological Function and Biochemical Disorders in a Rat Model of Prolonged Asphyxia-Induced Cardiac Arrest followed by Cardio Pulmonary Bypass Resuscitation

PubMed Central

Kim, Junhwan; Yin, Tai; Yin, Ming; Zhang, Wei; Shinozaki, Koichiro; Selak, Mary A.; Pappan, Kirk L.; Lampe, Joshua W.; Becker, Lance B.

2014-01-01

Background Cardiac arrest induces whole body ischemia, which causes damage to multiple organs particularly the heart and the brain. There is clinical and preclinical evidence that neurological injury is responsible for high mortality and morbidity of patients even after successful cardiopulmonary resuscitation. A better understanding of the metabolic alterations in the brain during ischemia will enable the development of better targeted resuscitation protocols that repair the ischemic damage and minimize the additional damage caused by reperfusion. Method A validated whole body model of rodent arrest followed by resuscitation was utilized; animals were randomized into three groups: control, 30 minute asphyxial arrest, or 30 minutes asphyxial arrest followed by 60 min cardiopulmonary bypass (CPB) resuscitation. Blood gases and hemodynamics were monitored during the procedures. An untargeted metabolic survey of heart and brain tissues following cardiac arrest and after CPB resuscitation was conducted to better define the alterations associated with each condition. Results After 30 min cardiac arrest and 60 min CPB, the rats exhibited no observable brain function and weakened heart function in a physiological assessment. Heart and brain tissues harvested following 30 min ischemia had significant changes in the concentration of metabolites in lipid and carbohydrate metabolism. In addition, the brain had increased lysophospholipid content. CPB resuscitation significantly normalized metabolite concentrations in the heart tissue, but not in the brain tissue. Conclusion The observation that metabolic alterations are seen primarily during cardiac arrest suggests that the events of ischemia are the major cause of neurological damage in our rat model of asphyxia-CPB resuscitation. Impaired glycolysis and increased lysophospholipids observed only in the brain suggest that altered energy metabolism and phospholipid degradation may be a central mechanism in unresuscitatable brain damage. PMID:25383962

Examination of physiological function and biochemical disorders in a rat model of prolonged asphyxia-induced cardiac arrest followed by cardio pulmonary bypass resuscitation.

PubMed

Kim, Junhwan; Yin, Tai; Yin, Ming; Zhang, Wei; Shinozaki, Koichiro; Selak, Mary A; Pappan, Kirk L; Lampe, Joshua W; Becker, Lance B

2014-01-01

Cardiac arrest induces whole body ischemia, which causes damage to multiple organs particularly the heart and the brain. There is clinical and preclinical evidence that neurological injury is responsible for high mortality and morbidity of patients even after successful cardiopulmonary resuscitation. A better understanding of the metabolic alterations in the brain during ischemia will enable the development of better targeted resuscitation protocols that repair the ischemic damage and minimize the additional damage caused by reperfusion. A validated whole body model of rodent arrest followed by resuscitation was utilized; animals were randomized into three groups: control, 30 minute asphyxial arrest, or 30 minutes asphyxial arrest followed by 60 min cardiopulmonary bypass (CPB) resuscitation. Blood gases and hemodynamics were monitored during the procedures. An untargeted metabolic survey of heart and brain tissues following cardiac arrest and after CPB resuscitation was conducted to better define the alterations associated with each condition. After 30 min cardiac arrest and 60 min CPB, the rats exhibited no observable brain function and weakened heart function in a physiological assessment. Heart and brain tissues harvested following 30 min ischemia had significant changes in the concentration of metabolites in lipid and carbohydrate metabolism. In addition, the brain had increased lysophospholipid content. CPB resuscitation significantly normalized metabolite concentrations in the heart tissue, but not in the brain tissue. The observation that metabolic alterations are seen primarily during cardiac arrest suggests that the events of ischemia are the major cause of neurological damage in our rat model of asphyxia-CPB resuscitation. Impaired glycolysis and increased lysophospholipids observed only in the brain suggest that altered energy metabolism and phospholipid degradation may be a central mechanism in unresuscitatable brain damage.

CB2 Receptor Agonists Protect Human Dopaminergic Neurons against Damage from HIV-1 gp120

PubMed Central

Hu, Shuxian; Sheng, Wen S.; Rock, R. Bryan

2013-01-01

Despite the therapeutic impact of anti-retroviral therapy, HIV-1-associated neurocognitive disorder (HAND) remains a serious threat to AIDS patients, and there currently remains no specific therapy for the neurological manifestations of HIV-1. Recent work suggests that the nigrostriatal dopaminergic area is a critical brain region for the neuronal dysfunction and death seen in HAND and that human dopaminergic neurons have a particular sensitivity to gp120-induced damage, manifested as reduced function (decreased dopamine uptake), morphological changes, and reduced viability. Synthetic cannabinoids inhibit HIV-1 expression in human microglia, suppress production of inflammatory mediators in human astrocytes, and there is substantial literature demonstrating the neuroprotective properties of cannabinoids in other neuropathogenic processes. Based on these data, experiments were designed to test the hypothesis that synthetic cannabinoids will protect dopaminergic neurons against the toxic effects of the HIV-1 protein gp120. Using a human mesencephalic neuronal/glial culture model, which contains dopaminergic neurons, microglia, and astrocytes, we were able to show that the CB1/CB2 agonist WIN55,212-2 blunts gp120-induced neuronal damage as measured by dopamine transporter function, apoptosis and lipid peroxidation; these actions were mediated principally by the CB2 receptor. Adding supplementary human microglia to our cultures enhances gp120-induced damage; WIN55,212-2 is able to alleviate this enhanced damage. Additionally, WIN55,212-2 inhibits gp120-induced superoxide production by purified human microglial cells, inhibits migration of human microglia towards supernatants generated from gp120-stimulated human mesencephalic neuronal/glial cultures and reduces chemokine and cytokine production from the human mesencephalic neuronal/glial cultures. These data suggest that synthetic cannabinoids are capable of protecting human dopaminergic neurons from gp120 in a variety of ways, acting principally through the CB2 receptors and microglia. PMID:24147028

The oxidative damage and disbalance of calcium homeostasis in brain of chicken induced by selenium deficiency.

PubMed

Xu, Shi-Wen; Yao, Hai-Dong; Zhang, Jian; Zhang, Zi-Wei; Wang, Jin-Tao; Zhang, Jiu-Li; Jiang, Zhi-Hui

2013-02-01

Dietary selenium (Se) deficiency can influence the function of the brain. Our objective was to investigate the effects of Se deficiency on oxidative damage and calcium (Ca) homeostasis in brain of chicken. In the present study, 1-day-old chickens were fed either a commercial diet (as control group) with 0.15 mg/kg Se or a Se-deficient diet (as L group) with 0.033 mg/kg Se for 75 days. Then, brain injury biomarkers were examined, including histological analysis, ultrastructure assay, and apoptosis assay. We also examined the effect of Se deficiency on the Se-containing antioxidative enzyme glutathione peroxidase (GSH-Px), the level of glutathione (GSH), and the Ca homeostasis in brain of chicken. The results showed that the levels of Se and GSH and activity of GSH-Px are seriously reduced by 33.8-96 % (P < 0.001), 24.51-27.84 % (P < 0.001), and 20.70-64.24 % (P < 0.01), respectively. In the present study, we also perform histological analysis and ultrastructure assay and find that Se deficiency caused disorganized histological structure, damage to the mitochondria, fusion of nuclear membrane and nucleus shrinkage, higher apoptosis rate (P < 0.001), and increase of Ca homeostasis (P < 0.05 or P < 0.01 or P < 0.001) in the brain of chicken. In conclusion, the results demonstrated that Se deficiency induced oxidative damage and disbalance of Ca homeostasis in the brain of chicken. Similar to mammals, chickens brain is also extremely susceptible to oxidative damage and selenium deficiency.

The p38 mitogen activated protein kinase regulates β-amyloid protein internalization through the α7 nicotinic acetylcholine receptor in mouse brain.

PubMed

Ma, Kai-Ge; Lv, Jia; Yang, Wei-Na; Chang, Ke-Wei; Hu, Xiao-Dan; Shi, Li-Li; Zhai, Wan-Ying; Zong, Hang-Fan; Qian, Yi-Hua

2018-03-01

Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders. Intracellular β-amyloid protein (Aβ) is an early event in AD. It induces the formation of amyloid plaques and neuron damage. The α7 nicotinic acetylcholine receptor (α7nAChR) has been suggested to play an important role in Aβ caused cognition. It has high affinity with Aβ and could mediate Aβ internalization in vitro. However, whether in mouse brain the p38 MAPK signaling pathway is involved in the regulation of the α7nAChR mediated Aβ internalization and their role in mitochondria remains little known. Therefore, in this study, we revealed that Aβ is internalized by cholinergic and GABAergic neurons. The internalized Aβ were found deposits in lysosomes/endosomes and mitochondria. Aβ could form Aβ-α7nAChR complex with α7nAChR, activates the p38 mitogen activated protein kinase (MAPK). And the increasing of α7nAChR could in return mediate Aβ internalization in the cortex and hippocampus. In addition, by using the α7nAChR agonist PNU282987, the p38 phosphorylation level decreases, rescues the biochemical changes which are tightly associated with Aβ-induced apoptosis, such as Bcl2/Bax level, cytochrome c (Cyt c) release. Collectively, the p38 MAPK signaling pathway could regulate the α7nAChR-mediated internalization of Aβ. The activation of α7nAChR or the inhibition of p38 MAPK signaling pathway may be a beneficial therapy to AD. Copyright © 2017 Elsevier Inc. All rights reserved.

Processing verbal morphology in patients with congenital left-hemispheric brain lesions.

PubMed

Knecht, Marion; Lidzba, Karen

2016-01-01

The goal of this study was to test whether children, teenagers and adults with congenital left-hemispheric brain lesions master the regularities of German verbal inflectional morphology. Thirteen patients and 35 controls without brain damage participated in three experiments. A grammaticality judgment task, a participle inflection task and a nonce-verb inflection task revealed significant differences between patients and controls. In addition, a main effect of verb type could be observed as patients and controls made more mistakes with irregular than with regular verbs. The findings indicate that the congenitally damaged brain not only has difficulties with complex syntactic structures during language development, as reported by earlier studies, but also has persistent deficits on the morphological level. These observations suggest that the plasticity of the developing brain cannot fully compensate for congenital brain damage which affects regions associated with language functions. Copyright © 2016 Elsevier Inc. All rights reserved.

[Disorders of emotional control in schizophrenia and unilateral brain damage].

PubMed

Kucharska-Pietura, K; Kopacz, G

2001-01-01

Although, emotions play a crucial role in schizophrenia, the changes in emotional dimension still remain controversial. The aim of our work was: 1) to compare the disorders of emotional control between the examined groups: S--non-chronic schizophrenic patients (n = 50), CS--chronic schizophrenic patients (n = 50), N--healthy controls (n = 50), R--right brain-damaged patients (n = 30), and L--left brain-damaged patients (n = 30), 2) to assess a level of impairment of emotional control, its relation to lateralised hemisphere damage and chronicity of schizophrenic process. All psychiatric subjects were diagnosed as paranoid schizophrenics according to DSM-IV criteria and were scored on the PANSS scale after four weeks of neuroleptic treatment. Brain-damaged patients were included if they experienced single-episode cerebrovascular accidents causing right or left hemisphere damage (confirmed in CT scan reports). The neurological patients were examined at least 3 weeks after the onset of cerebrovascular episode. Emotional control was assessed using Brzeziński Questionnaire of Emotional Control aimed at the evaluation of: 1) control in perception and interpretation of emotive situation, 2) emotional arousal, 3) emotional-rational motivation, and 4) acting caused by emotions. Our results revealed significantly greater impairment of emotional control in schizophrenics (chronic schizophrenics, in particular) compared to healthy volunteers. Chronicity of the schizophrenic process seemed to intensify emotional control impairment. Interestingly, no significant qualitative and quantitative differences in emotional control mechanism between unilateral brain-damaged patients and the control group were found.

Costunolide inhibits proinflammatory cytokines and iNOS in activated murine BV2 microglia.

PubMed

Rayan, Nirmala Arul; Baby, Nimmi; Pitchai, Daisy; Indraswari, Fransisca; Ling, Eng-Ang; Lu, Jia; Dheen, Thameem

2011-06-01

Costunolide, a sesquiterpene lactone present in Costus speciosus root exerts a variety of pharmacological activity but its effects on neuroinflammation have not been studied. Microglia, the resident phagocytic cells in the central nervous system respond to neuroinflammation and their overwhelming response in turn aggravate brain damage during infection, ischemia and neurodegenerative diseases. In this study, we report the effect of Costunolide on the production of proinflammatory mediators and mechanisms involved in BV2 microglial cells stimulated with LPS. Costunolide attenuated the expression of tumour necrosis factor-alpha, interleukin-1,6, inducible nitric oxide synthase, monocyte chemotactic protein 1 and cyclooxygenase 2 in activated microglia. This Costunolide-mediated inhibition was correspondent with the inhibition of NFkappaB activation. It has been further shown that Costunolide suppressed MAPK pathway activation by inducing MKP-1 production. Collectively our results suggest that Costunolide shows an ability to inhibit expression of multiple neuroinflammatory mediators and this is attributable to the compounds inhibition of NFkappaB and MAPK activation. This novel role of Costunolide upon investigation may aid in developing better therapeutic strategies for treatment of neuroinflammatory diseases.

IL-13Rα1 expression in dopaminergic neurons contributes to their oxidative stress-mediated loss following chronic peripheral treatment with LPS

PubMed Central

Morrison, Brad E.; Marcondes, Maria Cecilia Garibaldi; Nomura, Daniel K.; Sanchez-Alavez, Manuel; Sanchez-Gonzalez, Alejandro; Saar, Indrek; Kim, Kwang-Soo; Bartfai, Tamas; Maher, Pamela; Sugama, Shuei; Conti, Bruno

2012-01-01

Inflammation and its mediators, including cytokines and reactive oxigen species, are believed to contribute to neurodegeneration. In the mouse brain, we found that the interleukin 13 receptor alpha 1 chain (IL-13Rα1) was expressed in the dopaminergic (DA) neurons of the substantia nigra pars compacta which are preferentially lost in human Parkinson’s disease (PD). Mice deficient for Il13ra1 exhibited resistance to loss of DA neurons in a model of chronic peripheral inflammation using bacterial lipopolysaccharide. Interleukin-13, as well as interleukin-4, potentiated the cytotoxic effects of t-butyl hydroperoxide and hydrogen peroxide on mouse dopaminergic MN9D cells. Collectively, our data indicate that expression of IL-13Rα1 on DA neurons can increase their susceptibility to oxidative stress-mediated damage thereby contributing to their preferential loss. In humans, Il13ra1 lies on the X chromosome within the PARK12 locus of susceptibility to PD suggesting that IL-13Rα1 may have a role in the pathogenesis of this neurodegenerative disease. PMID:23169588

Fluoxetine and WAY 100,635 dissociate increases in scototaxis and analgesia induced by conspecific alarm substance in zebrafish (Danio rerio Hamilton 1822).

PubMed

Maximino, Caio; Lima, Monica Gomes; Costa, Carina Cardoso; Guedes, Iêda Maria Louzada; Herculano, Anderson Manoel

2014-09-01

Alarm reactions to a substance secreted by the damaged skin of conspecifics and closely-related species are increasingly being recognized as fear-like responses in fish. The neurochemical underpinnings of these effects are so far unknown; however, given the role of the serotonergic system on defensive behavior, it is possible that the alarm reaction is mediated by this monoamine. Exposure to conspecific alarm substance (CAS) increased anxiety-like behavior in the light/dark test in zebrafish and decreased nocifensive behavior. These effects were accompanied by increases in blood glucose, hemoglobin, epinephrine and norepinephrine levels, as well as extracellular levels of serotonin in the brain. Pretreatment with fluoxetine blocked the anxiogenic effects of CAS on the light/dark test as well as all physiological parameters and the increase in extracellular brain 5-HT, but not the reduction in nocifensive behavior. Conversely, pretreatment with the 5-HT1AR antagonist WAY 100635 blocked the effects on nocifensive behavior, but not the effects on anxiety-like behavior nor on physiological parameters. These results point to an important and complex role of the serotonergic system in the mediation of fear-potentiated behavior in the light/dark test and in fear-induced analgesia in zebrafish. Copyright © 2014 Elsevier Inc. All rights reserved.

Nerve cell damage in mammalian brain after exposure to microwaves from GSM mobile phones.

PubMed

Salford, Leif G; Brun, Arne E; Eberhardt, Jacob L; Malmgren, Lars; Persson, Bertil R R

2003-06-01

The possible risks of radio-frequency electromagnetic fields for the human body is a growing concern for our society. We have previously shown that weak pulsed microwaves give rise to a significant leakage of albumin through the blood-brain barrier. In this study we investigated whether a pathologic leakage across the blood-brain barrier might be combined with damage to the neurons. Three groups each of eight rats were exposed for 2 hr to Global System for Mobile Communications (GSM) mobile phone electromagnetic fields of different strengths. We found highly significant (p< 0.002) evidence for neuronal damage in the cortex, hippocampus, and basal ganglia in the brains of exposed rats.

Widespread and highly persistent gene transfer to the CNS by retrovirus vector in utero: implication for gene therapy to Krabbe disease.

PubMed

Shen, Jin-Song; Meng, Xing-Li; Yokoo, Takashi; Sakurai, Ken; Watabe, Kazuhiko; Ohashi, Toya; Eto, Yoshikatsu

2005-05-01

Brain-directed prenatal gene therapy may benefit some lysosomal storage diseases that affect the central nervous system (CNS) before birth. Our previous study showed that intrauterine introduction of recombinant adenoviruses into cerebral ventricles results in efficient gene transfer to the CNS in the mouse. However, transgene expression decreased with time due to the non-integrative property of adenoviral vectors. In this study, in order to obtain permanent gene transduction, we investigated the feasibility of retrovirus-mediated in utero gene transduction. Concentrated retrovirus encoding the LacZ gene was injected into the cerebral ventricles of the embryos of normal and twitcher mice (a murine model of Krabbe disease) at embryonic day 12. The distribution and maintenance of the transgene expression in the recipient brain were analyzed histochemically, biochemically and by the quantitative polymerase chain reaction method pre- and postnatally. Efficient and highly persistent gene transduction to the brain was achieved both in normal and the twitcher mouse. Transduced neurons, astrocytes and oligodendrocytes were distributed throughout the brain. The transduced LacZ gene, its transcript and protein expression in the brain were maintained for 14 months without decrement. In addition, gene transduction to multiple tissues other than the brain was also detected at low levels. This study suggests that brain-directed in utero gene transfer using retrovirus vector may be beneficial to the treatment of lysosomal storage diseases with severe brain damage early in life, such as Krabbe disease. Copyright (c) 2005 John Wiley & Sons, Ltd.

Modeling the impact of COPD on the brain.

PubMed

Borson, Soo; Scanlan, James; Friedman, Seth; Zuhr, Elizabeth; Fields, Julie; Aylward, Elizabeth; Mahurin, Rodney; Richards, Todd; Anzai, Yoshimi; Yukawa, Michi; Yeh, Shingshing

2008-01-01

Previous studies have shown that COPD adversely affects distant organs and body systems, including the brain. This pilot study aims to model the relationships between respiratory insufficiency and domains related to brain function, including low mood, subtly impaired cognition, systemic inflammation, and brain structural and neurochemical abnormalities. Nine healthy controls were compared with 18 age- and education-matched medically stable-COPD patients, half of whom were oxygen-dependent. Measures included depression, anxiety, cognition, health status, spirometry, oximetry at rest and during 6-minute walk, and resting plasma cytokines and soluble receptors, brain MRI, and MR spectroscopy in regions relevant to mood and cognition. ANOVA was used to compare controls with patients and with COPD subgroups (oxygen users [n = 9] and nonusers [n = 9]), and only variables showing group differences at p < or = 0.05 were included in multiple regressions controlling for age, gender, and education to develop the final model. Controls and COPD patients differed significantly in global cognition and memory, mood, and soluble TNFR1 levels but not brain structural or neurochemical measures. Multiple regressions identified pathways linking disease severity with impaired performance on sensitive cognitive processing measures, mediated through oxygen dependence, and with systemic inflammation (TNFR1), related through poor 6-minute walk performance. Oxygen desaturation with activity was related to indicators of brain tissue damage (increased frontal choline, which in turn was associated with subcortical white matter attenuation). This empirically derived model provides a conceptual framework for future studies of clinical interventions to protect the brain in patients with COPD, such as earlier oxygen supplementation for patients with desaturation during everyday activities.

Modeling the impact of COPD on the brain

PubMed Central

Borson, Soo; Scanlan, James; Friedman, Seth; Zuhr, Elizabeth; Fields, Julie; Aylward, Elizabeth; Mahurin, Rodney; Richards, Todd; Anzai, Yoshimi; Yukawa, Michi; Yeh, Shingshing

2008-01-01

Previous studies have shown that COPD adversely affects distant organs and body systems, including the brain. This pilot study aims to model the relationships between respiratory insufficiency and domains related to brain function, including low mood, subtly impaired cognition, systemic inflammation, and brain structural and neurochemical abnormalities. Nine healthy controls were compared with 18 age- and education-matched medically stable COPD patients, half of whom were oxygen-dependent. Measures included depression, anxiety, cognition, health status, spirometry, oximetry at rest and during 6-minute walk, and resting plasma cytokines and soluble receptors, brain MRI, and MR spectroscopy in regions relevant to mood and cognition. ANOVA was used to compare controls with patients and with COPD subgroups (oxygen users [n = 9] and nonusers [n = 9]), and only variables showing group differences at p ≤ 0.05 were included in multiple regressions controlling for age, gender, and education to develop the final model. Controls and COPD patients differed significantly in global cognition and memory, mood, and soluble TNFR1 levels but not brain structural or neurochemical measures. Multiple regressions identified pathways linking disease severity with impaired performance on sensitive cognitive processing measures, mediated through oxygen dependence, and with systemic inflammation (TNFR1), related through poor 6-minute walk performance. Oxygen desaturation with activity was related to indicators of brain tissue damage (increased frontal choline, which in turn was associated with subcortical white matter attenuation). This empirically derived model provides a conceptual framework for future studies of clinical interventions to protect the brain in patients with COPD, such as earlier oxygen supplementation for patients with desaturation during everyday activities. PMID:18990971

The characterization of neural tissue ablation rate and corresponding heat affected zone of a 2 micron Tm3+ doped fiber laser(Conference Presentation)

NASA Astrophysics Data System (ADS)

Marques, Andrew J.; Jivraj, Jamil; Reyes, Robnier; Ramjist, Joel; Gu, Xijia J.; Yang, Victor X. D.

2017-02-01

Tissue removal using electrocautery is standard practice in neurosurgery since tissue can be cut and cauterized simultaneously. Thermally mediated tissue ablation using lasers can potentially possess the same benefits but with increased precision. However, given the critical nature of the spine, brain, and nerves, the effects of direct photo-thermal interaction on neural tissue needs to be known, yielding not only high precision of tissue removal but also increased control of peripheral heat damage. The proposed use of lasers as a neurosurgical tool requires that a common ground is found between ablation rates and resulting peripheral heat damage. Most surgical laser systems rely on the conversion of light energy into heat resulting in both desirable and undesirable thermal damage to the targeted tissue. Classifying the distribution of thermal energy in neural tissue, and thus characterizing the extent of undesirable thermal damage, can prove to be exceptionally challenging considering its highly inhomogenous composition when compared to other tissues such as muscle and bone. Here we present the characterization of neural tissue ablation rate and heat affected zone of a 1.94 micron thulium doped fiber laser for neural tissue ablation. In-Vivo ablation of porcine cerebral cortex is performed. Ablation volumes are studied in association with laser parameters. Histological samples are taken and examined to characterize the extent of peripheral heat damage.

Retinal Ganglion Cell Damage in an Experimental Rodent Model of Blast-Mediated Traumatic Brain Injury

PubMed Central

Mohan, Kabhilan; Kecova, Helga; Hernandez-Merino, Elena; Kardon, Randy H.; Harper, Matthew M.

2013-01-01

Purpose. To evaluate retina and optic nerve damage following experimental blast injury. Methods. Healthy adult mice were exposed to an overpressure blast wave using a custom-built blast chamber. The effects of blast exposure on retina and optic nerve function and structure were evaluated using the pattern electroretinogram (pERG), spectral domain optical coherence tomography (OCT), and the chromatic pupil light reflex. Results. Assessment of the pupil response to light demonstrated decreased maximum pupil constriction diameter in blast-injured mice using red light or blue light stimuli 24 hours after injury compared with baseline in the eye exposed to direct blast injury. A decrease in the pupil light reflex was not observed chronically following blast exposure. We observed a biphasic pERG decrease with the acute injury recovering by 24 hours postblast and the chronic injury appearing at 4 months postblast injury. Furthermore, at 3 months following injury, a significant decrease in the retinal nerve fiber layer was observed using OCT compared with controls. Histologic analysis of the retina and optic nerve revealed punctate regions of reduced cellularity in the ganglion cell layer and damage to optic nerves. Additionally, a significant upregulation of proteins associated with oxidative stress was observed acutely following blast exposure compared with control mice. Conclusions. Our study demonstrates that decrements in retinal ganglion cell responses can be detected after blast injury using noninvasive functional and structural tests. These objective responses may serve as surrogate tests for higher CNS functions following traumatic brain injury that are difficult to quantify. PMID:23620426

The tissue-type plasminogen activator–plasminogen activator inhibitor 1 complex promotes neurovascular injury in brain trauma: evidence from mice and humans

PubMed Central

Sashindranath, Maithili; Sales, Eunice; Daglas, Maria; Freeman, Roxann; Samson, Andre L.; Cops, Elisa J.; Beckham, Simone; Galle, Adam; McLean, Catriona; Morganti-Kossmann, Cristina; Rosenfeld, Jeffrey V.; Madani, Rime; Vassalli, Jean-Dominique; Su, Enming J.; Lawrence, Daniel A.

2012-01-01

The neurovascular unit provides a dynamic interface between the circulation and central nervous system. Disruption of neurovascular integrity occurs in numerous brain pathologies including neurotrauma and ischaemic stroke. Tissue plasminogen activator is a serine protease that converts plasminogen to plasmin, a protease that dissolves blood clots. Besides its role in fibrinolysis, tissue plasminogen activator is abundantly expressed in the brain where it mediates extracellular proteolysis. However, proteolytically active tissue plasminogen activator also promotes neurovascular disruption after ischaemic stroke; the molecular mechanisms of this process are still unclear. Tissue plasminogen activator is naturally inhibited by serine protease inhibitors (serpins): plasminogen activator inhibitor-1, neuroserpin or protease nexin-1 that results in the formation of serpin:protease complexes. Proteases and serpin:protease complexes are cleared through high-affinity binding to low-density lipoprotein receptors, but their binding to these receptors can also transmit extracellular signals across the plasma membrane. The matrix metalloproteinases are the second major proteolytic system in the mammalian brain, and like tissue plasminogen activators are pivotal to neurological function but can also degrade structures of the neurovascular unit after injury. Herein, we show that tissue plasminogen activator potentiates neurovascular damage in a dose-dependent manner in a mouse model of neurotrauma. Surprisingly, inhibition of activity following administration of plasminogen activator inhibitor-1 significantly increased cerebrovascular permeability. This led to our finding that formation of complexes between tissue plasminogen activator and plasminogen activator inhibitor-1 in the brain parenchyma facilitates post-traumatic cerebrovascular damage. We demonstrate that following trauma, the complex binds to low-density lipoprotein receptors, triggering the induction of matrix metalloproteinase-3. Accordingly, pharmacological inhibition of matrix metalloproteinase-3 attenuates neurovascular permeability and improves neurological function in injured mice. Our results are clinically relevant, because concentrations of tissue plasminogen activator: plasminogen activator inhibitor-1 complex and matrix metalloproteinase-3 are significantly elevated in cerebrospinal fluid of trauma patients and correlate with neurological outcome. In a separate study, we found that matrix metalloproteinase-3 and albumin, a marker of cerebrovascular damage, were significantly increased in brain tissue of patients with neurotrauma. Perturbation of neurovascular homeostasis causing oedema, inflammation and cell death is an important cause of acute and long-term neurological dysfunction after trauma. A role for the tissue plasminogen activator–matrix metalloproteinase axis in promoting neurovascular disruption after neurotrauma has not been described thus far. Targeting tissue plasminogen activator: plasminogen activator inhibitor-1 complex signalling or downstream matrix metalloproteinase-3 induction may provide viable therapeutic strategies to reduce cerebrovascular permeability after neurotrauma. PMID:22822039

Systemic Prenatal Insults Disrupt Telencephalon Development

PubMed Central

Robinson, Shenandoah

2006-01-01

Infants born prematurely are prone to chronic neurologic deficits including cerebral palsy (CP), epilepsy, cognitive delay, behavioral problems, and neurosensory impairments. In affected children, imaging and neuropathological findings demonstrate significant damage to white matter. The extent of cortical damage has been less obvious. Advances in the understanding of telencephalon development provide insights into how systemic intrauterine insults affect the developing white matter, subplate and cortex, and lead to multiple neurologic impairments. In addition to white matter oligodendrocytes and axons, other elements at risk for perinatal brain injury include subplate neurons, GABAergic neurons migrating through white matter and subplate, and afferents of maturing neurotransmitter systems. Common insults including hypoxia-ischemia and infection often affect the developing brain differently than the mature brain, and insults precipitate a cascade of damage to multiple neural lineages. Insights from development can identify potential targets for therapies to repair the damaged neonatal brain before it has matured. PMID:16061421

Leukotriene-mediated neuroinflammation, toxic brain damage, and neurodegeneration in acute methanol poisoning.

PubMed

Zakharov, Sergey; Kotikova, Katerina; Nurieva, Olga; Hlusicka, Jiri; Kacer, Petr; Urban, Pavel; Vaneckova, Manuela; Seidl, Zdenek; Diblik, Pavel; Kuthan, Pavel; Navratil, Tomas; Pelclova, Daniela

2017-04-01

The role of neuroinflammation in methanol-induced toxic brain damage has not been studied. We studied acute concentrations and the dynamics of leukotrienes (LT) in serum in hospitalized patients with acute methanol poisoning and in survivors. Series of acute cysteinyl-LT and LTB4 concentration measurements were performed in 28/101 hospitalized patients (mean observation time: 88 ± 20 h). In 36 survivors, control LT measurements were performed 2 years after discharge. The acute maximum (C max ) LT concentrations were higher than concentrations in survivors: C max for LTC4 was 80.7 ± 5.6 versus 47.9 ± 4.5 pg/mL; for LTD4, 51.0 ± 6.6 versus 23.1 ± 2.1 pg/mL; for LTE4, 64.2 ± 6.0 versus 26.2 ± 3.9 pg/mL; for LTB4, 59.8 ± 6.2 versus 27.2 ± 1.4 pg/mL (all p < 0.001). The patients who survived had higher LT concentrations than those who died (all p < 0.01). Among survivors, patients with CNS sequelae had lower LTE4 and LTB4 than did those without sequelae (both p < 0.05). The LT concentrations increased at a rate of 0.4-0.5 pg/mL/h and peaked 4-5 days after admission. The patients with better outcomes had higher cys-LTs (all p < 0.01) and LTB4 (p < 0.05). More severely poisoned patients had lower acute LT concentrations than those with minor acidemia. The follow-up LT concentrations in survivors with and without CNS sequelae did not differ (all p > 0.05). The mean decrease in LT concentration was 30.9 ± 9.0 pg/mL for LTC4, 26.3 ± 8.6 pg/mL for LTD4, 37.3 ± 6.4 pg/mL for LTE4, and 32.0 ± 8.8 pg/mL for LTB4. Our findings suggest that leukotriene-mediated neuroinflammation may play an important role in the mechanisms of toxic brain damage in acute methanol poisoning in humans. Acute elevation of LT concentrations was moderate, transitory, and was not followed by chronic neuroinflammation in survivors.

Prediction of specific damage or infarction from the measurement of tissue impedance following repetitive brain ischaemia in the rat.

PubMed

Klein, H C; Krop-Van Gastel, W; Go, K G; Korf, J

1993-02-01

The development of irreversible brain damage during repetitive periods of hypoxia and normoxia was studied in anaesthetized rats with unilateral occlusion of the carotid artery (modified Levine model). Rats were exposed to 10 min hypoxia and normoxia until severe damage developed. As indices of damage, whole striatal tissue impedance (reflecting cellular water uptake), sodium/potassium contents (due to exchange with blood). Evans Blue staining (blood-brain barrier [BBB] integrity) and silver staining (increased in irreversibly damaged neurons) were used. A substantial decrease in blood pressure was observed during the hypoxic periods possibly producing severe ischaemia. Irreversibly increased impedance, massive changes in silver staining, accumulation of whole tissue Na and loss of K occurred only after a minimum of two periods of hypoxia, but there was no disruption of the BBB. Microscopic examination of tissue sections revealed that cell death was selective with reversible impedance changes, but became massive and non-specific after irreversible increase of the impedance. The development of brain infarcts could, however, not be predicted from measurements of physiological parameters in the blood. We suggest that the development of cerebral infarction during repetitive periods of hypoxia may serve as a model for the development of brain damage in a variety of clinical conditions. Furthermore, the present model allows the screening of potential therapeutic measuring of the prevention and treatment of both infarction and selective cell death.

Hyperglycaemia promotes human brain microvascular endothelial cell apoptosis via induction of protein kinase C-ßI and prooxidant enzyme NADPH oxidase.

PubMed

Shao, Beili; Bayraktutan, Ulvi

2014-01-01

Blood-brain barrier disruption represents a key feature in hyperglycaemia-aggravated cerebral damage after an ischaemic stroke. Although the underlying mechanisms remain largely unknown, activation of protein kinase C (PKC) is thought to play a critical role. This study examined whether apoptosis of human brain microvascular endothelial cells (HBMEC) might contribute to hyperglycaemia-evoked barrier damage and assessed the specific role of PKC in this phenomenon. Treatments with hyperglycaemia (25 mM) or phorbol myristate acetate (PMA, a protein kinase C activator, 100 nM) significantly increased NADPH oxidase activity, O2 (•-) generation, proapoptotic protein Bax expression, TUNEL-positive staining and caspase-3/7 activities. Pharmacological inhibition of NADPH oxidase, PKC-a, PKC-ß or PKC-ßI via their specific inhibitors and neutralisation of O2 (•-) by a cell-permeable superoxide dismutase mimetic, MnTBAP normalised all the aforementioned increases induced by hyperglycaemia. Suppression of these PKC isoforms also negated the stimulatory effects of hyperglycaemia on the protein expression of NADPH oxidase membrane-bound components, Nox2 and p22-phox which determine the overall enzymatic activity. Silencing of PKC-ßI gene through use of specific siRNAs abolished the effects of both hyperglycaemia and PMA on endothelial cell NADPH oxidase activity, O2 (•-) production and apoptosis and consequently improved the integrity and function of an in vitro model of human cerebral barrier comprising HBMEC, astrocytes and pericytes. Hyperglycaemia-mediated apoptosis of HBMEC contributes to cerebral barrier dysfunction and is modulated by sequential activations of PKC-ßI and NADPH oxidase.

Are the endocannabinoid-like compounds N-acyl aminoacids neuroprotective after traumatic brain injury?

PubMed

Mann, Aniv; Cohen-Yeshurun, Ayelet; Trembovler, Victoria; Mechoulam, Raphael; Shohami, Esther

2016-05-01

In recent years, a library of approx. 70 N-acyl aminoacids (NAAAs) was discovered in the rat brain. A particular member of this family of compounds is arachidonoyl serine (AraS), which has generated special interest as a potential therapy for traumatic brain injury (TBI). This is due to its structural similarity to the endocannabinoid (eCB) 2-arachidonoyl glycerol (2-AG), which was previously shown to be beneficial in the recovery in a closed head injury model of TBI. Indeed, AraS exerted eCB-mediated neuroprotection, which was evident in numerous aspects related to the secondary damage characterizing TBI. These findings promoted broadening of the research to additional compounds of the NAAA family that share a structural similarity to AraS, namely, palmitoyl serine (PalmS) and oleoyl serine. The latter did not exhibit any improvement in recovery, whereas the former displayed some neuroprotection, albeit inferior to 2-AG and AraS, via unknown mechanisms. Interestingly, when a combined treatment of 2-AG, AraS and PalmS was tested, the overall effect on the severity score was inferior to their individual effects, suggesting not only a lack of direct or indirect synergism, but also possibly some spatial hindrance. Taken together, the complexity of the damage caused by TBI and the many open questions concerning the role of the eCB system in health and disease, the findings so far may serve as a small trace to the understanding of the eCB system, as well as of the mechanisms underlying TBI.

Nitric oxide-mediated oxidative damage and the progressive demise of motor neurons in ALS.

PubMed

Drechsel, Derek A; Estévez, Alvaro G; Barbeito, Luis; Beckman, Joseph S

2012-11-01

Oxidative damage is a common and early feature of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and other neurodegenerative disorders. Dr. Mark Smith and his colleagues have built the case for oxidative stress being a primary progenitor rather than a secondary end-stage epiphenomenon of neurodegeneration. They proposed that reactive oxygen species contribute to the "age-related cascade of neurodegeneration," whereby accumulative oxidative damage with age promotes other characteristic pathological changes in afflicted brain regions, including protein aggregation, metabolic deficiencies, and inflammation. Nitric oxide (NO) likely plays a critical role in this age-related cascade. NO is a major signaling molecule produced in the central nervous system to modulate neurological activity through stimulating cyclic GMP synthesis. However, the same physiological concentrations of NO, relevant in cellular signaling, may also initiate and amplify oxidative damage by diffusion-limited reactions with superoxide (O(2)(•-)) to produce peroxynitrite (ONOO(-)). This is perhaps best illustrated in ALS where physiological levels of NO promote survival of motor neurons, but the same concentrations can stimulate motor neuron apoptosis and glial cell activation under pathological conditions. While these changes represent a complex mechanism involving multiple cell types in the pathogenesis of ALS, they also reveal general processes underlying neurodegeneration.

S100 B: A new concept in neurocritical care

PubMed Central

Rezaei, Omidvar; Pakdaman, Hossein; Gharehgozli, Kurosh; Simani, Leila; Vahedian-Azimi, Amir; Asaadi, Sina; Sahraei, Zahra; Hajiesmaeili, Mohammadreza

2017-01-01

After brain injuries, concentrations of some brain markers such as S100B protein in serum and cerebrospinal fluid (CSF) are correlated with the severity and outcome of brain damage. To perform an updated review of S100B roles in human neurocritical care domain, an electronic literature search was carried among articles published in English prior to March 2017. They were retrieved from PubMed, Scopus, EMBSCO, CINAHL, ISC and the Cochrane Library using keywords including “brain”, “neurobiochemical marker”, “neurocritical care”, and “S100B protein”. The integrative review included 48 studies until March 2017. S100B protein can be considered as a marker for blood brain barrier damage. The marker has an important role in the development and recovery of normal central nervous system (CNS) after injury. In addition to extra cerebral sources of S100B, the marker is principally built in the astroglial and Schwann cells. The neurobiochemical marker, S100B, has a pathognomonic role in the diagnosis of a broad spectrum of brain damage including traumatic brain injury (TBI), brain tumor, and stroke. Moreover, a potential predicting role for the neurobiochemical marker has been presumed in the efficiency of brain damage treatment and prognosis. However further animal and human studies are required before widespread routine clinical introduction of S100 protein. PMID:28761630

Remodeling Functional Connectivity in Multiple Sclerosis: A Challenging Therapeutic Approach.

PubMed

Stampanoni Bassi, Mario; Gilio, Luana; Buttari, Fabio; Maffei, Pierpaolo; Marfia, Girolama A; Restivo, Domenico A; Centonze, Diego; Iezzi, Ennio

2017-01-01

Neurons in the central nervous system are organized in functional units interconnected to form complex networks. Acute and chronic brain damage disrupts brain connectivity producing neurological signs and/or symptoms. In several neurological diseases, particularly in Multiple Sclerosis (MS), structural imaging studies cannot always demonstrate a clear association between lesion site and clinical disability, originating the "clinico-radiological paradox." The discrepancy between structural damage and disability can be explained by a complex network perspective. Both brain networks architecture and synaptic plasticity may play important roles in modulating brain networks efficiency after brain damage. In particular, long-term potentiation (LTP) may occur in surviving neurons to compensate network disconnection. In MS, inflammatory cytokines dramatically interfere with synaptic transmission and plasticity. Importantly, in addition to acute and chronic structural damage, inflammation could contribute to reduce brain networks efficiency in MS leading to worse clinical recovery after a relapse and worse disease progression. These evidence suggest that removing inflammation should represent the main therapeutic target in MS; moreover, as synaptic plasticity is particularly altered by inflammation, specific strategies aimed at promoting LTP mechanisms could be effective for enhancing clinical recovery. Modulation of plasticity with different non-invasive brain stimulation (NIBS) techniques has been used to promote recovery of MS symptoms. Better knowledge of features inducing brain disconnection in MS is crucial to design specific strategies to promote recovery and use NIBS with an increasingly tailored approach.

Assessment of genotoxic effects of flumorph by the comet assay in mice organs.

PubMed

Zhang, T; Zhao, Q; Zhang, Y; Ning, J

2014-03-01

The present study investigated the genotoxic effects of flumorph in various organs (brain, liver, spleen, kidney and sperm) of mice. The DNA damage, measured as comet tail length (µm), was determined using the alkaline comet assay. The comet assay is a sensitive assay for the detection of genotoxicity caused by flumorph using mice as a model. Statistically significant increases in comet assay for both dose-dependent and duration-dependent DNA damage were observed in all the organs assessed. The organs exhibited the maximum DNA damage in 96 h at 54 mg/kg body weight. Brain showed maximum DNA damage followed by spleen > kidney > liver > sperm. Our data demonstrated that flumorph had induced systemic genotoxicity in mammals as it caused DNA damage in all tested vital organs, especially in brain and spleen.

Types of traumatic brain injury and regional cerebral blood flow assessed by 99mTc-HMPAO SPECT.

PubMed

Yamakami, I; Yamaura, A; Isobe, K

1993-01-01

To investigate the relationship between focal and diffuse traumatic brain injury (TBI) and regional cerebral blood flow (rCBF), rCBF changes in the first 24 hours post-trauma were studied in 12 severe head trauma patients using single photon emission computed tomography (SPECT) with 99mtechnetium-hexamethyl propyleneamine oxime. Patients were classified as focal or diffuse TBI based on x-ray computed tomographic (X-CT) findings and neurological signs. In six patients with focal damage, SPECT demonstrated 1) perfusion defect (focal severe ischemia) in the brain region larger than the brain contusion by X-CT, 2) hypoperfusion (focal CBF reduction) in the brain region without abnormality by X-CT, and 3) localized hyperperfusion (focal CBF increase) in the surgically decompressed brain after decompressive craniectomy. Focal damage may be associated with a heterogeneous CBF change by causing various focal CBF derangements. In six patients with diffuse damage, SPECT revealed hypoperfusion in only one patient. Diffuse damage may be associated with a homogeneous CBF change by rarely causing focal CBF derangements. The type of TBI, focal or diffuse, determines the type of CBF change, heterogeneous or homogeneous, in the acute severe head trauma patient.

Protection from cyanide-induced brain injury by the Nrf2 transcriptional activator carnosic acid

PubMed Central

Zhang, Dongxian; Lee, Brian; Nutter, Anthony; Song, Paul; Dolatabadi, Nima; Parker, James; Sanz-Blasco, Sara; Newmeyer, Traci; Ambasudhan, Rajesh; McKercher, Scott R.; Masliah, Eliezer; Lipton, Stuart A.

2015-01-01

Cyanide is a life threatening, bioterrorist agent, preventing cellular respiration by inhibiting cytochrome c oxidase, resulting in cardiopulmonary failure, hypoxic brain injury, and death within minutes. However, even after treatment with various antidotes to protect cytochrome oxidase, cyanide intoxication in humans can induce a delayed-onset neurological syndrome that includes symptoms of Parkinsonism. Additional mechanisms are thought to underlie cyanide-induced neuronal damage, including generation of reactive oxygen species (ROS). This may account for the fact that antioxidants prevent some aspects of cyanide-induced neuronal damage. Here, as a potential preemptive countermeasure against a bioterrorist attack with cyanide, we tested the CNS protective effect of carnosic acid (CA), a pro-electrophilic compound found in the herb rosemary. CA crosses the blood-brain-barrier to upregulate endogenous antioxidant enzymes via activation of the Nrf2 transcriptional pathway. We demonstrate that CA exerts neuroprotective effects on cyanide-induced brain damage in cultured rodent and human induced pluripotent stem cell (hiPSC)-derived neurons in vitro, and in vivo in various brain areas of a non-Swiss albino (NSA) mouse model of cyanide poisoning that simulates damage observed in the human brain. PMID:25692407

Anti-lysophosphatidic acid antibodies improve traumatic brain injury outcomes

PubMed Central

2014-01-01

Background Lysophosphatidic acid (LPA) is a bioactive phospholipid with a potentially causative role in neurotrauma. Blocking LPA signaling with the LPA-directed monoclonal antibody B3/Lpathomab is neuroprotective in the mouse spinal cord following injury. Findings Here we investigated the use of this agent in treatment of secondary brain damage consequent to traumatic brain injury (TBI). LPA was elevated in cerebrospinal fluid (CSF) of patients with TBI compared to controls. LPA levels were also elevated in a mouse controlled cortical impact (CCI) model of TBI and B3 significantly reduced lesion volume by both histological and MRI assessments. Diminished tissue damage coincided with lower brain IL-6 levels and improvement in functional outcomes. Conclusions This study presents a novel therapeutic approach for the treatment of TBI by blocking extracellular LPA signaling to minimize secondary brain damage and neurological dysfunction. PMID:24576351

Cerebralcare Granule(®), a Chinese Herb Compound Preparation, Attenuates D-Galactose Induced Memory Impairment in Mice.

PubMed

Qu, Zhuo; Yang, Honggai; Zhang, Jingze; Huo, Liqin; Chen, Hong; Li, Yuming; Liu, Changxiao; Gao, Wenyuan

2016-09-01

Cerebralcare granule(®) (CG) is a preparation of Traditional Chinese Medicine that widely used in China. It was approved by the China State Food and Drug Administration for treatment of headache and dizziness associated with cerebrovascular diseases. In the present study, we aimed to investigate whether CG had protective effect against D-galactose (gal)-induced memory impairment and to explore the mechanism of its action. D-gal was administered (100 mg/kg, subcutaneously) once daily for 8 weeks to induced memory deficit and neurotoxicity in the brain of aging mouse and CG (7.5, 15, and 30 g/kg) were simultaneously administered orally. The present study demonstrates that CG can alleviate aging in the mouse brain induced by D-gal through improving behavioral performance and reducing brain cell damage in the hippocampus. CG prevents aging mainly via suppression of oxidative stress response, such as decreasing NO and MDA levels, renewing activities of SOD, CAT, and GPx, as well as decreasing AChE activity in the brain of D-gal-treated mice. In addition, CG prevents aging through inhibiting NF-κB-mediated inflammatory response and caspase-3-medicated neurodegeneration in the brain of D-gal treated mice. Taken together, these data clearly demonstrates that subcutaneous injection of D-gal produced memory deficit, meanwhile CG can protect neuron from D-gal insults and improve memory ability.

Neural Stability, Sparing, and Behavioral Recovery Following Brain Damage

ERIC Educational Resources Information Center

LeVere, T. E.

1975-01-01

The present article discusses the possibility that behavioral recovery following brain damage is not dependent on the functional reorganization of neural tissue but is rather the result of the continued normal operation of spared neural mechanisms. (Editor)

PREDICTING APHASIA TYPE FROM BRAIN DAMAGE MEASURED WITH STRUCTURAL MRI

PubMed Central

Yourganov, Grigori; Smith, Kimberly G.; Fridriksson, Julius; Rorden, Chris

2015-01-01

Chronic aphasia is a common consequence of a left-hemisphere stroke. Since the early insights by Broca and Wernicke, studying the relationship between the loci of cortical damage and patterns of language impairment has been one of the concerns of aphasiology. We utilized multivariate classification in a cross-validation framework to predict the type of chronic aphasia from the spatial pattern of brain damage. Our sample consisted of 98 patients with five types of aphasia (Broca’s, Wernicke’s, global, conduction, and anomic), classified based on scores on the Western Aphasia Battery. Binary lesion maps were obtained from structural MRI scans (obtained at least 6 months poststroke, and within 2 days of behavioural assessment); after spatial normalization, the lesions were parcellated into a disjoint set of brain areas. The proportion of damage to the brain areas was used to classify patients’ aphasia type. To create this parcellation, we relied on five brain atlases; our classifier (support vector machine) could differentiate between different kinds of aphasia using any of the five parcellations. In our sample, the best classification accuracy was obtained when using a novel parcellation that combined two previously published brain atlases, with the first atlas providing the segmentation of grey matter, and the second atlas used to segment the white matter. For each aphasia type, we computed the relative importance of different brain areas for distinguishing it from other aphasia types; our findings were consistent with previously published reports of lesion locations implicated in different types of aphasia. Overall, our results revealed that automated multivariate classification could distinguish between aphasia types based on damage to atlas-defined brain areas. PMID:26465238

Predicting aphasia type from brain damage measured with structural MRI.

PubMed

Yourganov, Grigori; Smith, Kimberly G; Fridriksson, Julius; Rorden, Chris

2015-12-01

Chronic aphasia is a common consequence of a left-hemisphere stroke. Since the early insights by Broca and Wernicke, studying the relationship between the loci of cortical damage and patterns of language impairment has been one of the concerns of aphasiology. We utilized multivariate classification in a cross-validation framework to predict the type of chronic aphasia from the spatial pattern of brain damage. Our sample consisted of 98 patients with five types of aphasia (Broca's, Wernicke's, global, conduction, and anomic), classified based on scores on the Western Aphasia Battery (WAB). Binary lesion maps were obtained from structural MRI scans (obtained at least 6 months poststroke, and within 2 days of behavioural assessment); after spatial normalization, the lesions were parcellated into a disjoint set of brain areas. The proportion of damage to the brain areas was used to classify patients' aphasia type. To create this parcellation, we relied on five brain atlases; our classifier (support vector machine - SVM) could differentiate between different kinds of aphasia using any of the five parcellations. In our sample, the best classification accuracy was obtained when using a novel parcellation that combined two previously published brain atlases, with the first atlas providing the segmentation of grey matter, and the second atlas used to segment the white matter. For each aphasia type, we computed the relative importance of different brain areas for distinguishing it from other aphasia types; our findings were consistent with previously published reports of lesion locations implicated in different types of aphasia. Overall, our results revealed that automated multivariate classification could distinguish between aphasia types based on damage to atlas-defined brain areas. Copyright © 2015 Elsevier Ltd. All rights reserved.

Evolutionary aspects of human exercise--born to run purposefully.

PubMed

Mattson, Mark P

2012-07-01

This article is intended to raise awareness of the adaptive value of endurance exercise (particularly running) in the evolutionary history of humans, and the implications of the genetic disposition to exercise for the aging populations of modern technology-driven societies. The genome of Homo sapiens has evolved to support the svelte phenotype of an endurance runner, setting him/her apart from all other primates. The cellular and molecular mechanisms underlying the competitive advantages conferred by exercise capacity in youth can also provide a survival benefit beyond the reproductive period. These mechanisms include up-regulation of genes encoding proteins involved in protecting cells against oxidative stress, disposing of damaged proteins and organelles, and enhancing bioenergetics. Particularly fascinating are the signaling mechanisms by which endurance running changes the structure and functional capabilities of the brain and, conversely, the mechanisms by which the brain integrates metabolic, cardiovascular and behavioral responses to exercise. As an emerging example, I highlight the roles of brain-derived neurotrophic factor (BDNF) as a mediator of the effects of exercise on the brain, and BDNF's critical role in regulating metabolic and cardiovascular responses to endurance running. A better understanding of such 'healthspan-extending' actions of endurance exercise may lead to new approaches for improving quality of life as we advance in the coming decades and centuries. Published by Elsevier B.V.

Hemorrhagic transformation after ischemic stroke in animals and humans

PubMed Central

Jickling, Glen C; Liu, DaZhi; Stamova, Boryana; Ander, Bradley P; Zhan, Xinhua; Lu, Aigang; Sharp, Frank R

2014-01-01

Hemorrhagic transformation (HT) is a common complication of ischemic stroke that is exacerbated by thrombolytic therapy. Methods to better prevent, predict, and treat HT are needed. In this review, we summarize studies of HT in both animals and humans. We propose that early HT (<18 to 24 hours after stroke onset) relates to leukocyte-derived matrix metalloproteinase-9 (MMP-9) and brain-derived MMP-2 that damage the neurovascular unit and promote blood–brain barrier (BBB) disruption. This contrasts to delayed HT (>18 to 24 hours after stroke) that relates to ischemia activation of brain proteases (MMP-2, MMP-3, MMP-9, and endogenous tissue plasminogen activator), neuroinflammation, and factors that promote vascular remodeling (vascular endothelial growth factor and high-moblity-group-box-1). Processes that mediate BBB repair and reduce HT risk are discussed, including transforming growth factor beta signaling in monocytes, Src kinase signaling, MMP inhibitors, and inhibitors of reactive oxygen species. Finally, clinical features associated with HT in patients with stroke are reviewed, including approaches to predict HT by clinical factors, brain imaging, and blood biomarkers. Though remarkable advances in our understanding of HT have been made, additional efforts are needed to translate these discoveries to the clinic and reduce the impact of HT on patients with ischemic stroke. PMID:24281743

Adenovirus-mediated p53 gene delivery potentiates the radiation-induced growth inhibition of experimental brain tumors.

PubMed

Badie, B; Kramar, M H; Lau, R; Boothman, D A; Economou, J S; Black, K L

1998-05-01

Patients with malignant gliomas continue to have very poor prognosis even after surgical resection, radiation and chemotherapy. Because these tumors often have alterations in the p53 tumor suppressor gene, which plays a key role in the cellular response to DNA damaging agents, we investigated the role of p53 gene therapy in conjunction with ionizing radiation in a rat brain tumor model. Exposure of cultured rat 9L gliosarcoma cells, which contain a mutant p53 gene, to a recombinant adenovirus-vector bearing the wild-type p53 gene (Adp53), induced apoptosis within 24 hours. Although ionizing radiation had no additional effect on apoptosis within this time frame, it caused G1 arrest in non-apoptotic cells after Adp53 therapy. In contrast, wild-type 9L cells demonstrated little G1 arrest after X-irradiation. When animals bearing brain tumors were irradiated after intratumoral Adp53 injections, more than 85% reduction in tumor size was noted. Moreover, the group of rats receiving both radiation and Adp53 therapy had a significant increase in survival as compared to animals receiving either therapy alone. These results support the use of p53 gene therapy as an adjunct to radiation in treatment of malignant brain tumors.

Inhibition of angiogenesis by β-galactosylceramidase deficiency in globoid cell leukodystrophy

PubMed Central

Belleri, Mirella; Ronca, Roberto; Coltrini, Daniela; Nico, Beatrice; Ribatti, Domenico; Poliani, Pietro L.; Giacomini, Arianna; Alessi, Patrizia; Marchesini, Sergio; Santos, Marta B.; Bongarzone, Ernesto R.

2013-01-01

Globoid cell leukodystrophy (Krabbe disease) is a neurological disorder of infants caused by genetic deficiency of the lysosomal enzyme β-galactosylceramidase leading to accumulation of the neurotoxic metabolite 1-β-d-galactosylsphingosine (psychosine) in the central nervous system. Angiogenesis plays a pivotal role in the physiology and pathology of the brain. Here, we demonstrate that psychosine has anti-angiogenic properties by causing the disassembling of endothelial cell actin structures at micromolar concentrations as found in the brain of patients with globoid cell leukodystrophy. Accordingly, significant alterations of microvascular endothelium were observed in the post-natal brain of twitcher mice, an authentic model of globoid cell leukodystrophy. Also, twitcher endothelium showed a progressively reduced capacity to respond to pro-angiogenic factors, defect that was corrected after transduction with a lentiviral vector harbouring the murine β-galactosylceramidase complementary DNA. Finally, RNA interference-mediated β-galactosylceramidase gene silencing causes psychosine accumulation in human endothelial cells and hampers their mitogenic and motogenic response to vascular endothelial growth factor. Accordingly, significant alterations were observed in human microvasculature from brain biopsy of a globoid cell leukodystrophy case. Together these data demonstrate that β-galactosylceramidase deficiency induces significant alterations in endothelial neovascular responses that may contribute to central nervous system and systemic damages that occur in globoid cell leukodystrophy. PMID:23983033

Beneficial effects of n-acetylcysteine on ischaemic brain injury

PubMed Central

Cuzzocrea, Salvatore; Mazzon, Emanuela; Costantino, Giuseppina; Serraino, Ivana; Dugo, Laura; Calabrò, Giusy; Cucinotta, Giovanni; De Sarro, Angela; Caputi, A P

2000-01-01

Nitric oxide (NO), peroxynitrite, formed from NO and superoxide anion, poly (ADP-ribole) synthetase have been implicated as mediators of neuronal damage following focal ischaemia. Here we have investigated the effects of n-acetylcysteine (NAC) treatment in Mongolian gerbils subjected to cerebral ischaemia.Treatment of gerbils with NAC (20 mg kg−1 30 min before reperfusion and 1, 2 and 6 h after reperfusion) reduced the formation of post-ischaemic brain oedema, evaluated by water content.NAC also attenuated the increase in the brain levels of malondialdehyde (MDA) and the increase in the hippocampus of myeloperoxidase (MPO) caused by cerebral ischaemia.Positive staining for nitrotyrosine was found in the hippocampus in Mongolian gerbils subjected to cerebral ischaemia. Hippocampus tissue sections from Mongolian gerbils subjected to cerebral ischaemia also showed positive staining for poly (ADP-ribose) synthetase (PARS). The degree of staining for nitrotyrosine and for PARS were markedly reduced in tissue sections obtained from animals that received NAC.NAC treatment increased survival and reduced hyperactivity linked to neurodegeneration induced by cerebral ischaemia and reperfusion.Histological observations of the pyramidal layer of CA1 showed a reduction of neuronal loss in animals that received NAC.These results show that NAC improves brain injury induced by transient cerebral ischaemia. PMID:10903958

Evolutionary Aspects of Human Exercise – Born to Run Purposefully

PubMed Central

Mattson, Mark P.

2012-01-01

This article is intended to raise awareness of the adaptive value of endurance exercise (particularly running) in the evolutionary history of humans, and the implications of the genetic disposition to exercise for the aging populations of modern technology-driven societies. The genome of Homo sapiens has evolved to support the svelte phenotype of an endurance runner, setting him/her apart from all other primates. The cellular and molecular mechanisms underlying the competitive advantages conferred by exercise capacity in youth can also provide a survival benefit beyond the reproductive period. These mechanisms include up-regulation of genes encoding proteins involved in protecting cells against oxidative stress, disposing of damaged proteins and organelles, and enhancing bioenergetics. Particularly fascinating are the signaling mechanisms by which endurance running changes the structure and functional capabilities of the brain and, conversely, the mechanisms by which the brain integrates metabolic, cardiovascular and behavioral responses to exercise. As an emerging example, I highlight the roles of brain-derived neurotrophic factor (BDNF) as a mediator of the effects of exercise on the brain, and BDNF s critical role in regulating metabolic and cardiovascular responses to endurance running. A better understanding of such healthspan-extending actions of endurance exercise may lead to new approaches for improving quality of life as we advance in the coming decades and centuries. PMID:22394472

Running, swimming and diving modifies neuroprotecting globins in the mammalian brain

PubMed Central

Williams, Terrie M; Zavanelli, Mary; Miller, Melissa A; Goldbeck, Robert A; Morledge, Michael; Casper, Dave; Pabst, D. Ann; McLellan, William; Cantin, Lucas P; Kliger, David S

2007-01-01

The vulnerability of the human brain to injury following just a few minutes of oxygen deprivation with submergence contrasts markedly with diving mammals, such as Weddell seals (Leptonychotes weddellii), which can remain underwater for more than 90 min while exhibiting no neurological or behavioural impairment. This response occurs despite exposure to blood oxygen levels concomitant with human unconsciousness. To determine whether such aquatic lifestyles result in unique adaptations for avoiding ischaemic–hypoxic neural damage, we measured the presence of circulating (haemoglobin) and resident (neuroglobin and cytoglobin) oxygen-carrying globins in the cerebral cortex of 16 mammalian species considered terrestrial, swimming or diving specialists. Here we report a striking difference in globin levels depending on activity lifestyle. A nearly 9.5-fold range in haemoglobin concentration (0.17–1.62 g Hb 100 g brain wet wt−1) occurred between terrestrial and deep-diving mammals; a threefold range in resident globins was evident between terrestrial and swimming specialists. Together, these two globin groups provide complementary mechanisms for facilitating oxygen transfer into neural tissues and the potential for protection against reactive oxygen and nitrogen groups. This enables marine mammals to maintain sensory and locomotor neural functions during prolonged submergence, and suggests new avenues for averting oxygen-mediated neural injury in the mammalian brain. PMID:18089537

Formononetin protects TBI rats against neurological lesions and the underlying mechanism.

PubMed

Li, Zhengzhao; Dong, Xianhong; Zhang, Jianfeng; Zeng, Guang; Zhao, Huimin; Liu, Yun; Qiu, Rubiao; Mo, Linjian; Ye, Yu

2014-03-15

Traumatic brain injury (TBI) is a major cause of disability or death worldwide, especially in the young. Thus, effective medication with few side effects needs to be developed. This work aimed to explore the potential benefits of formononetin (FN) on TBI rodent model and to discuss the regarding mechanism. These findings showed that FN effectively increased the activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in brain tissue of TBI rats (P<0.01), while it reduced intracephalic malonaldehyde (MDA), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) concentrations (P<0.01). Meanwhile, the hydrocephalus in the TBI rat was alleviated, and the injured nerve cell of the lesioned brain was reduced as showed in hematoxylin-eosin (HE) staining assay. In addition, the endogenous mRNA level of cyclooxygenase-2 (COX-2) in the brain of the TBI rat was significantly down-regulated (P<0.01). Furthermore, the protein expression of nuclear factor E2-related factor 2 (Nrf2) was effectively up-regulated (P<0.01). Taken together, we conclude that formononetin mediates the promising anti-TBI effects against neurocyte damage, which the underlying mechanisms are associated with inhibiting intracephalic inflammatory response and oxidative stress for neuroprotection. Copyright © 2013 Elsevier B.V. All rights reserved.

Function and Dysfunction of Prefrontal Brain Circuitry in Alcoholic Korsakoff’s Syndrome

PubMed Central

Oscar-Berman, Marlene

2013-01-01

The signature symptom of alcohol-induced persisting amnestic disorder, more commonly referred to as alcoholic Korsakoff’s syndrome (KS), is anterograde amnesia, or memory loss for recent events, and until the mid 20th Century, the putative brain damage was considered to be in diencephalic and medial temporal lobe structures. Overall intelligence, as measured by standardized IQ tests, usually remains intact. Preservation of IQ occurs because memories formed before the onset of prolonged heavy drinking — the types of information and abilities tapped by intelligence tests — remain relatively well preserved compared with memories recently acquired. However, clinical and experimental evidence has shown that neurobehavioral dysfunction in alcoholic patients with KS does include nonmnemonic abilities, and further brain damage involves extensive frontal and limbic circuitries. Among the abnormalities are confabulation, disruption of elements of executive functioning and cognitive control, and emotional impairments. Here, we discuss the relationship between neurobehavioral impairments in KS and alcoholism-related brain damage. More specifically, we examine the role of damage to prefrontal brain systems in the neuropsychological profile of alcoholic KS. PMID:22538385

Docosahexaenoic acid Confers Neuroprotection in a Rat Model of Perinatal Hypoxia-ischemia potentiated by E. coli lipopolysaccharide-induced systemic inflammation

PubMed Central

BERMAN, Deborah R; LIU, YiQing; BARKS, John; MOZURKEWICH, Ellen

2010-01-01

Objective Lipopolysaccharide (LPS) pretreatment potentiates HI injury. We hypothesized that docosahexaenoic acid (DHA) pretreatment would improve function and reduce brain damage in this rat model of perinatal brain injury and inflammation. Study Design Seven-day-old Wistar rats were divided into 3 groups. One received intraperitoneal (IP) DHA 1 mg/kg and LPS 0.1mg/kg. The second received 25% Albumin and LPS. The third received normal saline (NS). Injections were given 2.5 hours prior to right carotid ligation, followed by 90 minutes 8% O2. Rats underwent sensorimotor testing and brain damage assessment on P14. Results DHA pretreatment improved forepaw placing compared to albumin/LPS. (Mean±SD successes/10 trials: 8.57±1.7 DHA/LPS vs 6.72±2.2 Albumin/LPS, p<.0009). There were no significant differences in brain damage among groups. Conclusions Inflammatory stimulation before HI resulted in poorer function than HI alone. Although DHA pretreatment had no impact on brain damage, it significantly improved function in neonatal rats exposed to LPS and HI. PMID:19254588

Blocking leukotriene synthesis attenuates the pathophysiology of traumatic brain injury and associated cognitive deficits

PubMed Central

Corser-Jensen, Chelsea E.; Goodell, Dayton J.; Freund, Ronald K.; Serbedzija, Predrag; Murphy, Robert C.; Farias, Santiago E.; Dell'Acqua, Mark L.; Frey, Lauren C.; Serkova, Natalie; Heidenreich, Kim A.

2014-01-01

Neuroinflammation is a component of secondary injury following traumatic brain injury (TBI) that can persist beyond the acute phase. Leukotrienes are potent, pro-inflammatory lipid mediators generated from membrane phospholipids. In the absence of injury, leukotrienes are undetectable in brain, but after trauma they are rapidly synthesized by a transcellular event involving infiltrating neutrophils and endogenous brain cells. Here, we investigate the efficacy of MK-886, an inhibitor of 5-lipoxygenase activating protein (FLAP), in blocking leukotriene synthesis, secondary brain damage, synaptic dysfunction, and cognitive impairments after TBI. Male Sprague Dawley rats (9-11 weeks) received either MK-886 or vehicle after they were subjected to unilateral moderate fluid percussion injury (FPI) to assess the potential clinical use of FLAP inhibitors for TBI. MK-886 was also administered before FPI to determine the preventative potential of FLAP inhibitors. MK-886 given before or after injury significantly blocked the production of leukotrienes, measured by reverse-phase liquid chromatography coupled to tandem mass spectrometry (RP LC-MS/MS), and brain edema, measured by T2-weighted magnetic resonance imaging (MRI). MK-886 significantly attenuated blood-brain barrier disruption in the CA1 hippocampal region and deficits in long-term potentiation (LTP) at CA1 hippocampal synapses. The prevention of FPI-induced synaptic dysfunction by MK-886 was accompanied by fewer deficits in post-injury spatial learning and memory performance in the radial arms water maze (RAWM). These results indicate that leukotrienes contribute significantly to secondary brain injury and subsequent cognitive deficits. FLAP inhibitors represent a novel anti-inflammatory approach for treating human TBI that is feasible for both intervention and prevention of brain injury and neurologic deficits. PMID:24681156

An update on the clinical trial of BNCT at the BMRR

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

Ma, R.; Capala, J.; Chanana, A.D.

1999-09-01

Boron neutron capture therapy (BNCT) was proposed more than six decades ago. It is a binary treatment modality that requires selective delivery of a {sup 10}B-labeled compound to a tumor and slow neutron irradiation of the tumor-bearing tissues. In order to improve the penetration of the neutron beam, an epithermal neutron beam was developed at the Brookhaven Medical Research Reactor (BMRR). This epithermal neutron beam can deliver relatively high thermal neutron fluence at depth without severe skin damage. Boronophenylalanine-fructose (BPA-F), a nontoxic boron carrier, was found to preferentially accumulate in tumor cells following intravenous infusion in patients with GBM. Inmore » preclinical BNCT studies in rats bearing 9L gliosarcoma, BPA-mediated BNCT was shown to be more efficacious than photon irradiation. In 1994, improvements in the neutron beam and in the understanding of the radiobiology of BPA-mediated BNCT led to the initiation of BNCT trials for human GBM at BMRR using BPA-F and epithermal neutrons. The primary objective of the phase I/II clinical trial of BPA-mediated BNCT at BMRR is to evaluate the safety of the BPA-F-mediated BNCT using epithermal neutrons in patients with GBM at a series of escalating BNCT doses. An incidental objective is to evaluate the therapeutic effectiveness of BNCT at each dose level. For each dose escalation group, the average brain dose (ABD) is escalated, as well as the minimum tumor dose. In summary, the BNCT procedure employed in the phase I/II clinical trial of BPA-F-mediated BNCT for GBM at BNL was found to be safe in all patients. The palliation afforded by a single session of BNCT compares favorably with palliation provided by fractionated photon therapy and adjuvant chemotherapy. If no evidence of radiation-induced brain toxicity is found in the current protocol, BNCT radiation dose will be further escalated.« less

Global Efficiency of Structural Networks Mediates Cognitive Control in Mild Cognitive Impairment

PubMed Central

Berlot, Rok; Metzler-Baddeley, Claudia; Ikram, M. Arfan; Jones, Derek K.; O’Sullivan, Michael J.

2016-01-01

Background: Cognitive control has been linked to both the microstructure of individual tracts and the structure of whole-brain networks, but their relative contributions in health and disease remain unclear. Objective: To determine the contribution of both localized white matter tract damage and disruption of global network architecture to cognitive control, in older age and Mild Cognitive Impairment (MCI). Materials and Methods: Twenty-five patients with MCI and 20 age, sex, and intelligence-matched healthy volunteers were investigated with 3 Tesla structural magnetic resonance imaging (MRI). Cognitive control and episodic memory were evaluated with established tests. Structural network graphs were constructed from diffusion MRI-based whole-brain tractography. Their global measures were calculated using graph theory. Regression models utilized both global network metrics and microstructure of specific connections, known to be critical for each domain, to predict cognitive scores. Results: Global efficiency and the mean clustering coefficient of networks were reduced in MCI. Cognitive control was associated with global network topology. Episodic memory, in contrast, correlated with individual temporal tracts only. Relationships between cognitive control and network topology were attenuated by addition of single tract measures to regression models, consistent with a partial mediation effect. The mediation effect was stronger in MCI than healthy volunteers, explaining 23-36% of the effect of cingulum microstructure on cognitive control performance. Network clustering was a significant mediator in the relationship between tract microstructure and cognitive control in both groups. Conclusion: The status of critical connections and large-scale network topology are both important for maintenance of cognitive control in MCI. Mediation via large-scale networks is more important in patients with MCI than healthy volunteers. This effect is domain-specific, and true for cognitive control but not for episodic memory. Interventions to improve cognitive control will need to address both dysfunction of local circuitry and global network architecture to be maximally effective. PMID:28018208

[Intrauterine infection and the preterm brain: dimensions of aetiology research].

PubMed

Dammann, O

2006-02-01

Perinatal brain damage has a diverse and complex aetiology. Over the past decades, much progress has been made in this research field. In this article, I offer a discussion of seven dimensions of aetiological perinatal brain damage research: (1) hypoxia-ischaemia vs. inflammation; (2) "classic" vs. "remote" intrauterine infection; (3) focal vs. diffuse white matter damage; (4) maternal vs. foetal inflammatory response; (5) clinical vs. experimental data; (6) bacterial vs. viral infection; and (7) preterm vs. term delivery. Despite these complexities, it is hoped that obstetricians, neonatologists, and neuropaediatricians will agree on a perinatal neuroprotective strategy in the near future.

The 8-oxoguanine DNA glycosylase 1 (ogg1) decreases the vulnerability of the developing brain to DNA damage.

PubMed

Gu, Aihua; Ji, Guixiang; Yan, Lifeng; Zhou, Yong

2013-12-01

The developing brain is particularly vulnerable to oxidative DNA damage, which may be the cause of most major congenital mental anomalies. The repair enzyme ogg1 initiates the highly conserved base-excision repair pathway. However, its function in the embryonic brain is largely unknown. This study is the first to validate the function of ogg1 during brain development using zebrafish embryos. Ogg1 was found to be highly expressed in the brain throughout early embryonic development, with particularly enrichment observed in the midbrain. The lack of ogg1 causes severe brain defects including changes in brain volume and integrity, destruction of the midbrain-hindbrain boundary, and balance and motor impairment, while overexpression of ogg1 can partially rescue these defects. Multiple cellular and molecular events were involved in the manifestation of brain defects due primarily to the lack of ogg1. These included (1) increased apoptosis; (2) decreased proliferation; and (3) aberrant axon distribution and extension from the inner surface towards the outer layers. The results of a microarray analysis showed that the expression of genes involved in cell cycle checkpoint, apoptosis, and neurogenesis were significantly changed in response to ogg1 knockdown. Cmyb was the key downstream gene that responses to DNA damage caused by ogg1 deficiency. Notably, the recruitment of ogg1 mRNA can alleviate the effects on the brain due to neural DNA damage. In summary, we introduce here that ogg1 is fundamentally required for protecting the developing brain, which may be helpful in understanding the aetiology of congenital brain deficits. Copyright © 2013 Elsevier B.V. All rights reserved.

The Brain As a Mixer, I. Preliminary Literature Review: Auditory Integration. Studies in Language and Language Behavior, Progress Report Number VII.

ERIC Educational Resources Information Center

Semmel, Melvyn I.; And Others

Methods to evaluate central hearing deficiencies and to localize brain damage are reviewed beginning with Bocca who showed that patients with temporal lobe tumors made significantly lower discrimination scores in the ear opposite the tumor when speech signals were distorted. Tests were devised to attempt to pinpoint brain damage on the basis of…

Dl-3-n-Butylphthalide Inhibits NLRP3 Inflammasome and Mitigates Alzheimer's-Like Pathology via Nrf2-TXNIP-TrX Axis.

PubMed

Wang, Chun-Yan; Xu, Ye; Wang, Xu; Guo, Chuang; Wang, Tao; Wang, Zhan-You

2018-04-25

Oxidative stress and neuroinflammation play important roles in the pathology of Alzheimer's disease (AD). Thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of antioxidant thioredoxin, is suspected to be an important modulator of oxidative stress and inflammation. However, the underlying mechanism involved in the abnormal homeostasis of TXNIP-thioredoxin (TrX) in AD pathogenesis remains unclear. Using the Swedish mutant form of APP (APPswe)/PSEN1dE9 transgenic mouse (APP/PS1) and human-derived neuronal cells as model systems, we disclosed the impairment of the nuclear factor erythroid 2-related factor 2 (Nrf2)-TXNIP-TrX signaling in Alzheimer's-like pathology. We observed that the immune staining of TXNIP was increased in postmortem AD brain. The chronic accumulation of inflammatory mediator in neuronal cells facilitates interactions of TXNIP-nucleotide binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) and NLRP3-ASC, which increases β-amyloid (Aβ) secretion. The antioxidant Dl-3-n-butylphthalide (Dl-NBP) is commonly used for cerebral ischemia treatment. In our study, we elucidated for new mechanisms by which Dl-NBP enhanced TrX activity, suppressed TXNIP, and ameliorated neuronal apoptosis in the APP/PS1 mouse brains. In human glioblastoma A172 cells and neuroblastoma SH-SY5Y cells, we delineated the Dl-NBP-mediated signaling pathways by which Dl-NBP-dependent upregulation of Nrf2 mediated the reciprocal regulation of reducing proinflammatory cytokine and inhibiting Aβ production in the glial and neuronal cells overexpressing APPswe. Our data provide a novel insight into the molecular mechanism that impairments of Nrf2-TXNIP-TrX system may be involved in the imbalance of cellular redox homeostasis and inflammatory damage in the AD brain. Dl-NBP treatment could suppress TXNIP-NLRP3 interaction and inhibit NLRP3 inflammasome activation via upregulating Nrf2. These findings may provide an instrumental therapeutic approach for AD. Antioxid. Redox Signal. 00, 000-000.

Ketosis may promote brain macroautophagy by activating Sirt1 and hypoxia-inducible factor-1.

PubMed

McCarty, Mark F; DiNicolantonio, James J; O'Keefe, James H

2015-11-01

Ketogenic diets are markedly neuroprotective, but the basis of this effect is still poorly understood. Recent studies demonstrate that ketone bodies increase neuronal levels of hypoxia-inducible factor-1α (HIF-1α), possibly owing to succinate-mediated inhibition of prolyl hydroxylase activity. Moreover, there is reason to suspect that ketones can activate Sirt1 in neurons, in part by increasing cytoplasmic and nuclear levels of Sirt1's obligate cofactor NAD(+). Another recent study has observed reduced activity of mTORC1 in the hippocampus of rats fed a ketogenic diet - an effect plausibly attributable to Sirt1 activation. Increased activities of HIF-1 and Sirt1, and a decrease in mTORC1 activity, could be expected to collaborate in the induction of neuronal macroautophagy. Considerable evidence points to moderate up-regulation of neuronal autophagy as a rational strategy for prevention of neurodegenerative disorders; elimination of damaged mitochondria that overproduce superoxide, as well as clearance of protein aggregates that mediate neurodegeneration, presumably contribute to this protection. Hence, autophagy may mediate some of the neuroprotective benefits of ketogenic diets. Brain-permeable agents which activate AMP-activated kinase, such as metformin and berberine, as well as the Sirt1 activator nicotinamide riboside, can also boost neuronal autophagy, and may have potential for amplifying the impact of ketogenesis on this process. Since it might not be practical for most people to adhere to ketogenic diets continuously, alternative strategies are needed to harness the brain-protective potential of ketone bodies. These may include ingestion of medium-chain triglycerides or coconut oil, intermittent ketogenic dieting, and possibly the use of supplements that promote hepatic ketogenesis - notably carnitine and hydroxycitrate - in conjunction with dietary regimens characterized by long daily episodes of fasting or carbohydrate avoidance. Copyright © 2015 Elsevier Ltd. All rights reserved.

Lipopolysaccharide hyporesponsiveness: protective or damaging response to the brain?

PubMed

Pardon, Marie Christine

2015-01-01

Lipopolysaccharide (LPS) endotoxins are widely used as experimental models of systemic bacterial infection and trigger robust inflammation by potently activating toll-like receptors 4 (TLR4) expressed on innate immune cells. Their ability to trigger robust neuroinflammation despite poor brain penetration can prove useful for the understanding of how inflammation induced by viral infections contributes to the pathogenesis of neurodegenerative diseases. A single LPS challenge often result in a blunted inflammatory response to subsequent stimulation by LPS and other TLR ligands, but the extent to which endotoxin tolerance occur in the brain requires further clarification. LPS is also thought to render the brain transiently resistant to subsequent brain injuries by attenuating the concomitant pro-inflammatory response. While LPS hyporesponsiveness and preconditioning are classically seen as protective mechanisms limiting the toxic effects of sustained inflammation, recent research casts doubt as to whether they have beneficial or detrimental roles on the brain and in neurodegenerative disease. These observations suggest that spatio-temporal aspects of the immune responses to LPS and the disease status are determinant factors. Endotoxin tolerance may lead to a late pro-inflammatory response with potential harmful consequences. And while reduced TLR4 signaling reduces the risk of neurodegenerative diseases, up-regulation of anti-inflammatory cytokines associated with LPS hyporesponsiveness can have deleterious consequences to the brain by inhibiting the protective phenotype of microglia, aggravating the progression of some neurodegenerative conditions such as Alzheimer's disease. Beneficial effects of LPS preconditioning, however appear to require a stimulation of anti-inflammatory mediators rather than an attenuation of the pro-inflammatory response.

Role of Interleukin-10 in Acute Brain Injuries

PubMed Central

Garcia, Joshua M.; Stillings, Stephanie A.; Leclerc, Jenna L.; Phillips, Harrison; Edwards, Nancy J.; Robicsek, Steven A.; Hoh, Brian L.; Blackburn, Spiros; Doré, Sylvain

2017-01-01

Interleukin-10 (IL-10) is an important anti-inflammatory cytokine expressed in response to brain injury, where it facilitates the resolution of inflammatory cascades, which if prolonged causes secondary brain damage. Here, we comprehensively review the current knowledge regarding the role of IL-10 in modulating outcomes following acute brain injury, including traumatic brain injury (TBI) and the various stroke subtypes. The vascular endothelium is closely tied to the pathophysiology of these neurological disorders and research has demonstrated clear vascular endothelial protective properties for IL-10. In vitro and in vivo models of ischemic stroke have convincingly directly and indirectly shown IL-10-mediated neuroprotection; although clinically, the role of IL-10 in predicting risk and outcomes is less clear. Comparatively, conclusive studies investigating the contribution of IL-10 in subarachnoid hemorrhage are lacking. Weak indirect evidence supporting the protective role of IL-10 in preclinical models of intracerebral hemorrhage exists; however, in the limited number of clinical studies, higher IL-10 levels seen post-ictus have been associated with worse outcomes. Similarly, preclinical TBI models have suggested a neuroprotective role for IL-10; although, controversy exists among the several clinical studies. In summary, while IL-10 is consistently elevated following acute brain injury, the effect of IL-10 appears to be pathology dependent, and preclinical and clinical studies often paradoxically yield opposite results. The pronounced and potent effects of IL-10 in the resolution of inflammation and inconsistency in the literature regarding the contribution of IL-10 in the setting of acute brain injury warrant further rigorously controlled and targeted investigation. PMID:28659854

Oxaloacetate restores the long-term potentiation impaired in rat hippocampus CA1 region by 2-vessel occlusion.

PubMed

Marosi, Máté; Fuzik, János; Nagy, Dávid; Rákos, Gabriella; Kis, Zsolt; Vécsei, László; Toldi, József; Ruban-Matuzani, Angela; Teichberg, Vivian I; Farkas, Tamás

2009-02-14

Various acute brain pathological conditions are characterized by the presence of elevated glutamate concentrations in the brain interstitial fluids. It has been established that a decrease in the blood glutamate level enhances the brain-to-blood efflux of glutamate, removal of which from the brain may prevent glutamate excitotoxicity and its contribution to the long-lasting neurological deficits seen in stroke. A decrease in blood glutamate level can be achieved by exploiting the glutamate-scavenging properties of the blood-resident enzyme glutamate-oxaloacetate transaminase, which transforms glutamate into 2-ketoglutarate in the presence of the glutamate co-substrate oxaloacetate. The present study had the aim of an evaluation of the effects of the blood glutamate scavenger oxaloacetate on the impaired long-term potentiation (LTP) induced in the 2-vessel occlusion ischaemic model in rat. Transient (30-min) incomplete forebrain ischaemia was produced 72 h before LTP induction. Although the short transient brain hypoperfusion did not induce histologically identifiable injuries in the CA1 region (Fluoro-Jade B, S-100 and cresyl violet), it resulted in an impaired LTP function in the hippocampal CA1 region without damaging the basal synaptic transmission between the Schaffer collaterals and the pyramidal neurons. This impairment could be fended off in a dose-dependent manner by the intravenous administration of oxaloacetate in saline (at doses between 1.5 mmol and 0.1 mumol) immediately after the transient hypoperfusion. Our results suggest that oxaloacetate-mediated blood and brain glutamate scavenging contributes to the restoration of the LTP after its impairment by brain ischaemia.

Overexpression of HIF-1α in mesenchymal stem cells contributes to repairing hypoxic-ischemic brain damage in rats.

PubMed

Lin, Deju; Zhou, Liping; Wang, Biao; Liu, Lizhen; Cong, Li; Hu, Chuanqin; Ge, Tingting; Yu, Qin

2017-01-01

Preclinical researches on mesenchymal stem cells (MSCs) transplantation, which is used to treat hypoxic-ischemic (HI) brain damage, have received inspiring achievements. However, the insufficient migration of active cells to damaged tissues has limited their potential therapeutic effects. There are some evidences that hypoxia inducible factor-1 alpha (HIF-1α) promotes the viability and migration of the cells. Here, we aim to investigate whether overexpression of HIF-1α in MSCs could improve the viability and migration capacity of cells, and its therapeutic efficiency on HI brain damage. In the study, MSCs with HIF-1α overexpression was achieved by recombinant lentiviral vector and transplanted to the rats subsequent to HI. Our data indicated that overexpression of HIF-1α promoted the viability and migration of MSCs, HIF-1α overexpressed MSCs also had a stronger therapeutic efficiency on HI brain damaged treatment by mitigating the injury on behavioral and histological changes evoked by HI insults, accompanied with more MSCs migrating to cerebral damaged area. This study demonstrated that HIF-1α overexpression could increase the MSCs' therapeutic efficiency in HI and the promotion of the cells' directional migration to cerebral HI area by overexpression may be responsible for it, which showed that transplantation of MSCs with HIF-1α overexpression is an attractive therapeutic option to treat HI-induced brain injury in the future. Copyright © 2016 Académie des sciences. Published by Elsevier SAS. All rights reserved.

Co-speech hand movements during narrations: What is the impact of right vs. left hemisphere brain damage?

PubMed

Hogrefe, Katharina; Rein, Robert; Skomroch, Harald; Lausberg, Hedda

2016-12-01

Persons with brain damage show deviant patterns of co-speech hand movement behaviour in comparison to healthy speakers. It has been claimed by several authors that gesture and speech rely on a single production mechanism that depends on the same neurological substrate while others claim that both modalities are closely related but separate production channels. Thus, findings so far are contradictory and there is a lack of studies that systematically analyse the full range of hand movements that accompany speech in the condition of brain damage. In the present study, we aimed to fill this gap by comparing hand movement behaviour in persons with unilateral brain damage to the left and the right hemisphere and a matched control group of healthy persons. For hand movement coding, we applied Module I of NEUROGES, an objective and reliable analysis system that enables to analyse the full repertoire of hand movements independent of speech, which makes it specifically suited for the examination of persons with aphasia. The main results of our study show a decreased use of communicative conceptual gestures in persons with damage to the right hemisphere and an increased use of these gestures in persons with left brain damage and aphasia. These results not only suggest that the production of gesture and speech do not rely on the same neurological substrate but also underline the important role of right hemisphere functioning for gesture production. Copyright © 2016 Elsevier Ltd. All rights reserved.

Docosahexaenoic acid augments hypothermic neuroprotection in a neonatal rat asphyxia model.

PubMed

Berman, Deborah R; Mozurkewich, Ellen; Liu, Yiqing; Shangguan, Yu; Barks, John D; Silverstein, Faye S

2013-01-01

In neonatal rats, early post-hypoxia-ischemia (HI) administration of the omega-3 fatty acid docosahexaenoic acid (DHA) improves sensorimotor function, but does not attenuate brain damage. To determine if DHA administration in addition to hypothermia, now standard care for neonatal asphyxial brain injury, attenuates post-HI damage and sensorimotor deficits. Seven-day-old (P7) rats underwent right carotid ligation followed by 90 min of 8% O2 exposure. Fifteen minutes later, pups received injections of DHA 2.5 mg/kg (complexed to 25% albumin) or equal volumes of albumin. After a 1-hour recovery, pups were cooled (3 h, 30°C). Sensorimotor and pathology outcomes were initially evaluated on P14. In subsequent experiments, sensorimotor function was evaluated on P14, P21, and P28; histopathology was assessed on P28. At P14, left forepaw function scores (normal: 20/20) were near normal in DHA + hypothermia-treated animals (mean ± SD 19.7 ± 0.7 DHA + hypothermia vs. 12.7 ± 3.5 albumin + hypothermia, p < 0.0001) and brain damage was reduced (mean ± SD right hemisphere damage 38 ± 17% with DHA + hypothermia vs. 56 ± 15% with albumin + hypothermia, p = 0.003). Substantial improvements on three sensorimotor function measures and reduced brain damage were evident up to P28. Unlike post-HI treatment with DHA alone, treatment with DHA + hypothermia produced both sustained functional improvement and reduced brain damage after neonatal HI. Copyright © 2013 S. Karger AG, Basel.

Characterization of N-methyl-D-aspartate-evoked taurine release in the developing and adult mouse hippocampus.

PubMed

Saransaari, P; Oja, S S

2003-01-01

Taurine is an inhibitory amino acid acting as an osmoregulator and neuroromodulator in the brain, with neuroprotective properties. The ionotropic glutamate receptor agonist N-methyl-D-aspartate (NMDA) greatly potentiates taurine release from brain preparations in both normal and ischemic conditions, the effect being particularly marked in the developing hippocampus. We now characterized the regulation of NMDA-stimulated taurine release from hippocampal slices from adult (3-month-old) and developing (7-day-old) mouse using a superfusion system. The NMDA-stimulated taurine release was receptor-mediated in both adult and developing mouse hippocampus. In adults, only NO-generating compounds, sodium nitroprusside, S-nitroso-N-acetylpenicillamine and hydroxylamine reduced the release, as did also NO synthase inhibitors, 7-nitroindazole and nitroarginine, indicating that the release is mediated by the NO/cGMP pathway. On the other hand, the regulation of the NMDA-evoked taurine release proved to be somewhat complex in the immature hippocampus. It was not affected by the NOergic compounds, but enhanced by the protein kinase C activator 4 beta-phorbol 12-myristate 13-acetate and adenosine receptor A(1) agonists, N(6)-cyclohexyladenosine and R(-)N(6)-(2-phenylisopropyl)adenosine in a receptor-mediated manner. The activation of both ionotropic 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors and metabotropic glutamate group I receptors also enhanced the evoked release. The NMDA-receptor-stimulated taurine release could be a part of the neuroprotective properties of taurine, being important particularly under cell-damaging conditions in the developing hippocampus and hence preventing excitotoxicity.

Hand gestures support word learning in patients with hippocampal amnesia.

PubMed

Hilverman, Caitlin; Cook, Susan Wagner; Duff, Melissa C

2018-06-01

Co-speech hand gesture facilitates learning and memory, yet the cognitive and neural mechanisms supporting this remain unclear. One possibility is that motor information in gesture may engage procedural memory representations. Alternatively, iconic information from gesture may contribute to declarative memory representations mediated by the hippocampus. To investigate these alternatives, we examined gesture's effects on word learning in patients with hippocampal damage and declarative memory impairment, with intact procedural memory, and in healthy and in brain-damaged comparison groups. Participants learned novel label-object pairings while producing gesture, observing gesture, or observing without gesture. After a delay, recall and object identification were assessed. Unsurprisingly, amnesic patients were unable to recall the labels at test. However, they correctly identified objects at above chance levels, but only if they produced a gesture at encoding. Comparison groups performed well above chance at both recall and object identification regardless of gesture. These findings suggest that gesture production may support word learning by engaging nondeclarative (procedural) memory. © 2018 Wiley Periodicals, Inc.

Diet-gene interactions underlie metabolic individuality and influence brain development: implications for clinical practice derived from studies on choline metabolism.

PubMed

Zeisel, Steven H

2012-01-01

One of the underlying mechanisms for metabolic individuality is genetic variation. Single nucleotide polymorphisms (SNPs) in genes of metabolic pathways can create metabolic inefficiencies that alter the dietary requirement for, and responses to, nutrients. These SNPs can be detected using genetic profiling and the metabolic inefficiencies they cause can be detected using metabolomic profiling. Studies on the human dietary requirement for choline illustrate how useful these new approaches can be, as this requirement is influenced by SNPs in genes of choline and folate metabolism. In adults, these SNPs determine whether people develop fatty liver, liver damage and muscle damage when eating diets low in choline. Because choline is very important for fetal development, these SNPs may identify women who need to eat more choline during pregnancy. Some of the actions of choline are mediated by epigenetic mechanisms that permit 'retuning' of metabolic pathways during early life. Copyright © 2012 S. Karger AG, Basel.

CEP63 deficiency promotes p53-dependent microcephaly and reveals a role for the centrosome in meiotic recombination.

PubMed

Marjanović, Marko; Sánchez-Huertas, Carlos; Terré, Berta; Gómez, Rocío; Scheel, Jan Frederik; Pacheco, Sarai; Knobel, Philip A; Martínez-Marchal, Ana; Aivio, Suvi; Palenzuela, Lluís; Wolfrum, Uwe; McKinnon, Peter J; Suja, José A; Roig, Ignasi; Costanzo, Vincenzo; Lüders, Jens; Stracker, Travis H

2015-07-09

CEP63 is a centrosomal protein that facilitates centriole duplication and is regulated by the DNA damage response. Mutations in CEP63 cause Seckel syndrome, a human disease characterized by microcephaly and dwarfism. Here we demonstrate that Cep63-deficient mice recapitulate Seckel syndrome pathology. The attrition of neural progenitor cells involves p53-dependent cell death, and brain size is rescued by the deletion of p53. Cell death is not the result of an aberrant DNA damage response but is triggered by centrosome-based mitotic errors. In addition, Cep63 loss severely impairs meiotic recombination, leading to profound male infertility. Cep63-deficient spermatocytes display numerical and structural centrosome aberrations, chromosome entanglements and defective telomere clustering, suggesting that a reduction in centrosome-mediated chromosome movements underlies recombination failure. Our results provide novel insight into the molecular pathology of microcephaly and establish a role for the centrosome in meiotic recombination.

CEP63 deficiency promotes p53-dependent microcephaly and reveals a role for the centrosome in meiotic recombination

PubMed Central

Marjanović, Marko; Sánchez-Huertas, Carlos; Terré, Berta; Gómez, Rocío; Scheel, Jan Frederik; Pacheco, Sarai; Knobel, Philip A.; Martínez-Marchal, Ana; Aivio, Suvi; Palenzuela, Lluís; Wolfrum, Uwe; McKinnon, Peter J.; Suja, José A.; Roig, Ignasi; Costanzo, Vincenzo; Lüders, Jens; Stracker, Travis H.

2015-01-01

CEP63 is a centrosomal protein that facilitates centriole duplication and is regulated by the DNA damage response. Mutations in CEP63 cause Seckel syndrome, a human disease characterized by microcephaly and dwarfism. Here we demonstrate that Cep63 deficient mice recapitulate Seckel syndrome pathology. The attrition of neural progenitor cells involves p53-dependent cell death and brain size is rescued by the deletion of p53. Cell death is not the result of an aberrant DNA damage response but is triggered by centrosome-based mitotic errors. In addition, Cep63 loss severely impairs meiotic recombination, leading to profound male infertility. Cep63 deficient spermatocytes display numerical and structural centrosome aberrations, chromosome entanglements and defective telomere clustering, suggesting that a reduction in centrosome-mediated chromosome movements underlies recombination failure. Our results provide novel insight into the molecular pathology of microcephaly and establish a role for the centrosome in meiotic recombination. PMID:26158450

Methamphetamine- and Trauma-Induced Brain Injuries: Comparative Cellular and Molecular Neurobiological Substrates

PubMed Central

Gold, Mark S.; Kobeissy, Firas H.; Wang, Kevin K.W.; Merlo, Lisa J.; Bruijnzeel, Adriaan W.; Krasnova, Irina N.; Cadet, Jean Lud

2009-01-01

The use of methamphetamine (METH) is a growing public health problem because its abuse is associated with long-term biochemical and structural effects on the human brain. Neurodegeneration is often observed in humans as a result of mechanical injuries (e.g. traumatic brain injury, TBI) and ischemic damage (strokes). In this review, we discuss recent findings documenting the fact that the psychostimulant drug, METH, can cause neuronal damage in several brain regions. The accumulated evidence from our laboratories and those of other investigators indicates that acute administration of METH leads to activation of calpain and caspase proteolytic systems. These systems are also involved in causing neuronal damage secondary to traumatic and ischemic brain injuries. Protease activation is accompanied by proteolysis of endogenous neuronal structural proteins (αII-spectrin and MAP-tau protein) evidenced by the appearance of their breakdown products after these injuries. When taken together, these observations suggest that METH exposure, like TBI, can cause substantial damage to the brain by causing both apoptotic and necrotic cell death in the brains of METH addicts who use large doses of the drug during their lifetimes. Finally, because METH abuse is accompanied by functional and structural changes in the brain similar to those in TBI, METH addicts might experience greater benefit if their treatment involved greater emphasis on rehabilitation in conjunction with the use of potential neuroprotective pharmacological agents such as calpain and caspase inhibitors similar to those used in TBI. PMID:19345341

Subacute Fluoxetine Reduces Signs of Hippocampal Damage Induced by a Single Convulsant Dose of 4-Aminopyridine in Rats.

PubMed

Shiha, Ahmed A; de la Rosa, Rubén Fernández; Delgado, Mercedes; Pozo, Miguel A; García-García, Luis

2017-01-01

Epilepsy is a central disorder associated with neuronal damage and brain hypometabolism. It has been reported that antidepressant drugs show anticonvulsant and neuroprotective effects in different animal models of seizures and epilepsy. The purpose of this study was to investigate the eventual short-term brain impairment induced by a single low convulsant dose of the potassium channel blocker 4-aminopyridine (4-AP) and the eventual neuroprotective effects exerted by fluoxetine, a prototypical selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI). In vivo 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) and several histological assessments were carried out in adult male rats after i.p. administration of 3 mg/kg 4-AP for evaluating eventual brain metabolism impairment and signs of hippocampal damage. We also evaluated the effects of a short-term fluoxetine treatment (10 mg/kg, i.p. for 7 days) in this seizure model. [18F]FDG PET analysis revealed no changes in the regional brain metabolism on day 3 after 4-AP injection. The histological assessments revealed signs of damage in the hippocampus, a brain area usually affected by seizures. Thus, reactive gliosis and a significant increase in the expression of caspase-9 were found in the aforementioned brain area. By contrast, we observed no signs of neurodegeneration or neuronal death. Regarding the effects of fluoxetine, this SSRI showed beneficial neurologic effects, since it significantly increased the seizure latency time and reduced the abovementioned 4-AP-induced hippocampal damage markers. Overall, our results point to SSRIs and eventually endogenous 5-HT as neuroprotective agents against convulsant-induced hippocampal damage. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Markers of oxidative damage to lipids, nucleic acids and proteins and antioxidant enzymes activities in Alzheimer's disease brain: A meta-analysis in human pathological specimens.

PubMed

Zabel, Matthew; Nackenoff, Alex; Kirsch, Wolff M; Harrison, Fiona E; Perry, George; Schrag, Matthew

2018-02-01

Oxidative stress and decreased cellular responsiveness to oxidative stress are thought to influence brain aging and Alzheimer's disease, but the specific patterns of oxidative damage and the underlying mechanism leading to this damage are not definitively known. The objective of this study was to define the pattern of changes in oxidative-stress related markers by brain region in human Alzheimer's disease and mild cognitive impairment brain tissue. Observational case-control studies were identified from systematic queries of PubMed, ISI Web of Science and Scopus databases and studies were evaluated with appropriate quality measures. The data was used to construct a region-by-region meta-analysis of malondialdehyde, 4-hydroxynonenal, protein carbonylation, 8-hydroxyguanine levels and superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase activities. We also evaluated ascorbic acid, tocopherol, uric acid and glutathione levels. The analysis was complicated in several cases by publication bias and/or outlier data. We found that malondialdehyde levels were slightly increased in the temporal and occipital lobes and hippocampus, but this analysis was significantly impacted by publication bias. 4-hydroxynonenal levels were unchanged in every brain region. There was no change in 8-hydroxyguanine level in any brain region and protein carbonylation levels were unchanged except for a slight increase in the occipital lobe. Superoxide dismutase, glutathione peroxidase and reductase and catalase activities were not decreased in any brain region. There was limited data reporting non-enzymatic antioxidant levels in Alzheimer's disease brain, although glutathione and tocopherol levels appear to be unchanged. Minimal quantitative data is available from brain tissue from patients with mild cognitive impairment. While there is modest evidence supporting minor regional changes in markers of oxidative damage, this analysis fails to identify a consistent pattern of pro-oxidative changes and accumulation of oxidative damage in bulk tissue analysis in the setting of Alzheimer's disease, as has been widely reported. Copyright © 2017 Elsevier Inc. All rights reserved.

Linking loss of sodium-iodide symporter expression to DNA damage

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

Lyckesvärd, Madeleine Nordén; Department of Medical Chemistry and Cell Biology, University of Gothenburg, Göteborg; Kapoor, Nirmal

Radiotherapy of thyroid cancer with I-131 is abrogated by inherent loss of radioiodine uptake due to loss of sodium iodide symporter (NIS) expression in poorly differentiated tumor cells. It is also known that ionizing radiation per se down-regulates NIS (the stunning effect), but the mechanism is unknown. Here we investigated whether loss of NIS-mediated iodide transport may be elicited by DNA damage. Calicheamicin, a fungal toxin that specifically cleaves double-stranded DNA, induced a full scale DNA damage response mediated by the ataxia-telangiectasia mutated (ATM) kinase in quiescent normal thyrocytes. At sublethal concentrations (<1 nM) calicheamicin blocked NIS mRNA expression andmore » transepithelial iodide transport as stimulated by thyrotropin; loss of function occurred at a much faster rate than after I-131 irradiation. KU-55933, a selective ATM kinase inhibitor, partly rescued NIS expression and iodide transport in DNA-damaged cells. Prolonged ATM inhibition in healthy cells also repressed NIS-mediated iodide transport. ATM-dependent loss of iodide transport was counteracted by IGF-1. Together, these findings indicate that NIS, the major iodide transporter of the thyroid gland, is susceptible to DNA damage involving ATM-mediated mechanisms. This uncovers novel means of poor radioiodine uptake in thyroid cells subjected to extrinsic or intrinsic genotoxic stress. - Highlights: • DNA damage inhibits polarized iodide transport in normal thyroid cells. • Down-regulation of NIS expression is mediated by activation of the ATM kinase. • Long-term ATM inhibition also represses NIS-mediated iodide transport. • IGF-1 rescues NIS expression and iodide transport in DNA-damaged cells.« less

Investigating emotion in moral cognition: a review of evidence from functional neuroimaging and neuropsychology.

PubMed

Young, Liane; Koenigs, Michael

2007-01-01

Human moral decision-making has long been a topic of philosophical debate, and, more recently, a topic for empirical investigation. Central to this investigation is the extent to which emotional processes underlie our decisions about moral right and wrong. Neuroscience offers a unique perspective on this question by addressing whether brain regions associated with emotional processing are involved in moral cognition. We conduct a narrative review of neuroscientific studies focused on the role of emotion in morality. Specifically, we describe evidence implicating the ventromedial prefrontal cortex (VMPC), a brain region known to be important for emotional processing. Functional imaging studies demonstrate VMPC activation during tasks probing moral cognition. Studies of clinical populations, including patients with VMPC damage, reveal an association between impairments in emotional processing and impairments in moral judgement and behaviour. Considered together, these studies indicate that not only are emotions engaged during moral cognition, but that emotions, particularly those mediated by VMPC, are in fact critical for human morality.

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.

Behavioral and genetic effects promoted by sleep deprivation in rats submitted to pilocarpine-induced status epilepticus.

PubMed

Matos, Gabriela; Ribeiro, Daniel A; Alvarenga, Tathiana A; Hirotsu, Camila; Scorza, Fulvio A; Le Sueur-Maluf, Luciana; Noguti, Juliana; Cavalheiro, Esper A; Tufik, Sergio; Andersen, Monica L

2012-05-02

The interaction between sleep deprivation and epilepsy has been well described in electrophysiological studies, but the mechanisms underlying this association remain unclear. The present study evaluated the effects of sleep deprivation on locomotor activity and genetic damage in the brains of rats treated with saline or pilocarpine-induced status epilepticus (SE). After 50 days of pilocarpine or saline treatment, both groups were assigned randomly to total sleep deprivation (TSD) for 6 h, paradoxical sleep deprivation (PSD) for 24 h, or be kept in their home cages. Locomotor activity was assessed with the open field test followed by resection of brain for quantification of genetic damage by the single cell gel electrophoresis (comet) assay. Status epilepticus induced significant hyperactivity in the open field test and caused genetic damage in the brain. Sleep deprivation procedures (TSD and PSD) did not affect locomotor activity in epileptic or healthy rats, but resulted in significant DNA damage in brain cells. Although PSD had this effect in both vehicle and epileptic groups, TSD caused DNA damage only in epileptic rats. In conclusion, our results revealed that, despite a lack of behavioral effects of sleep deprivation, TSD and PSD induced genetic damage in rats submitted to pilocarpine-induced SE. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Are endogenous sex hormones related to DNA damage in paradoxically sleep-deprived female rats?

PubMed

Andersen, Monica L; Ribeiro, Daniel A; Alvarenga, Tathiana A; Silva, Andressa; Araujo, Paula; Zager, Adriano; Tenorio, Neuli M; Tufik, Sergio

2010-02-01

The aim of this investigation was to evaluate overall DNA damage induced by experimental paradoxical sleep deprivation (PSD) in estrous-cycling and ovariectomized female rats to examine possible hormonal involvement during DNA damage. Intact rats in different phases of the estrous cycle (proestrus, estrus, and diestrus) or ovariectomized female Wistar rats were subjected to PSD by the single platform technique for 96 h or were maintained for the equivalent period as controls in home-cages. After this period, peripheral blood and tissues (brain, liver, and heart) were collected to evaluate genetic damage using the single cell gel (comet) assay. The results showed that PSD caused extensive genotoxic effects in brain cells, as evident by increased DNA migration rates in rats exposed to PSD for 96 h when compared to negative control. This was observed for all phases of the estrous cycle indistinctly. In ovariectomized rats, PSD also led to DNA damage in brain cells. No significant statistically differences were detected in peripheral blood, the liver or heart for all groups analyzed. In conclusion, our data are consistent with the notion that genetic damage in the form of DNA breakage in brain cells induced by sleep deprivation overrides the effects related to endogenous female sex hormones. Copyright 2009 Elsevier Inc. All rights reserved.

Candida albicans Pathogenesis: Fitting within the Host-Microbe Damage Response Framework

PubMed Central

Kong, Eric F.; Tsui, Christina; Nguyen, M. Hong; Clancy, Cornelius J.; Fidel, Paul L.; Noverr, Mairi

2016-01-01

Historically, the nature and extent of host damage by a microbe were considered highly dependent on virulence attributes of the microbe. However, it has become clear that disease is a complex outcome which can arise because of pathogen-mediated damage, host-mediated damage, or both, with active participation from the host microbiota. This awareness led to the formulation of the damage response framework (DRF), a revolutionary concept that defined microbial virulence as a function of host immunity. The DRF outlines six classifications of host damage outcomes based on the microbe and the strength of the immune response. In this review, we revisit this concept from the perspective of Candida albicans, a microbial pathogen uniquely adapted to its human host. This fungus commonly colonizes various anatomical sites without causing notable damage. However, depending on environmental conditions, a diverse array of diseases may occur, ranging from mucosal to invasive systemic infections resulting in microbe-mediated and/or host-mediated damage. Remarkably, C. albicans infections can fit into all six DRF classifications, depending on the anatomical site and associated host immune response. Here, we highlight some of these diverse and site-specific diseases and how they fit the DRF classifications, and we describe the animal models available to uncover pathogenic mechanisms and related host immune responses. PMID:27430274

AUTEN-67 (Autophagy Enhancer-67) Hampers the Progression of Neurodegenerative Symptoms in a Drosophila model of Huntington's Disease.

PubMed

Billes, Viktor; Kovács, Tibor; Hotzi, Bernadette; Manzéger, Anna; Tagscherer, Kinga; Komlós, Marcell; Tarnóci, Anna; Pádár, Zsolt; Erdős, Attila; Bjelik, Annamaria; Legradi, Adam; Gulya, Károly; Gulyás, Balázs; Vellai, Tibor

2016-05-07

Autophagy, a lysosome-mediated self-degradation process of eukaryotic cells, serves as a main route for the elimination of cellular damage [1-3]. Such damages include aggregated, oxidized or misfolded proteins whose accumulation can cause various neurodegenerative pathologies, including Huntington's disease (HD). Here we examined whether enhanced autophagic activity can alleviate neurophatological features in a Drosophila model of HD (the transgenic animals express a human mutant Huntingtin protein with a long polyglutamine repeat, 128Q). We have recently identified an autophagy-enhancing small molecule, AUTEN-67 (autophagy enhancer 67), with potent neuroprotective effects [4]. AUTEN-67 was applied to induce autophagic activity in the HD model used in this study. We showed that AUTEN-67 treatment interferes with the progressive accumulation of ubiquitinated proteins in the brain of Drosophila transgenic for the pathological 128Q form of human Huntingtin protein. The compound significantly improved the climbing ability and moderately extended the mean life span of these flies. Furthermore, brain tissue samples from human patients diagnosed for HD displayed increased levels of the autophagy substrate SQSTM1/p62 protein, as compared with controls. These results imply that AUTEN-67 impedes the progression of neurodegenerative symptoms characterizing HD, and that autophagy is a promising therapeutic target for treating this pathology. In humans, AUTEN-67 may have the potential to delay the onset and decrease the severity of HD.

Endogenous IL-6 of mesenchymal stem cell improves behavioral outcome of hypoxic-ischemic brain damage neonatal rats by supressing apoptosis in astrocyte.

PubMed

Gu, Yan; He, Mulan; Zhou, Xiaoqin; Liu, Jinngjing; Hou, Nali; Bin, Tan; Zhang, Yun; Li, Tingyu; Chen, Jie

2016-01-14

Mesenchymal stem cell (MSC) transplantation reduces the neurological impairment caused by hypoxic-ischemic brain damage (HIBD) via immunomodulation. In the current study, we found that MSC transplantation improved learning and memory function and enhanced long-term potentiation in neonatal rats subjected to HIBD and the amount of IL-6 released from MSCs was far greater than that of other cytokines. However, the neuroprotective effect of MSCs infected with siIL-6-transduced recombinant lentivirus (siIL-6 MSCs) was significantly weakened in the behavioural tests and electrophysiological analysis. Meanwhile, the hippocampal IL-6 levels were decreased following siIL-6 MSC transplantation. In vitro, the levels of IL-6 release and the levels of IL-6R and STAT3 expression were increased in both primary neurons and astrocytes subjected to oxygen and glucose deprivation (OGD) following MSCs co-culture. The anti-apoptotic protein Bcl-2 was upregulated and the pro-apoptotic protein Bax was downregulated in OGD-injured astrocytes co-cultured with MSCs. However, the siIL-6 MSCs suppressed ratio of Bcl-2/Bax in the injured astrocytes and induced apoptosis number of the injured astrocytes. Taken together, these data suggest that the neuroprotective effect of MSC transplantation in neonatal HIBD rats is partly mediated by IL-6 to enhance anti-apoptosis of injured astrocytes via the IL-6/STAT3 signaling pathway.

The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice

PubMed Central

Liu, Mingfu; Spellberg, Brad; Phan, Quynh T.; Fu, Yue; Fu, Yong; Lee, Amy S.; Edwards, John E.; Filler, Scott G.; Ibrahim, Ashraf S.

2010-01-01

Mucormycosis is a fungal infection of the sinuses, brain, or lungs that causes a mortality rate of at least 50% despite first-line therapy. Because angioinvasion is a hallmark of mucormycosis infections, we sought to define the endothelial cell receptor(s) for fungi of the order Mucorales (the fungi that cause mucormycosis). Furthermore, since patients with elevated available serum iron, including those with diabetic ketoacidosis (DKA), are uniquely susceptible to mucormycosis, we sought to define the role of iron and glucose in regulating the expression of such a receptor. Here, we have identified glucose-regulated protein 78 (GRP78) as what we believe to be a novel host receptor that mediates invasion and damage of human endothelial cells by Rhizopus oryzae, the most common etiologic species of Mucorales, but not Candida albicans or Aspergillus fumigatus. Elevated concentrations of glucose and iron, consistent with those seen during DKA, enhanced GRP78 expression and the resulting R. oryzae invasion and damage of endothelial cells in a receptor-dependent manner. Mice with DKA, which have enhanced susceptibility to mucormycosis, exhibited increased expression of GRP78 in sinus, lungs, and brain compared with normal mice. Finally, GRP78-specific immune serum protected mice with DKA from mucormycosis. These results suggest a unique susceptibility of patients with DKA to mucormycosis and provide a foundation for the development of new therapeutic interventions for these deadly infections. PMID:20484814

Concepts and strategies for clinical management of blast-induced traumatic brain injury and posttraumatic stress disorder.

PubMed

Chen, Yun; Huang, Wei; Constantini, Shlomi

2013-01-01

After exposure of the human body to blast, kinetic energy of the blast shock waves might be transferred into hydraulic energy in the cardiovascular system to cause a rapid physical movement or displacement of blood (a volumetric blood surge). The volumetric blood surge moves through blood vessels from the high-pressure body cavity to the low-pressure cranial cavity, causing damage to tiny cerebral blood vessels and the blood-brain barrier (BBB). Large-scale cerebrovascular insults and BBB damage that occur globally throughout the brain may be the main causes of non-impact, blast-induced brain injuries, including the spectrum of traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD). The volumetric blood surge may be a major contributor not only to blast-induced brain injuries resulting from physical trauma, but may also be the trigger to psychiatric disorders resulting from emotional and psychological trauma. Clinical imaging technologies, which are able to detect tiny cerebrovascular insults, changes in blood flow, and cerebral edema, may help diagnose both TBI and PTSD in the victims exposed to blasts. Potentially, prompt medical treatment aiming at prevention of secondary neuronal damage may slow down or even block the cascade of events that lead to progressive neuronal damage and subsequent long-term neurological and psychiatric impairment.

Performance of brain-damaged and non-brain-damaged institutionalized children on the Minnesota Percepto-Diagnostic Test.

PubMed

Holland, J M; Fuller, G B; Barth, C E

1982-01-01

Examined the performance of 64 children on the Minnesota Percepto-Diagnostic test (MPD) who were diagnosed as either Brain-Damaged (BD) or emotionally impaired Non-Brain-Damaged (NBD). There were 31 children in the NBD group and 33 in the BD group. The MPD T-score and Actuarial Table significantly differentiated between the two groups. Seventy-four percent of the combined BD-NBD groups were identified correctly. Additional discriminant analysis on this sample yielded combined BD-NBD groups classification rates that ranged from 77% with the MPD variables Separation of Circle-Diamond (SPCD), Distortion of Circle-Diamond (DCD) and Distortion of Dots (DD) to 83% with the WISC-R three IQ scores plus the MPD T-score, SPCD and DD. The MPD T-score and Actuarial Table (MPD Two-Step Diagnosis) appeared to generalize to other populations more readily than discriminant analysis formulae, which tend to be sensitive to the samples from which they are derived.

Car Accident Reconstruction and Head Injury Correlation

NASA Astrophysics Data System (ADS)

Chawla, A.; Grover, V.; Mukherjee, S.; Hassan, A. M.

2013-04-01

Estimation of brain damage remains an elusive issue and controlled tests leading to brain damage cannot be carried out on volunteers. This study reconstructs real-world car accidents to estimate the kinematics of the head impact. This data is to be used to estimate the head injury measures through computer simulations and then correlate reported skull as well as brain damage to impact measures; whence validating the head FE model (Willinger, IJCrash 8:605-617, 2003). In this study, two crash cases were reconstructed. Injury correlation was successful in one of these cases in that the injuries to the brain of one of the car drivers could be correlated in terms of type, location and severity when compared with the tolerance limits of relevant injury parameters (Willinger, IJCrash 8:605-617, 2003).

Inflammatory cytokines and neurological and neurocognitive alterations in the course of schizophrenia

PubMed Central

Fineberg, Anna M.; Ellman, Lauren M.

2013-01-01

A growing body of evidence suggests that immune alterations, especially those related to inflammation, are associated with increased risk of schizophrenia and schizophrenia-related brain alterations. Much of this work has focused on the prenatal period, since infections during pregnancy have been repeatedly (albeit inconsistently) linked to risk of schizophrenia. Given that most infections do not cross the placenta, cytokines associated with inflammation (proinflammatory cytokines) have been targeted as potential mediators of the damaging effects of infection on the fetal brain in prenatal studies. Moreover, additional evidence from both human and animal studies suggests links between increased levels of proinflammatory cytokines, immune-related genes, and schizophrenia, as well as brain alterations associated with the disorder. Additional support for the role of altered immune factors in the etiology of schizophrenia comes from neuroimaging studies, which have linked proinflammatory cytokine gene polymorphisms with some of the structural and functional abnormalities repeatedly found in schizophrenia. These findings are reviewed and discussed using a life course perspective, examining the contribution of inflammation from the fetal period to disorder presentation. Unexplored areas and future directions, such as the interplay between inflammation, genes, and individual-level environmental factors (e.g., stress, sleep, and nutrition), are also discussed. PMID:23414821

Spatio-Temporal Features of Visual Exploration in Unilaterally Brain-Damaged Subjects with or without Neglect: Results from a Touchscreen Test

PubMed Central

Rabuffetti, Marco; Farina, Elisabetta; Alberoni, Margherita; Pellegatta, Daniele; Appollonio, Ildebrando; Affanni, Paola; Forni, Marco; Ferrarin, Maurizio

2012-01-01

Cognitive assessment in a clinical setting is generally made by pencil-and-paper tests, while computer-based tests enable the measurement and the extraction of additional performance indexes. Previous studies have demonstrated that in a research context exploration deficits occur also in patients without evidence of unilateral neglect at pencil-and-paper tests. The objective of this study is to apply a touchscreen-based cancellation test, feasible also in a clinical context, to large groups of control subjects and unilaterally brain-damaged patients, with and without unilateral spatial neglect (USN), in order to assess disturbances of the exploratory skills. A computerized cancellation test on a touchscreen interface was used for assessing the performance of 119 neurologically unimpaired control subjects and 193 patients with unilateral right or left hemispheric brain damage, either with or without USN. A set of performance indexes were defined including Latency, Proximity, Crossings and their spatial lateral gradients, and Preferred Search Direction. Classic outcome scores were computed as well. Results show statistically significant differences among groups (assumed p<0.05). Right-brain-damaged patients with USN were significantly slower (median latency per detected item was 1.18 s) and less efficient (about 13 search-path crossings) in the search than controls (median latency 0.64 s; about 3 crossings). Their preferred search direction (53.6% downward, 36.7% leftward) was different from the one in control patients (88.2% downward, 2.1% leftward). Right-brain-damaged patients without USN showed a significantly abnormal behavior (median latency 0.84 s, about 5 crossings, 83.3% downward and 9.1% leftward direction) situated half way between controls and right-brain-damaged patients with USN. Left-brain-damaged patients without USN were significantly slower and less efficient than controls (latency 1.19 s, about 7 crossings), preserving a normal preferred search direction (93.7% downward). Therefore, the proposed touchscreen-based assessment had evidenced disorders in spatial exploration also in patients without clinically diagnosed USN. PMID:22347489

C-type natriuretic peptide functions as an innate neuroprotectant in neonatal hypoxic-ischemic brain injury in mouse via natriuretic peptide receptor 2.

PubMed

Ma, Qingyi; Zhang, Lubo

2018-06-01

Neonatal hypoxia-ischemia (HI) is the most common cause of brain injury in neonates, which leads to high neonatal mortality and severe neurological morbidity in later life (Vannucci, 2000; Volpe, 2001). Yet the molecular mechanisms of neuronal death and brain damage induced by neonatal HI remain largely elusive. Herein, using both in vivo and in vitro models, we determine an endogenous neuroprotectant role of c-type natriuretic peptide (CNP) in preserving neuronal survival after HI brain injury in mouse pups. Postnatal day 7 (P7) mouse pups with CNP deficiency (Nppc lbab/lbab ) exhibit increased brain infarct size and worsened long-term locomotor function after neonatal HI compared with wildtype control (Nppc +/+ ). In isolated primary cortical neurons, recombinant CNP dose-dependently protects primary neurons from oxygen-glucose deprivation (OGD) insult. This neuroprotective effect appears to be mediated through its cognate natriuretic peptide receptor 2 (NPR2), in that antagonization of NPR2, but not NPR3, exacerbates neuronal death and counteracts the protective effect of CNP on primary neurons exposed to OGD insult. Immunoblot and confocal microscopy demonstrate the abundant expression of NPR2 in neurons of the neonatal brain and in isolated primary cortical neurons as well. Moreover, similar to CNP deficiency, administration of NPR2 antagonist P19 via intracerebroventricular injection prior to HI results in exacerbated neuronal death and brain injury after HI. Altogether, the present study indicates that CNP and its cognate receptor NPR2 mainly expressed in neurons represent an innate neuroprotective mechanism in neonatal HI brain injury. Copyright © 2018 Elsevier Inc. All rights reserved.

Vulnerability of the developing brain to hypoxic-ischemic damage: contribution of the cerebral vasculature to injury and repair?

PubMed Central

Baburamani, Ana A.; Ek, C. Joakim; Walker, David W.; Castillo-Melendez, Margie

2012-01-01

As clinicians attempt to understand the underlying reasons for the vulnerability of different regions of the developing brain to injury, it is apparent that little is known as to how hypoxia-ischemia may affect the cerebrovasculature in the developing infant. Most of the research investigating the pathogenesis of perinatal brain injury following hypoxia-ischemia has focused on excitotoxicity, oxidative stress and an inflammatory response, with the response of the developing cerebrovasculature receiving less attention. This is surprising as the presentation of devastating and permanent injury such as germinal matrix-intraventricular haemorrhage (GM-IVH) and perinatal stroke are of vascular origin, and the origin of periventricular leukomalacia (PVL) may also arise from poor perfusion of the white matter. This highlights that cerebrovasculature injury following hypoxia could primarily be responsible for the injury seen in the brain of many infants diagnosed with hypoxic-ischemic encephalopathy (HIE). Interestingly the highly dynamic nature of the cerebral blood vessels in the fetus, and the fluctuations of cerebral blood flow and metabolic demand that occur following hypoxia suggest that the response of blood vessels could explain both regional protection and vulnerability in the developing brain. However, research into how blood vessels respond following hypoxia-ischemia have mostly been conducted in adult models of ischemia or stroke, further highlighting the need to investigate how the developing cerebrovasculature responds and the possible contribution to perinatal brain injury following hypoxia. This review discusses the current concepts on the pathogenesis of perinatal brain injury, the development of the fetal cerebrovasculature and the blood brain barrier (BBB), and key mediators involved with the response of cerebral blood vessels to hypoxia. PMID:23162470

Identification of elevated urea as a severe, ubiquitous metabolic defect in the brain of patients with Huntington's disease.

PubMed

Patassini, Stefano; Begley, Paul; Reid, Suzanne J; Xu, Jingshu; Church, Stephanie J; Curtis, Maurice; Dragunow, Mike; Waldvogel, Henry J; Unwin, Richard D; Snell, Russell G; Faull, Richard L M; Cooper, Garth J S

Huntington's disease (HD) is a neurodegenerative disorder wherein the aetiological defect is a mutation in the Huntington's gene (HTT), which alters the structure of the huntingtin protein through the lengthening of a polyglutamine tract and initiates a cascade that ultimately leads to dementia and premature death. However, neurodegeneration typically manifests in HD only in middle age, and processes linking the causative mutation to brain disease are poorly understood. Here, our objective was to elucidate further the processes that cause neurodegeneration in HD, by measuring levels of metabolites in brain regions known to undergo varying degrees of damage. We applied gas-chromatography/mass spectrometry-based metabolomics in a case-control study of eleven brain regions in short post-mortem-delay human tissue from nine well-characterized HD patients and nine controls. Unexpectedly, a single major abnormality was evident in all eleven brain regions studied across the forebrain, midbrain and hindbrain, namely marked elevation of urea, a metabolite formed in the urea cycle by arginase-mediated cleavage of arginine. Urea cycle activity localizes primarily in the liver, where it functions to incorporate protein-derived amine-nitrogen into urea for recycling or urinary excretion. It also occurs in other cell-types, but systemic over-production of urea is not known in HD. These findings are consistent with impaired local urea regulation in brain, by up-regulation of synthesis and/or defective clearance. We hypothesize that defective brain urea metabolism could play a substantive role in the pathogenesis of neurodegeneration, perhaps via defects in osmoregulation or nitrogen metabolism. Brain urea metabolism is therefore a target for generating novel monitoring/imaging strategies and/or therapeutic interventions aimed at ameliorating the impact of HD in patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Judo as a possible cause of anoxic brain damage. A case report.

PubMed

Owens, R G; Ghadiali, E J

1991-12-01

The rules of judo provide for strangulation techniques in which the blood supply to the brain is blocked by pressure on the carotid arteries; such techniques produce anoxia and possible unconsciousness if the victim fails to submit. A case is presented of a patient with signs of anoxic brain damage, with psychometric investigation showing memory disturbance consistent with a left temporal lobe lesion. This patient had been frequently strangled during his career as a judo player; it is suggested that such frequent strangulation was the cause of the damage. Such an observation indicates the need for caution in the use of such techniques.

In vivo evaluation of needle force and friction stress during insertion at varying insertion speed into the brain.

PubMed

Casanova, Fernando; Carney, Paul R; Sarntinoranont, Malisa

2014-11-30

Convection enhanced delivery (CED) infuses drugs directly into brain tissue. Needle insertion is required and results in tissue damage which can promote flowback along the needle track and improper targeting. The goal of this study was to evaluate friction stress (calculated from needle insertion force) as a measure of tissue contact and damage during needle insertion for varying insertion speeds. Forces and surface dimpling during needle insertion were measured in rat brain in vivo. Needle retraction forces were used to calculate friction stresses. These measures were compared to track damage from a previous study. Differences between brain tissues and soft hydrogels were evaluated for varying insertion speeds: 0.2, 2, and 10mm/s. In brain tissue, average insertion force and surface dimpling increased with increasing insertion speed. Average friction stress along the needle-tissue interface decreased with insertion speed (from 0.58 ± 0.27 to 0.16 ± 0.08 kPa). Friction stress varied between brain regions: cortex (0.227 ± 0.27 kPa), external capsule (0.222 ± 0.19 kPa), and CPu (0.383 ± 0.30 kPa). Hydrogels exhibited opposite trends for dimpling and friction stress with insertion speed. Previously, increasing needle damage with insertion speed has been measured with histological methods. Friction stress appears to decrease with increasing tissue damage and decreasing tissue contact, providing the potential for in vivo and real time evaluation along the needle track. Force derived friction stress decreased with increasing insertion speed and was smaller within white matter regions. Hydrogels exhibited opposite trends to brain tissue. Copyright © 2014 Elsevier B.V. All rights reserved.

Changes in motor function, cognition, and emotion-related behavior after right hemispheric intracerebral hemorrhage in various brain regions of mouse.

PubMed

Zhu, Wei; Gao, Yufeng; Wan, Jieru; Lan, Xi; Han, Xiaoning; Zhu, Shanshan; Zang, Weidong; Chen, Xuemei; Ziai, Wendy; Hanley, Daniel F; Russo, Scott J; Jorge, Ricardo E; Wang, Jian

2018-03-01

Intracerebral hemorrhage (ICH) is a detrimental type of stroke. Mouse models of ICH, induced by collagenase or blood infusion, commonly target striatum, but not other brain sites such as ventricular system, cortex, and hippocampus. Few studies have systemically investigated brain damage and neurobehavioral deficits that develop in animal models of ICH in these areas of the right hemisphere. Therefore, we evaluated the brain damage and neurobehavioral dysfunction associated with right hemispheric ICH in ventricle, cortex, hippocampus, and striatum. The ICH model was induced by autologous whole blood or collagenase VII-S (0.075 units in 0.5 µl saline) injection. At different time points after ICH induction, mice were assessed for brain tissue damage and neurobehavioral deficits. Sham control mice were used for comparison. We found that ICH location influenced features of brain damage, microglia/macrophage activation, and behavioral deficits. Furthermore, the 24-point neurologic deficit scoring system was most sensitive for evaluating locomotor abnormalities in all four models, especially on days 1, 3, and 7 post-ICH. The wire-hanging test was useful for evaluating locomotor abnormalities in models of striatal, intraventricular, and cortical ICH. The cylinder test identified locomotor abnormalities only in the striatal ICH model. The novel object recognition test was effective for evaluating recognition memory dysfunction in all models except for striatal ICH. The tail suspension test, forced swim test, and sucrose preference test were effective for evaluating emotional abnormality in all four models but did not correlate with severity of brain damage. These results will help to inform future preclinical studies of ICH outcomes. Copyright © 2018 Elsevier Inc. All rights reserved.

Brain Malformations

MedlinePlus

Most brain malformations begin long before a baby is born. Something damages the developing nervous system or causes it ... medicines, infections, or radiation during pregnancy interferes with brain development. Parts of the brain may be missing, ...

Coping with brain damage

NASA Technical Reports Server (NTRS)

Waring, W.

1974-01-01

Two neurological disorders, cerebral palsy, and traumatic brain damage as from an accident, are considered. The discussion covers the incidence of disabilities, their characteristics, and what is now being done to deal with them, particularly in reference to areas in which the capabilities of the engineer can be effectively applied.

Brain hemorrhage after electrical burn injury: Case report and probable mechanism.

PubMed

Axayacalt, Gutierrez Aceves Guillermo; Alejandro, Ceja Espinosa; Marcos, Rios Alanis; Inocencio, Ruiz Flores Milton; Alfredo, Herrera Gonzalez Jose

2016-01-01

High-voltage electric injury may induce lesion in different organs. In addition to the local tissue damage, electrical injuries may lead to neurological deficits, musculoskeletal damage, and cardiovascular injury. Severe vascular damage may occur making the blood vessels involved prone to thrombosis and spontaneous rupture. Here, we present the case of a 39-year-old male who suffered an electrical burn with high tension wire causing intracranial bleeding. He presented with an electrical burn in the parietal area (entry zone) and the left forearm (exit zone). The head tomography scan revealed an intraparenchimatous bleeding in the left parietal area. In this case, the electric way was the scalp, cranial bone, blood vessels and brain, upper limb muscle, and skin. The damage was different according to the dielectric property in each tissue. The injury was in the scalp, cerebral blood vessel, skeletal muscle, and upper limb skin. The main damage was in brain's blood vessels because of the dielectric and geometric features that lead to bleeding, high temperature, and gas delivering. This is a report of a patient with an electric brain injury that can be useful to elucidate the behavior of the high voltage electrical current flow into the nervous system.

Blood glutamate scavenging as a novel neuroprotective treatment for paraoxon intoxication.

PubMed

Ruban, Angela; Mohar, Boaz; Jona, Ghil; Teichberg, Vivian I

2014-02-01

Organophosphate-induced brain damage is an irreversible neuronal injury, likely because there is no pharmacological treatment to prevent or block secondary damage processes. The presence of free glutamate (Glu) in the brain has a substantial role in the propagation and maintenance of organophosphate-induced seizures, thus contributing to the secondary brain damage. This report describes for the first time the ability of blood glutamate scavengers (BGS) oxaloacetic acid in combination with glutamate oxaloacetate transaminase to reduce the neuronal damage in an animal model of paraoxon (PO) intoxication. Our method causes a rapid decrease of blood Glu levels and creates a gradient that leads to the efflux of the excess brain Glu into the blood, thus reducing neurotoxicity. We demonstrated that BGS treatment significantly prevented the peripheral benzodiazepine receptor (PBR) density elevation, after PO exposure. Furthermore, we showed that BGS was able to rescue neurons in the piriform cortex of the treated rats. In conclusion, these results suggest that treatment with BGS has a neuroprotective effect in the PO intoxication. This is the first time that this approach is used in PO intoxication and it may be of high clinical significance for the future treatment of the secondary neurologic damage post organophosphates exposure.

Blood glutamate scavenging as a novel neuroprotective treatment for paraoxon intoxication

PubMed Central

Ruban, Angela; Mohar, Boaz; Jona, Ghil; Teichberg, Vivian I

2014-01-01

Organophosphate-induced brain damage is an irreversible neuronal injury, likely because there is no pharmacological treatment to prevent or block secondary damage processes. The presence of free glutamate (Glu) in the brain has a substantial role in the propagation and maintenance of organophosphate-induced seizures, thus contributing to the secondary brain damage. This report describes for the first time the ability of blood glutamate scavengers (BGS) oxaloacetic acid in combination with glutamate oxaloacetate transaminase to reduce the neuronal damage in an animal model of paraoxon (PO) intoxication. Our method causes a rapid decrease of blood Glu levels and creates a gradient that leads to the efflux of the excess brain Glu into the blood, thus reducing neurotoxicity. We demonstrated that BGS treatment significantly prevented the peripheral benzodiazepine receptor (PBR) density elevation, after PO exposure. Furthermore, we showed that BGS was able to rescue neurons in the piriform cortex of the treated rats. In conclusion, these results suggest that treatment with BGS has a neuroprotective effect in the PO intoxication. This is the first time that this approach is used in PO intoxication and it may be of high clinical significance for the future treatment of the secondary neurologic damage post organophosphates exposure. PMID:24149933

Somatosensory pleasure circuit: from skin to brain and back.

PubMed

Lloyd, Donna M; McGlone, Francis P; Yosipovitch, Gil

2015-05-01

The skin senses serve a discriminative function, allowing us to manipulate objects and detect touch and temperature, and an affective/emotional function, manifested as itch or pain when the skin is damaged. Two different classes of nerve fibre mediate these dissociable aspects of cutaneous somatosensation: (i) myelinated A-beta and A-delta afferents that provide rapid information about the location and physical characteristics of skin contact; and (ii) unmyelinated, slow-conducting C-fibre afferents that are typically associated with coding the emotional properties of pain and itch. However, recent research has identified a third class of C-fibre afferents that code for the pleasurable properties of touch - c-tactile afferents or CTs. Clinical application of treatments that target pleasant, CT-mediated touch (such as massage therapy) could, in the future, provide a complementary, non-pharmacological means of treating both the physical and psychological aspects of chronic skin conditions such as itch and eczema. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Role of platelet adhesion in homeostasis and immunopathology.

PubMed Central

Männel, D N; Grau, G E

1997-01-01

Various molecules expressed on the surface of platelets have been shown to mediate the protective or deleterious role of these cells in immuno-inflammatory mechanisms. Increasing evidence points to the involvement of the cell adhesion molecules, gpIIb-IIIa, P-selectin, CD31, LFA-1, and CD36 in the interaction between platelets and endothelial cells as well as other cell types. The possible role of these molecules in the ability of platelets to support endothelium and to protect against tumour necrosis factor mediated cytolysis or parasitic invasion are reviewed. The involvement of platelets as effectors of tissue damage in cerebral malaria, lipopolysaccharide induced pathology, and pulmonary fibrosis is also discussed. This has then been extended to include the intercellular mechanisms underpinning their pathogenic role in metastasis, transplant rejection, stroke, brain hypoxia, and related conditions. A better understanding of the complex regulation and hierarchical organisation of these various platelet adhesion molecules may prove useful in the development of new approaches to the treatment of such diseases. Images PMID:9350300

The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer’s disease

PubMed Central

2013-01-01

Background The pathological features of the common neurodegenerative conditions, Alzheimer’s disease (AD), Parkinson’s disease and multiple sclerosis are all known to be associated with iron dysregulation in regions of the brain where the specific pathology is most highly expressed. Iron accumulates in cortical plaques and neurofibrillary tangles in AD where it participates in redox cycling and causes oxidative damage to neurons. To understand these abnormalities in the distribution of iron the expression of proteins that maintain systemic iron balance was investigated in human AD brains and in the APP-transgenic (APP-tg) mouse. Results Protein levels of hepcidin, the iron-homeostatic peptide, and ferroportin, the iron exporter, were significantly reduced in hippocampal lysates from AD brains. By histochemistry, hepcidin and ferroportin were widely distributed in the normal human brain and co-localised in neurons and astrocytes suggesting a role in regulating iron release. In AD brains, hepcidin expression was reduced and restricted to the neuropil, blood vessels and damaged neurons. In the APP-tg mouse immunoreactivity for ferritin light-chain, the iron storage isoform, was initially distributed throughout the brain and as the disease progressed accumulated in the core of amyloid plaques. In human and mouse tissues, extensive AD pathology with amyloid plaques and severe vascular damage with loss of pericytes and endothelial disruption was seen. In AD brains, hepcidin and ferroportin were associated with haem-positive granular deposits in the region of damaged blood vessels. Conclusion Our results suggest that the reduction in ferroportin levels are likely associated with cerebral ischaemia, inflammation, the loss of neurons due to the well-characterised protein misfolding, senile plaque formation and possibly the ageing process itself. The reasons for the reduction in hepcidin levels are less clear but future investigation could examine circulating levels of the peptide in AD and a possible reduction in the passage of hepcidin across damaged vascular endothelium. Imbalance in the levels and distribution of ferritin light-chain further indicate a failure to utilize and release iron by damaged and degenerating neurons. PMID:24252754

Inhibitory Effect of Lycopene on Amyloid-β-Induced Apoptosis in Neuronal Cells.

PubMed

Hwang, Sinwoo; Lim, Joo Weon; Kim, Hyeyoung

2017-08-16

Alzheimer's disease (AD) is a fatal neurodegenerative disease. Brain amyloid-β deposition is a crucial feature of AD, causing neuronal cell death by inducing oxidative damage. Reactive oxygen species (ROS) activate NF-κB, which induces expression of Nucling. Nucling is a pro-apoptotic factor recruiting the apoptosome complex. Lycopene is an antioxidant protecting from oxidative stress-induced cell damage. We investigated whether lycopene inhibits amyloid-β-stimulated apoptosis through reducing ROS and inhibiting mitochondrial dysfunction and NF-κB-mediated Nucling expression in neuronal SH-SY5Y cells. We prepared cells transfected with siRNA for Nucling or nontargeting control siRNA to determine the role of Nucling in amyloid-β-induced apoptosis. The amyloid-β increased intracellular and mitochondrial ROS levels, apoptotic indices (p53, Bax/Bcl-2 ratio, caspase-3 cleavage), NF-kB activation and Nucling expression, while cell viability, mitochondrial membrane potential, and oxygen consumption rate decreased in SH-SY5Y cells. Lycopene inhibited these amyloid-β-induced alterations. However, amyloid-β did not induce apoptosis, determined by cell viability and apoptotic indices (p53, Bax/Bcl-2 ratio, caspase-3 cleavage), in the cells transfected with siRNA for Nucling. Lycopene inhibited apoptosis by reducing ROS, and by inhibiting mitochondrial dysfunction and NF-κB-target gene Nucling expression in neuronal cells. Lycopene may be beneficial for preventing oxidative stress-mediated neuronal death in patients with neurodegeneration.

Prophylaxis with Bacopa monnieri attenuates acrylamide induced neurotoxicity and oxidative damage via elevated antioxidant function.

PubMed

Shinomol, George Kunnel; Raghunath, Narayanareddy; Bharath, Muchukunte Mukunda Srinivas; Muralidhara

2013-03-01

Acrylamide (ACR) is a water-soluble, vinyl monomer that has multiple chemical and industrial applications. Exposure to ACR causes neuropathy and associated neurological defects including gait abnormalities and skeletal muscle weakness, due to impaired neurotransmitter release and eventual neurodegeneration. Using in vivo and in vitro models, we examined whether oxidative events are involved in ACR-mediated neurotoxicity and whether these could be prevented by natural plant extracts. Administration (i.p.) of ACR in mice (40 mg/kg bw/ d for 5d) induced significant oxidative damage in the brain cortex and liver as evidenced by elevated lipid peroxidation, reactive oxygen species and protein carbonyls. This was associated with lowered antioxidant activities including antioxidant enzymes (catalase, glutathione-s-transferase) and reduced glutathione (GSH) compared to untreated controls. Similarly, exposure of N27 neuronal cells in culture to ACR (1-5 mM) caused dose-dependent neuronal death and lowered GSH. Interestingly, dietary supplementation with the leaf powder of Bacopa monnieri (BM) (which possesses neuroprotective properties and nootropic activity) in mice for 30 days offered significant protection against ACR toxicity and oxidative damage in vivo. Similarly, pretreatment with BM protected the N27 cells against ACR-induced cell death and associated oxidative damage. Co-treatment and pre-treatment of Drosophila melanogaster with BM extract protected against ACR-induced locomotor dysfunction and GSH depletion. We infer that BM displays prophylactic effects against ACR induced oxidative damage and neurotoxicity with potential therapeutic application in human pathology associated with neuropathy.

Global and Regional Brain Non-Gaussian Diffusion Changes in Newly Diagnosed Patients with Obstructive Sleep Apnea.

PubMed

Tummala, Sudhakar; Palomares, Jose; Kang, Daniel W; Park, Bumhee; Woo, Mary A; Harper, Ronald M; Kumar, Rajesh

2016-01-01

Obstructive sleep apnea (OSA) patients show brain structural injury and functional deficits in autonomic, affective, and cognitive regulatory sites, as revealed by mean diffusivity (MD) and other imaging procedures. The time course and nature of gray and white matter injury can be revealed in more detail with mean kurtosis (MK) procedures, which can differentiate acute from chronic injury, and better show extent of damage over MD procedures. Our objective was to examine global and regional MK changes in newly diagnosed OSA, relative to control subjects. Two diffusion kurtosis image series were collected from 22 recently-diagnosed, treatment-naïve OSA and 26 control subjects using a 3.0-Tesla MRI scanner. MK maps were generated, normalized to a common space, smoothed, and compared voxel-by-voxel between groups using analysis of covariance (covariates; age, sex). No age or sex differences appeared, but body mass index, sleep, neuropsychologic, and cognitive scores significantly differed between groups. MK values were significantly increased globally in OSA over controls, and in multiple localized sites, including the basal forebrain, extending to the hypothalamus, hippocampus, thalamus, insular cortices, basal ganglia, limbic regions, cerebellar areas, parietal cortices, ventral temporal lobe, ventrolateral medulla, and midline pons. Multiple sites, including the insular cortices, ventrolateral medulla, and midline pons showed more injury over previously identified damage with MD procedures, with damage often lateralized. Global mean kurtosis values are significantly increased in obstructive sleep apnea (OSA), suggesting acute tissue injury, and these changes are principally localized in critical sites mediating deficient functions in the condition. The mechanisms for injury likely include altered perfusion and hypoxemia-induced processes, leading to acute tissue changes in recently diagnosed OSA. © 2016 Associated Professional Sleep Societies, LLC.

Antioxidant properties of xanthones from Calophyllum brasiliense: prevention of oxidative damage induced by FeSO₄.

PubMed

Blanco-Ayala, Tonali; Lugo-Huitrón, Rafael; Serrano-López, Elizabeth M; Reyes-Chilpa, Ricardo; Rangel-López, Edgar; Pineda, Benjamín; Medina-Campos, Omar Noel; Sánchez-Chapul, Laura; Pinzón, Enrique; Cristina, Trejo-Solis; Silva-Adaya, Daniela; Pedraza-Chaverrí, José; Ríos, Camilo; de la Cruz, Verónica Pérez; Torres-Ramos, Mónica

2013-10-11

Reactive oxygen species (ROS) are important mediators in a number of degenerative diseases. Oxidative stress refers to the imbalance between the production of ROS and the ability to scavenge these species through endogenous antioxidant systems. Since antioxidants can inhibit oxidative processes, it becomes relevant to describe natural compounds with antioxidant properties which may be designed as therapies to decrease oxidative damage and stimulate endogenous cytoprotective systems. The present study tested the protective effect of two xanthones isolated from the heartwood of Calophyllum brasilienses against FeSO₄-induced toxicity. Through combinatory chemistry assays, we evaluated the superoxide (O₂·⁻), hydroxyl radical (OH·), hydrogen peroxide (H₂O₂) and peroxynitrite (ONO⁻) scavenging capacity of jacareubin (xanthone III) and 2-(3,3-dimethylallyl)-1,3,5,6-tetrahydroxyxanthone (xanthone V). The effect of these xanthones on murine DNA and bovine serum albumin degradation induced by an OH· generator system was also evaluated. Additionally, we investigated the effect of these xanthones on ROS production, lipid peroxidation and glutathione reductase (GR) activity in FeSO₄-exposed brain, liver and lung rat homogenates. Xanthone V exhibited a better scavenging capacity for O₂·⁻, ONOO⁻ and OH· than xanthone III, although both xanthones were unable to trap H₂O₂. Additionally, xanthones III and V prevented the albumin and DNA degradation induced by the OH· generator system. Lipid peroxidation and ROS production evoked by FeSO₄ were decreased by both xanthones in all tissues tested. Xanthones III and V also prevented the GR activity depletion induced by pro-oxidant activity only in the brain. Altogether, the collected evidence suggests that xanthones can play a role as potential agents to attenuate the oxidative damage produced by different pro-oxidants.

Contribution of Brain Tissue Oxidative Damage in Hypothyroidism-associated Learning and Memory Impairments

PubMed Central

Baghcheghi, Yousef; Salmani, Hossein; Beheshti, Farimah; Hosseini, Mahmoud

2017-01-01

The brain is a critical target organ for thyroid hormones, and modifications in memory and cognition happen with thyroid dysfunction. The exact mechanisms underlying learning and memory impairments due to hypothyroidism have not been understood yet. Therefore, this review was aimed to compress the results of previous studies which have examined the contribution of brain tissues oxidative damage in hypothyroidism-associated learning and memory impairments. PMID:28584813

Fluorescent Pressure Response of Protein-Nanocluster Polymer Composites

DTIC Science & Technology

2016-05-01

composites as pressure sensitive indicators of brain damage. The PNC composites are made up of protein coated gold nanoclusters and a styrene- ethylene ...styrene- ethylene /butylene-styrene (SEBS):mineral oil composites that were developed as a brain tissue surrogate at ARL. Finally, we would like to...allowing us to use solid samples and create a model for brain damage. To this end, we used styrene- ethylene /butylene-styrene (SEBS) as the matrix to

Neurodegenerative changes and apoptosis induced by intrauterine and extrauterine exposure of radiofrequency radiation.

PubMed

Güler, Göknur; Ozgur, Elcin; Keles, Hikmet; Tomruk, Arin; Vural, Sevil Atalay; Seyhan, Nesrin

2016-09-01

Adverse health effects of radiofrequency radiation (RFR) on the ongoing developmental stages of children from conception to childhood are scientifically anticipated subject. This study was performed to identify the effects of global system for mobile communications (GSM) modulated mobile phone like RFR in 1800MHz frequency on oxidative DNA damage and lipid peroxidation beside the apoptotic cell formation, using histopathological and immunohistochemical methods in the brain tissue of 1-month-old male and female New Zealand White rabbits that were exposed to these fields at their mother's womb and after the birth. Oxidative DNA damage and lipid peroxidation levels were investigated by measuring the 8-hydroxy-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) levels, respectively. Histopathological changes were observed using by hematoxylin and eosin (HE) staining. Apoptotic cells were detected in the examined organs by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. For both male and female infants; 8-OHdG levels increased in the group exposed to RFR in both intrauterine and extrauterine periods compared to the infants that were never exposed to RFR and the ones were exposed when they reached one month of age (p<0.05). MDA results were different for male and female rabbits. There was no difference between all female infant groups (p>0.05), while only intrauterine exposure significantly causes MDA level increase for the male infants. HE staining revealed mild lessions in neuronal necrobiosis in brain tissues of female rabbits that had only intaruterine exposure and male rabbits had only extrauterine exposure. Gliosis were mildly positive in brain tissues of rabbits that are exposed only intrauterine period, also the group exposed both intrauterine and extrauterine periods. However, there was no apoptotic change detected by TUNEL staining in the brain tissues of all groups. Copyright © 2015 Elsevier B.V. All rights reserved.

Traumatic Brain Injury: Effects on the Endocrine System

MedlinePlus

Fact Sheet BTrarainumInajutircy: Effects on the Endocrine System What is traumatic brain injury? Traumatic brain injury, also called TBI, is sudden damage to the brain. It happens when the head hits ...

Traumatic Brain Injury

MedlinePlus

Traumatic brain injury (TBI) happens when a bump, blow, jolt, or other head injury causes damage to the brain. Every year, millions of people in the U.S. suffer brain injuries. More than half are bad enough that ...

Octadecylpropyl Sulfamide Reduces Neurodegeneration and Restores the Memory Deficits Induced by Hypoxia-Ischemia in Mice

PubMed Central

Kossatz, Elk; Silva-Peña, Daniel; Suárez, Juan; de Fonseca, Fernando R.; Maldonado, Rafael; Robledo, Patricia

2018-01-01

The PPAR-α agonist, oleoylethanolamide (OEA) has neuroprotective properties in stroke models. However, its rapid degradation represents a limitation for an effective therapeutic approach. In this study, we evaluated the effects of a stable OEA-modeled compound, octadecylpropyl sulfamide (SUL) on the cognitive, behavioral, cellular and molecular alterations associated with hypoxia-ischemia (HI) in mice. Mice subjected to HI were treated with the PPAR-α antagonist GW6471 (GW) (1 mg/kg) followed 15 min later by SUL (3 and 10 mg/kg). Behavioral, motor, and cognitive tests were carried out 24 h and 7 days after the HI. The levels of microglia, reactive astrocytes and neuronal nuclei were studied using immunofluorescence, and the expression of genes related to the N-acyl-ethanolamides/endocannabinoid signaling systems was determined by qRT-PCR at the end of the experimental sequence. HI induced brain damage in the ipsilateral hippocampus and cortex, which lead to severe memory impairments, and motor coordination deficits. Significant neuronal loss, increased microglia and reactive astrocytes, and compensatory changes in genes associated with the inflammation/immune and endocannabinoid systems were observed in these brain structures of lesioned mice. SUL reversed the memory and motor deficits, decreased the overexpression of microglia and astrocytes, and reduced neurodegeneration induced by HI. Cnr1 and Cnr2 gene expression was modulated by SUL in both sham and HI mice, while Pparα and Faah expression was regulated in HI mice. GW completely blocked the beneficial actions of SUL. These findings suggest that treatment with SUL reduces brain damage and the associated motor and memory deficits induced by HI probably by normalizing the changes in neuroinflammation/immune system mediators. PMID:29725299

Octadecylpropyl Sulfamide Reduces Neurodegeneration and Restores the Memory Deficits Induced by Hypoxia-Ischemia in Mice.

PubMed

Kossatz, Elk; Silva-Peña, Daniel; Suárez, Juan; de Fonseca, Fernando R; Maldonado, Rafael; Robledo, Patricia

2018-01-01

The PPAR-α agonist, oleoylethanolamide (OEA) has neuroprotective properties in stroke models. However, its rapid degradation represents a limitation for an effective therapeutic approach. In this study, we evaluated the effects of a stable OEA-modeled compound, octadecylpropyl sulfamide (SUL) on the cognitive, behavioral, cellular and molecular alterations associated with hypoxia-ischemia (HI) in mice. Mice subjected to HI were treated with the PPAR-α antagonist GW6471 (GW) (1 mg/kg) followed 15 min later by SUL (3 and 10 mg/kg). Behavioral, motor, and cognitive tests were carried out 24 h and 7 days after the HI. The levels of microglia, reactive astrocytes and neuronal nuclei were studied using immunofluorescence, and the expression of genes related to the N -acyl-ethanolamides/endocannabinoid signaling systems was determined by qRT-PCR at the end of the experimental sequence. HI induced brain damage in the ipsilateral hippocampus and cortex, which lead to severe memory impairments, and motor coordination deficits. Significant neuronal loss, increased microglia and reactive astrocytes, and compensatory changes in genes associated with the inflammation/immune and endocannabinoid systems were observed in these brain structures of lesioned mice. SUL reversed the memory and motor deficits, decreased the overexpression of microglia and astrocytes, and reduced neurodegeneration induced by HI. Cnr1 and Cnr2 gene expression was modulated by SUL in both sham and HI mice, while Ppar α and Faah expression was regulated in HI mice. GW completely blocked the beneficial actions of SUL. These findings suggest that treatment with SUL reduces brain damage and the associated motor and memory deficits induced by HI probably by normalizing the changes in neuroinflammation/immune system mediators.

Hyperglycaemia promotes human brain microvascular endothelial cell apoptosis via induction of protein kinase C-ßI and prooxidant enzyme NADPH oxidase

PubMed Central

Shao, Beili; Bayraktutan, Ulvi

2014-01-01

Blood–brain barrier disruption represents a key feature in hyperglycaemia-aggravated cerebral damage after an ischaemic stroke. Although the underlying mechanisms remain largely unknown, activation of protein kinase C (PKC) is thought to play a critical role. This study examined whether apoptosis of human brain microvascular endothelial cells (HBMEC) might contribute to hyperglycaemia-evoked barrier damage and assessed the specific role of PKC in this phenomenon. Treatments with hyperglycaemia (25 mM) or phorbol myristate acetate (PMA, a protein kinase C activator, 100 nM) significantly increased NADPH oxidase activity, O2•- generation, proapoptotic protein Bax expression, TUNEL-positive staining and caspase-3/7 activities. Pharmacological inhibition of NADPH oxidase, PKC-a, PKC-ß or PKC-ßI via their specific inhibitors and neutralisation of O2•- by a cell-permeable superoxide dismutase mimetic, MnTBAP normalised all the aforementioned increases induced by hyperglycaemia. Suppression of these PKC isoforms also negated the stimulatory effects of hyperglycaemia on the protein expression of NADPH oxidase membrane-bound components, Nox2 and p22-phox which determine the overall enzymatic activity. Silencing of PKC-ßI gene through use of specific siRNAs abolished the effects of both hyperglycaemia and PMA on endothelial cell NADPH oxidase activity, O2•- production and apoptosis and consequently improved the integrity and function of an in vitro model of human cerebral barrier comprising HBMEC, astrocytes and pericytes. Hyperglycaemia-mediated apoptosis of HBMEC contributes to cerebral barrier dysfunction and is modulated by sequential activations of PKC-ßI and NADPH oxidase. PMID:24936444

A Molecular Approach to Epilepsy Management: from Current Therapeutic Methods to Preconditioning Efforts.

PubMed

Amini, Elham; Rezaei, Mohsen; Mohamed Ibrahim, Norlinah; Golpich, Mojtaba; Ghasemi, Rasoul; Mohamed, Zahurin; Raymond, Azman Ali; Dargahi, Leila; Ahmadiani, Abolhassan

2015-08-01

Epilepsy is the most common and chronic neurological disorder characterized by recurrent unprovoked seizures. The key aim in treating patients with epilepsy is the suppression of seizures. An understanding of focal changes that are involved in epileptogenesis may therefore provide novel approaches for optimal treatment of the seizure. Although the actual pathogenesis of epilepsy is still uncertain, recently growing lines of evidence declare that microglia and astrocyte activation, oxidative stress and reactive oxygen species (ROS) production, mitochondria dysfunction, and damage of blood-brain barrier (BBB) are involved in its pathogenesis. Impaired GABAergic function in the brain is probably the most accepted hypothesis regarding the pathogenesis of epilepsy. Clinical neuroimaging of patients and experimental modeling have demonstrated that seizures may induce neuronal apoptosis. Apoptosis signaling pathways are involved in the pathogenesis of several types of epilepsy such as temporal lobe epilepsy (TLE). The quality of life of patients is seriously affected by treatment-related problems and also by unpredictability of epileptic seizures. Moreover, the available antiepileptic drugs (AED) are not significantly effective to prevent epileptogenesis. Thus, novel therapies that are proficient to control seizure in people who are suffering from epilepsy are needed. The preconditioning method promises to serve as an alternative therapeutic approach because this strategy has demonstrated the capability to curtail epileptogenesis. For this reason, understanding of molecular mechanisms underlying brain tolerance induced by preconditioning is crucial to delineate new neuroprotective ways against seizure damage and epileptogenesis. In this review, we summarize the work to date on the pathogenesis of epilepsy and discuss recent therapeutic strategies in the treatment of epilepsy. We will highlight that novel therapy targeting such as preconditioning process holds great promise. In addition, we will also highlight the role of gene reprogramming and mitochondrial biogenesis in the preconditioning-mediated neuroprotective events.

(-)-Phenserine inhibits neuronal apoptosis following ischemia/reperfusion injury.

PubMed

Chang, Cheng-Fu; Lai, Jing-Huei; Wu, John Chung-Che; Greig, Nigel H; Becker, Robert E; Luo, Yu; Chen, Yen-Hua; Kang, Shuo-Jhen; Chiang, Yung-Hsiao; Chen, Kai-Yun

2017-12-15

Stroke commonly leads to adult disability and death worldwide. Its major symptoms are spastic hemiplegia and discordant motion, consequent to neuronal cell death induced by brain vessel occlusion. Acetylcholinesterase (AChE) is upregulated and allied with inflammation and apoptosis after stroke. Recent studies suggest that AChE inhibition ameliorates ischemia-reperfusion injury and has neuroprotective properties. (-)-Phenserine, a reversible AChE inhibitor, has a broad range of actions independent of its AChE properties, including neuroprotective ones. However, its protective effects and detailed mechanism of action in the rat middle cerebral artery occlusion model (MCAO) remain to be elucidated. This study investigated the therapeutic effects of (-)-phenserine for stroke in the rat focal cerebral ischemia model and oxygen-glucose deprivation/reperfusion (OGD/RP) damage model in SH-SY5Y neuronal cultures. (-)-Phenserine mitigated OGD/PR-induced SH-SY5Y cell death, providing an inverted U-shaped dose-response relationship between concentration and survival. In MCAO challenged rats, (-)-phenserine reduced infarction volume, cell death and improved body asymmetry, a behavioral measure of stoke impact. In both cellular and animal studies, (-)-phenserine elevated brain-derived neurotrophic factor (BDNF) and B-cell lymphoma 2 (Bcl-2) levels, and decreased activated-caspase 3, amyloid precursor protein (APP) and glial fibrillary acidic protein (GFAP) expression, potentially mediated through the ERK-1/2 signaling pathway. These actions mitigated neuronal apoptosis in the stroke penumbra, and decreased matrix metallopeptidase-9 (MMP-9) expression. In synopsis, (-)-phenserine significantly reduced neuronal damage induced by ischemia/reperfusion injury in a rat model of MCAO and cellular model of OGD/RP, demonstrating that its anti-apoptotic/neuroprotective/neurotrophic cholinergic and non-cholinergic properties warrant further evaluation in conditions of brain injury. Published by Elsevier B.V.

Anti-Inflammatory Targets for the Treatment of Reperfusion Injury in Stroke

PubMed Central

Mizuma, Atsushi; Yenari, Midori A.

2017-01-01

While the mainstay of acute stroke treatment includes revascularization via recombinant tissue plasminogen activator or mechanical thrombectomy, only a minority of stroke patients are eligible for treatment, as delayed treatment can lead to worsened outcome. This worsened outcome at the experimental level has been attributed to an entity known as reperfusion injury (R/I). R/I is occurred when revascularization is delayed after critical brain and vascular injury has occurred, so that when oxygenated blood is restored, ischemic damage is increased, rather than decreased. R/I can increase lesion size and also worsen blood barrier breakdown and lead to brain edema and hemorrhage. A major mechanism underlying R/I is that of poststroke inflammation. The poststroke immune response consists of the aberrant activation of glial cell, infiltration of peripheral leukocytes, and the release of damage-associated molecular pattern (DAMP) molecules elaborated by ischemic cells of the brain. Inflammatory mediators involved in this response include cytokines, chemokines, adhesion molecules, and several immune molecule effectors such as matrix metalloproteinases-9, inducible nitric oxide synthase, nitric oxide, and reactive oxygen species. Several experimental studies over the years have characterized these molecules and have shown that their inhibition improves neurological outcome. Yet, numerous clinical studies failed to demonstrate any positive outcomes in stroke patients. However, many of these clinical trials were carried out before the routine use of revascularization therapies. In this review, we cover mechanisms of inflammation involved in R/I, therapeutic targets, and relevant experimental and clinical studies, which might stimulate renewed interest in designing clinical trials to specifically target R/I. We propose that by targeting anti-inflammatory targets in R/I as a combined therapy, it may be possible to further improve outcomes from pharmacological thrombolysis or mechanical thrombectomy. PMID:28936196

Can Herpes Simplex Virus Encephalitis Cause Aphasia?

ERIC Educational Resources Information Center

Naude, H.; Pretorius, E.

2003-01-01

Aphasia implies the loss or impairment of language caused by brain damage. The key to understanding the nature of aphasic symptoms is the neuro-anatomical site of brain damage, and not the causative agent. However, because "Herpes simplex" virus (HSV) encephalitis infection usually affects the frontal and temporal lobes, subcortical…

Clinical Relevance of Discourse Characteristics after Right Hemisphere Brain Damage

ERIC Educational Resources Information Center

Blake, Margaret Lehman

2006-01-01

Purpose: Discourse characteristics of adults with right hemisphere brain damage are similar to those reported for healthy older adults, prompting the question of whether changes are due to neurological lesions or normal aging processes. The clinical relevance of potential differences across groups was examined through ratings by speech-language…

Perspectives on Treatment for Communication Deficits Associated with Right Hemisphere Brain Damage

ERIC Educational Resources Information Center

Blake, Margaret Lehman

2007-01-01

Purpose: To describe the current treatment research for communication (prosodic, discourse, and pragmatic) deficits associated with right hemisphere brain damage and to provide suggestions for treatment selection given the paucity of evidence specifically for this population. Method: The discussion covers (a) clinical decision processes and…

Cognitive Development in Children with Brain Damage.

ERIC Educational Resources Information Center

Bortner, Morton

Presented is a report on a cross-sectional and longitudinal study concerned with the course of intellectual development in 210 children (6-12 years old) educationally designated as brain damaged (learning disabled and/or behavior problems) and assigned to special school placement. The report is divided into four sections which focus on…

Conversation after Right Hemisphere Brain Damage: Motivations for Applying Conversation Analysis

ERIC Educational Resources Information Center

Barnes, Scott; Armstrong, Elizabeth

2010-01-01

Despite the well documented pragmatic deficits that can arise subsequent to Right Hemisphere Brain Damage (RHBD), few researchers have directly studied everyday conversations involving people with RHBD. In recent years, researchers have begun applying Conversation Analysis (CA) to the everyday talk of people with aphasia. This research programme…