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Sample records for 6-ohda lesion model

  1. T-Lymphocyte Deficiency Exacerbates Behavioral Deficits in the 6-OHDA Unilateral Lesion Rat Model for Parkinson’s Disease

    PubMed Central

    Wheeler, Christopher J; Seksenyan, Akop; Koronyo, Yosef; Rentsendorj, Altan; Sarayba, Danielle; Wu, Henry; Gragg, Ashley; Siegel, Emily; Thomas, Deborah; Espinosa, Andres; Thompson, Kerry; Black, Keith; Koronyo-Hamaoui, Maya; Pechnick, Robert; Irvin, Dwain K

    2014-01-01

    T-lymphocytes have been previously implicated in protecting dopaminergic neurons in the substantianigra from induced cell death. However, the role of T-cells in neurodegenerative models such as Parkinson’s disease (PD) has not been fully elucidated. To examine the role of T-lymphocytes on motor behavior in the 6-hydroxydopamine (6-OHDA) unilateral striatal partial lesion PD rat model, we assessed progression of hemi-parkinsonian lesions in the substantia nigra, induced by 6-OHDA striatal injections, in athymic rats (RNU−/−, T-lymphocyte-deficient) as compared to RNU−/+ rats (phenotypically normal). Motor skills were determined by the cylinder and D-amphetamine sulfate-induced rotational behavioral tests. Cylinder behavioral test showed no significant difference between unilaterally lesioned RNU−/− and RNU−/+ rats. However both unilaterally lesioned RNU−/− and RNU−/+ rats favored the use of the limb ipsilateral to lesion. Additionally, amphetamine-induced rotational test revealed greater rotational asymmetry in RNU−/− rats compared to RNU−/+ rats at two- and six-week post-lesion. Quantitative immunohistochemistry confirmed loss of striatal TH-immunopositive fibers in RNU−/− and RNU−/+ rat, as well as blood-brain-barrier changes associated with PD that may influence passage of immune cells into the central nervous system in RNU−/− brains. Specifically, GFAP immunopositive cells were decreased, as were astrocytic end-feet (AQP4) contacting blood vessels (laminin) in the lesioned relative to contralateral striatum. Flow cytometric analysis in 6-OHDA lesioned RNU−/+rats revealed increased CD4+ and decreased CD8+ T cells specifically within lesioned brain. These results suggest that both major T cell subpopulations are significantly and reciprocally altered following 6-OHDA-lesioning, and that global T cell deficiency exacerbates motor behavioral defects in this rat model of PD. PMID:25346865

  2. Caffeine improves attention deficit in neonatal 6-OHDA lesioned rats, an animal model of attention deficit hyperactivity disorder (ADHD).

    PubMed

    Caballero, Miguel; Núñez, Fabiana; Ahern, Siobhán; Cuffí, Maria L; Carbonell, Lourdes; Sánchez, Silvia; Fernández-Dueñas, Víctor; Ciruela, Francisco

    2011-04-20

    Nowadays the pharmacological treatment of the attention deficit hyperactivity disorder (ADHD) is based on amphetamine derivatives (i.e. methylphenidate). However, these drugs induce a large array of adverse side effects, thus less aggressive psychostimulant drugs (i.e. caffeine) are being proposed in the management of ADHD. Following this tendency, we decided to study the possible therapeutic use of caffeine in an animal model of ADHD, namely the neonatal 6-hydroxy-dopamine (6-OHDA)-lesioned rat. Therefore, at postnatal day 7 rats were lesioned at the left striatum with 6-OHDA or with saline. Thereafter, at postnatal day 25 their activity and attention were measured with the Olton maze before caffeine was administered ad libitum in the drinking water. Next, after 14 days of caffeine treatment, we repeated these measurements to assess the effect of caffeine on motor activity and attention deficit. Interestingly, while no changes in the motor activity measurements were observed before and after caffeine administration, a significant improvement in the attention deficit of the 6-OHDA lesioned rats was achieved after caffeine treatment. Thus, our results led us to hypothesize that caffeine might be useful to manage the attention deficit during the prepubertal period of ADHD.

  3. Effect of memantine on L-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat model of Parkinson's disease.

    PubMed

    Tronci, E; Fidalgo, C; Zianni, E; Collu, M; Stancampiano, R; Morelli, M; Gardoni, F; Carta, M

    2014-04-18

    An increasing body of experimental evidence demonstrates that the glutamatergic system is involved in the genesis of l-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID). Indeed, the N-methyl-d-aspartate (NMDA) receptor antagonist amantadine is the only anti-dyskinetic compound used in patients, albeit with limited efficacy and side effects. In this study, we investigated the anti-dyskinetic properties of memantine, a non-competitive NMDA receptor antagonist in clinical use for the treatment of dementia, in the 6-hydroxy-dopamine (6-OHDA)-lesion rat model of Parkinson's disease. For comparison, parallel experiments were also performed with amantadine. First, we investigated the acute effect of different doses of memantine (5, 10, 15 and 20mg/kg), and amantadine (10, 20, 40, 60mg/kg) on established dyskinesia induced by L-DOPA (6mg/kg plus benserazide). Results showed that both memantine and amantadine produced a significant reduction of LID. Afterward, drug-naïve and L-DOPA-primed 6-OHDA-lesioned rats were sub-chronically treated with daily injections of L-DOPA (6mg/kg plus benserazide) alone, or in combination with the effective doses of memantine, while amantadine was tested in already dyskinetic rats. Results showed that memantine significantly dampened dyskinesia in both drug-naïve and L-DOPA-primed rats, but only during the first few days of administration. In fact, the anti-dyskinetic effect of memantine was completely lost already at the fifth administration, indicating a rapid induction of tolerance. Interestingly, a 3-week washout period was not sufficient to restore the anti-dyskinetic effect of the drug. Similarly, amantadine was able to dampen already established dyskinesia only during the first day of administration. Moreover, memantine partially decreased the therapeutic effect of L-DOPA, as showed by the result of the stepping test. Finally, loss of the anti-dyskinetic effect of memantine was associated to increased synaptic GluN2A/GluN2B

  4. Subthalamic 6-OHDA-induced lesion attenuates levodopa-induced dyskinesias in the rat model of Parkinson's disease.

    PubMed

    Marin, C; Bonastre, M; Mengod, G; Cortés, R; Rodríguez-Oroz, M C; Obeso, J A

    2013-12-01

    The subthalamic nucleus (STN) receives direct dopaminergic innervation from the substantia nigra pars compacta that degenerates in Parkinson's disease. The present study aimed to investigate the role of dopaminergic denervation of STN in the origin of levodopa-induced dyskinesias. Rats were distributed in four groups which were concomitantly lesioned with 6-OHDA or vehicle (sham) in the STN and in the medial forebrain bundle (MFB) as follows: a) MFB-sham plus STN-sham, b) MFB-sham plus STN-lesion, c) MFB-lesion plus STN-sham, and d) MFB-lesion plus STN-lesion. Four weeks after lesions, animals were treated with levodopa (6mg/kg with 15mg/kg benserazide i.p.) twice daily for 22 consecutive days. Abnormal involuntary movements were measured. In situ hybridization was performed measuring the expression of striatal preproenkephalin, preprodynorphin, STN cytochrome oxidase (CO) and nigral GAD67 mRNAs. STN 6-OHDA denervation did not induce dyskinesias in levodopa-treated MFB-sham animals but attenuated axial (p<0.05), limb (p<0.05) and orolingual (p<0.01) dyskinesias in rats with a concomitant lesion of the nigrostriatal pathway. The attenuation of dyskinesias was associated with a decrease in the ipsilateral STN CO mRNA levels (p<0.05). No significant differences between MFB-lesion plus STN-sham and MFB-lesion plus STN-lesion groups in the extent of STN dopaminergic denervation were observed. Moreover, intrasubthalamic microinfusion of dopamine in the MFB-lesion plus STN-lesion group triggered orolingual (p<0.01), but not axial or limb, dyskinesias. These results suggest that dopaminergic STN innervation influences the expression of levodopa-induced dyskinesias but also the existence of non dopaminergic-mediated mechanisms. STN noradrenergic depletion induced by 6-OHDA in the STN needs to be taken in account as a possible mechanism explaining the attenuation of dyskinesias in the combined lesion group.

  5. The involvement of RGS9 in l-3,4-dihydroxyphenylalanine-induced dyskinesias in unilateral 6-OHDA lesion rat model.

    PubMed

    Yin, Lin-Lin; Geng, Xing-Chao; Zhu, Xing-Zu

    2011-11-25

    Chronic dopamine (DA) replacement therapy with L-3,4-dihydroxyphenylalanine (L-DOPA) in Parkinson's disease (PD) often leads to abnormal involuntary movements (AIMs) known as L-DOPA-induced dyskinesia (LID), mediated by DA receptors. However, mechanisms underlying LID occurrence are still unclear. Regulator of G-protein signaling RGS9, a member of the RGS family of GTPase accelerating proteins, is expressed specifically in the striatum, has been reported participated in LID. L-DOPA-induced AIMs can be modeled in rats with 6-hydroxydopamine (6-OHDA) lesions by chronic injection of L-DOPA. Herein, we compared the rotational responses and AIMs in 6-OHDA lesioned rats with L-DOPA/benserazide (10/2.5 mg/kg, once per day, i.p.) administration for 14 days whereas control animals received injections of saline. Furthermore, whether sub-chronic L-DOPA treatment impact RGS9 mRNA or protein expression in 6-OHDA lesion rats were also evaluated. As results shown, rotational behavior was not increased significantly, while an obvious AIMs were observed in rats with L-DOPA/benserazide (10/2.5mg/kg, i.p.) administration sub-chronically. In addition, expressions of RGS9 protein or mRNA analyzed by Western blot or real-time PCR with striatal extracts increased significantly after L-DOPA/benserazide. These data demonstrate that RGS9 expression can be modulated by sub-chronic L-DOPA/benserazide administration and increased RGS9 expression in striatum may be one of the reasons for the side effects such as dyskinesia induced by L-DOPA therapy.

  6. LPA signaling is required for dopaminergic neuron development and is reduced through low expression of the LPA1 receptor in a 6-OHDA lesion model of Parkinson's disease.

    PubMed

    Yang, Xiao-Yun; Zhao, Ethan Y; Zhuang, Wen-Xin; Sun, Feng-Xiang; Han, Hai-Lin; Han, Hui-Rong; Lin, Zhi-Juan; Pan, Zhi-Fang; Qu, Mei-Hua; Zeng, Xian-Wei; Ding, Yuchuan

    2015-11-01

    Lysophosphatidic acid (LPA) is a bioactive phospholipid that activates at least five known G-protein-coupled receptors (GPCRs): LPA1-LPA5. The nervous system is a major locus for LPA1 expression. LPA has been shown to regulate neuronal proliferation, migration, and differentiation during central nervous system development as well as neuronal survival. Furthermore, deficient LPA signaling has been implicated in several neurological disorders including neuropathic pain and schizophrenia. Parkinson's disease (PD) is a neurodegenerative movement disorder that results from the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). The specific molecular pathways that lead to DA neuron degeneration, however, are poorly understood. The influence of LPA in the differentiation of mesenchymal stem cells (MSCs) into DA neurons in vitro and LPA1 expression in a 6-hydroxydopamine (6-OHDA) lesion model of PD in vivo were examined in the present study. LPA induced neuronal differentiation in 80.2 % of the MSC population. These MSCs developed characteristic neuronal morphology and expressed the neuronal marker, neuron-specific enolase (NSE), while expression of the glial marker, glial fibrillary acidic protein (GFAP), was absent. Moreover, 27.6 % of differentiated MSCs were positive for tyrosine hydroxylase (TH), a marker for DA neurons. In the 6-OHDA PD rat model, LPA1 expression in the substantia nigra was significantly reduced compared to control. These results suggest LPA signaling via activation of LPA1 may be necessary for DA neuron development and survival. Furthermore, reduced LPA/LPA1 signaling may be involved in DA neuron degeneration thus contributing to the pathogenesis of PD.

  7. Antagonism of quercetin against tremor induced by unilateral striatal lesion of 6-OHDA in rats.

    PubMed

    Mu, Xin; Yuan, Xia; Du, Li-Da; He, Guo-Rong; Du, Guan-Hua

    2016-01-01

    Quercetin, a flavonoid present in many plants, is reported to be effective in models of neurodegenerative diseases. The aim of the present study was to evaluate the anti-tremor effects of quercetin in 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease. In rats, quercetin had no effect on apomorphine-induced rotations, but it could significantly attenuate muscle tremor of 6-OHDA lesioned rats. Interestingly, quercetin could decrease the burst frequency in a dose- and time-dependent manner. These results suggest that quercetin may have a protective effect on models to mimic muscle tremors of Parkinson's disease. This effect of quercetin may be associated with serotonergic system, but further study is needed.

  8. Decreased behavioral response to intranigrally administered GABAA agonist muscimol in the lactacystin model of Parkinson's disease may result from partial lesion of nigral non-dopamine neurons: comparison to the classical neurotoxin 6-OHDA.

    PubMed

    Konieczny, Jolanta; Czarnecka, Anna; Kamińska, Kinga; Lenda, Tomasz; Nowak, Przemysław

    2015-04-15

    Lactacystin is a selective UPS inhibitor recently used to destroy dopamine (DA) neurons in animal models of Parkinson's disease (PD). However, both in vitro and in vivo studies show discrepancies in terms of the sensitivity of non-DA neurons to its toxicity. Therefore, our study was aimed to examine the toxic effect of intranigral administration of lactacystin on DA and non-DA neurons in the rat substantia nigra (SN), compared to the classic neurotoxin 6-OHDA. Tissue DA levels in the striatum and SN and GABA levels in the SN were also examined. Moreover, behavioral response of nigral GABAA receptors to locally administered muscimol was evaluated in these two PD models. We found that both lactacystin and 6-OHDA induced a strong decrease in DA level in the lesioned striatum and SN but only lactacystin slightly reduced GABA levels in the SN. A stereological analysis showed that both neurotoxins highly decreased the number of DA neurons in the SN, while only lactacystin moderately reduced the number of non-DA ones. Finally, in the lactacystin group, the number of contralateral rotations after intranigrally administrated muscimol was decreased in contrast to the increased response in the 6-OHDA model. Our study proves that, although lactacystin is not a fully selective to DA neurons, these neurons are much more vulnerable to its toxicity. Partial lesion of nigral non-DA neurons in this model may explain the decreased behavioral response to the GABAA agonist muscimol.

  9. FTY720 Attenuates 6-OHDA-Associated Dopaminergic Degeneration in Cellular and Mouse Parkinsonian Models.

    PubMed

    Ren, Manru; Han, Minxing; Wei, Xinbing; Guo, Ying; Shi, Huanying; Zhang, Xiumei; Perez, Ruth G; Lou, Haiyan

    2017-02-01

    FTY720 (fingolimod) is the first oral drug approved for treating relapsing-remitting forms of multiple sclerosis. It is also protective in other neurological models including ischemia, Alzheimer's disease, Huntington disease and Rett syndrome. However, whether it might protect in a 6-hydroxydopamine (6-OHDA) mouse model associated with the dopaminergic pathology of Parkinson's disease (PD), has not been explored. Therefore, in the present study, we investigated the effects of FTY720 on 6-OHDA-induced neurotoxicity in cell cultures and mice. Here we show that FTY720 protected against 6-OHDA cytotoxicity and apoptosis in SH-SY5Y cells. We also show that prior administration of FTY720 to 6-OHDA lesioned mice ameliorated both motor deficits and nigral dopaminergic neurotoxicity, while also reducing 6-OHDA-associated inflammation. The protective effects of FTY720 were associated with activation of AKT and ERK1/2 pro-survival pathways and an increase in brain derived neurotrophic factor (BDNF) expression in vitro and in vivo. These findings suggest that FTY720 holds promise as a PD therapeutic acting, at least in part, through AKT/ERK1/2/P-CREB-associated BDNF expression.

  10. ACTIVATION OF PPAR GAMMA RECEPTORS REDUCES LEVODOPA-INDUCED DYSKINESIAS IN 6-OHDA-LESIONED RATS

    PubMed Central

    Martinez, A. A.; Morgese, M. G.; Pisanu, A.; Macheda, T.; Paquette, M. A.; Seillier, A.; Cassano, T.; Carta, A.R.; Giuffrida, A.

    2014-01-01

    Long-term administration of L-3,4-dihydroxyphenylalanine (levodopa), the mainstay treatment for Parkinson’s disease (PD), is accompanied by fluctuations in its duration of action and motor complications (dyskinesia) that dramatically affect the quality of life of patients. Levodopa-induced dyskinesias (LID) can be modeled in rats with unilateral 6-OHDA lesions via chronic administration of levodopa, which causes increasingly severe axial, limb and oro-facial abnormal involuntary movements (AIMs) over time. In previous studies, we showed that direct activation of CB1 cannabinoid receptors alleviated rat AIMs. Interestingly, elevation of the endocannabinoid anandamide by URB597 (URB), an inhibitor of endocannabinoid catabolism, produced an anti-dyskinetic response that was only partially mediated via CB1 receptors and required the concomitant blockade of transient receptor potential vanilloid type-1 (TRPV1) channels by capsazepine (CPZ) [1]. In this study, we showed that stimulation of peroxisome proliferator-activated receptors (PPAR), a family of transcription factors activated by anandamide, contributes to the anti-dyskinetic effects of URB+CPZ, and that direct activation of the PPARγ subtype by rosiglitazone (RGZ) alleviates levodopa-induced AIMs in 6-OHDA rats. AIM reduction was associated with an attenuation of levodopa-induced increase of dynorphin, zif-268 and of ERK phosphorylation in the denervated striatum. RGZ treatment did not decrease striatal levodopa and dopamine bioavailability, nor did it affect levodopa antiparkinsonian activity. Collectively, these data indicate that PPARγ may represent a new pharmacological target for the treatment of LID. PMID:25486547

  11. Decreased synaptic plasticity in the medial prefrontal cortex underlies short-term memory deficits in 6-OHDA-lesioned rats.

    PubMed

    Matheus, Filipe C; Rial, Daniel; Real, Joana I; Lemos, Cristina; Ben, Juliana; Guaita, Gisele O; Pita, Inês R; Sequeira, Ana C; Pereira, Frederico C; Walz, Roger; Takahashi, Reinaldo N; Bertoglio, Leandro J; Da Cunha, Cláudio; Cunha, Rodrigo A; Prediger, Rui D

    2016-03-15

    Parkinson's disease (PD) is characterized by motor dysfunction associated with dopaminergic degeneration in the dorsolateral striatum (DLS). However, motor symptoms in PD are often preceded by short-term memory deficits, which have been argued to involve deregulation of medial prefrontal cortex (mPFC). We now used a 6-hydroxydopamine (6-OHDA) rat PD model to explore if alterations of synaptic plasticity in DLS and mPFC underlie short-term memory impairments in PD prodrome. The bilateral injection of 6-OHDA (20μg/hemisphere) in the DLS caused a marked loss of dopaminergic neurons in the substantia nigra (>80%) and decreased monoamine levels in the striatum and PFC, accompanied by motor deficits evaluated after 21 days in the open field and accelerated rotarod. A lower dose of 6-OHDA (10μg/hemisphere) only induced a partial degeneration (about 60%) of dopaminergic neurons in the substantia nigra with no gross motor impairments, thus mimicking an early premotor stage of PD. Notably, 6-OHDA (10μg)-lesioned rats displayed decreased monoamine levels in the PFC as well as short-term memory deficits evaluated in the novel object discrimination and in the modified Y-maze tasks; this was accompanied by a selective decrease in the amplitude of long-term potentiation in the mPFC, but not in DLS, without changes of synaptic transmission in either brain regions. These results indicate that the short-term memory dysfunction predating the motor alterations in the 6-OHDA model of PD is associated with selective changes of information processing in PFC circuits, typified by persistent changes of synaptic plasticity.

  12. Adrenal Medullary Grafts Restore Olfactory Deficits and Catecholamine Levels of 6-OHDA Amygdala Lesioned Animals

    PubMed Central

    Fernández-Ruiz, Juan; Guzmán, Rubén; Martínez, María Dolores; Miranda, María Isabel; Bermúdez-Rattoni, Federico; Drucker-Colín, René

    1993-01-01

    Aside from motor and cognitive deficits, Parkinson patients also manifest a little-studied olfactory deficit. Since in Parkinson's disease there is a dopamine depletion of the amygdala due to mesocorticolimbic system degeneration, we decided to test olfactory and taste performance of 6-OHDA amygdala lesioned rats, as well as the possible restoration of either function with adrenal medullary transplants. Two 6-OHDA lesioned groups and one control group were tested in the potentiation of odor by taste aversion paradigm. On taste aversion none of the groups showed any impairment. In contrast, the 6-OHDA lesioned rats showed a marked impairment in olfactory aversion. At this point, one of the lesioned groups received a bilateral adrenal medullary graft within the lesioned area. After two months, all groups were submitted again to the behavioral paradigm. Taste remained unaffected, but the lesioned only group did not recover either olfactory aversion or normal catecholamine levels. The grafted group, on the other hand, restored olfactory aversion and catecholamine levels. It can be concluded from this study that catecholamine depletion of the amygdala is sufficient to produce a selective olfactory deficit, not accompanied by taste impairments, and that such a deficit can be reversed by adrenal medullary transplants, which in turn restore catecholamine levels. PMID:7948179

  13. Activation of PPAR gamma receptors reduces levodopa-induced dyskinesias in 6-OHDA-lesioned rats.

    PubMed

    Martinez, A A; Morgese, M G; Pisanu, A; Macheda, T; Paquette, M A; Seillier, A; Cassano, T; Carta, A R; Giuffrida, A

    2015-02-01

    Long-term administration of l-3,4-dihydroxyphenylalanine (levodopa), the mainstay treatment for Parkinson's disease (PD), is accompanied by fluctuations in its duration of action and motor complications (dyskinesia) that dramatically affect the quality of life of patients. Levodopa-induced dyskinesias (LID) can be modeled in rats with unilateral 6-OHDA lesions via chronic administration of levodopa, which causes increasingly severe axial, limb, and orofacial abnormal involuntary movements (AIMs) over time. In previous studies, we showed that the direct activation of CB1 cannabinoid receptors alleviated rat AIMs. Interestingly, elevation of the endocannabinoid anandamide by URB597 (URB), an inhibitor of endocannabinoid catabolism, produced an anti-dyskinetic response that was only partially mediated via CB1 receptors and required the concomitant blockade of transient receptor potential vanilloid type-1 (TRPV1) channels by capsazepine (CPZ) (Morgese et al., 2007). In this study, we showed that the stimulation of peroxisome proliferator-activated receptors (PPAR), a family of transcription factors activated by anandamide, contributes to the anti-dyskinetic effects of URB+CPZ, and that the direct activation of the PPARγ subtype by rosiglitazone (RGZ) alleviates levodopa-induced AIMs in 6-OHDA rats. AIM reduction was associated with an attenuation of levodopa-induced increase of dynorphin, zif-268, and of ERK phosphorylation in the denervated striatum. RGZ treatment did not decrease striatal levodopa and dopamine bioavailability, nor did it affect levodopa anti-parkinsonian activity. Collectively, these data indicate that PPARγ may represent a new pharmacological target for the treatment of LID.

  14. Protective effect of methanolic extract of Garcinia indica fruits in 6-OHDA rat model of Parkinson's disease

    PubMed Central

    Antala, Bhaveshkumar V.; Patel, Manishkumar S.; Bhuva, Satish V.; Gupta, Shiv; Rabadiya, Samir; Lahkar, Mangala

    2012-01-01

    Context: Several studies have reported that antioxidants play an important role in Parkinson's disease (PD). Garcinia indica extract is a natural antioxidant, the present study was undertaken to evaluate the neuroprotective effect of methanolic extract of Garcinia indica (GIM) against 6-hydroxydopamine (6-OHDA) neurotoxicity for striatal dopaminergic neurons in the rat. Materials and Methods: Thirty adult Wistar rats were randomly divided into five groups namely control, 6-OHDA model, and GIM (100, 200, and 400 mg/kg body weight suspended in one ml of 0.1% carboxymethyl cellulose). The treatment was started three days before surgery and continued for next 14 days. The surgery was done on third day in all groups for administration of 6-OHDA into the right striatum and right substantia nigra, whereas control group injected with 6-OHDA vehicle. Various behavior and biochemical tests (Apomorphine-induced rotational behavior, Stepping test, Initiation time, Postural balance test, and Disengage time) were used to evaluate the neuroprotective effect of GIM. One-way analysis of variance (ANOVA) followed by Dunnett's test was used to compare inter-group differences. P<0.05 was considered as statistically significant. Results: GIM had significant (P<0.05, P<0.01) preventive effect in biochemical tests, i.e., dopamine and its metabolites measurement and in various behavior tests, i.e., apomorphine-induced rotational behavior, stepping test, initiation time, postural balance test, and disengage time as compared to 6-OHDA-treated rats. Conclusions: Our results demonstrated that GIM acted as an effective neuroprotective agent for striatal dopaminergic neurons in 6-OHDA lesioned rat model of PD. PMID:23248394

  15. Caffeine neuroprotective effects on 6-OHDA-lesioned rats are mediated by several factors, including pro-inflammatory cytokines and histone deacetylase inhibitions.

    PubMed

    Machado-Filho, João Ananias; Correia, Alyne Oliveira; Montenegro, Anyssa Brilhante Aires; Nobre, Maria Elizabeth Pereira; Cerqueira, Gilberto Santos; Neves, Kelly Rose Tavares; Naffah-Mazzacoratti, Maria da Graça; Cavalheiro, Esper Abrão; de Castro Brito, Gerly Anne; de Barros Viana, Glauce Socorro

    2014-05-01

    Several lines of evidences have shown the inversion association between coffee consumption and Parkinson's disease (PD) development. Caffeine is a methylxanthine known as a non-selective inhibitor of A2A and A1 adenosine receptors in the brain and shown to be a neuroprotective drug. The objectives were to study caffeine effects in a unilateral 6-OHDA model of PD in rats. Male rats were divided into the following groups: sham-operated (SO), striatal 6-OHDA-lesioned and 6-OHDA-lesioned and treated for 2 weeks with caffeine (10 and 20mg/kg, p.o.). Then, animals were subjected to behavioral (open field and apomorphine-induced rotations), neurochemical (striatal determinations of DA and DOPAC), histological (cresyl violet staining) and immunohistochemical (TH, TNF-α, IL-1β and HDAC) evaluations. The results showed that while the 6-OHDA group presented a decreased locomotor activity and a high number of apomorphine-induced rotations, these behaviors were partially blocked by caffeine. Caffeine itself increased DA contents and reversed the decrease in striatal DA observed in the 6-OHDA-lesioned group. Furthermore, it improved the hippocampal neuronal viability and significantly increased TH immunoreactivity in the striatum of the 6-OHDA-lesioned group. In addition, caffeine treatment also decreased the number of immunopositive cells for HDAC and pro-inflammatory cytokines TNF-α and IL-1β. All these effects points out to a neuroprotective effect of caffeine and its potential benefit in the prevention and treatment of PD.

  16. The unilateral 6-OHDA rat model of Parkinson's disease revisited: an electromyographic and behavioural analysis.

    PubMed

    Metz, Gerlinde A; Tse, Arthur; Ballermann, Mark; Smith, Lori K; Fouad, Karim

    2005-08-01

    The characteristic locomotor disturbances of Parkinson's disease (PD) include shuffling gait, short steps and low walking velocity. In this study we investigated features of walking and turning in a rat model of PD caused by unilateral infusion of the neurotoxin 6-hydroxydopamine (6-OHDA). We assessed gait and electromyographic (EMG) patterns of the ankle flexor tibialis anterior and the knee extensor vastus lateralis of the hindlimb, and triceps brachii of the forelimb, during overground locomotion, spontaneous rotation (turning) and apomorphine-induced rotation. When compared with control rats, rats with unilateral dopamine depletion displayed a shuffling gait and short stride lengths. This locomotor pattern was accompanied by prolonged ankle flexor activity on the ipsilateral side, and prolonged activity of knee extensors on the contralateral side. The dopamine depletion also led to enhanced contraversive rotations after an apomorphine challenge. The EMG recordings during drug-induced rotation suggested that hindlimb stepping was a reflective response to an active drive produced by forelimbs. The EMG recordings of the contralateral side during rotation were marked by reduced ankle flexor activity and increased knee extensor activity. Furthermore, EMG recordings indicated that dopamine-agonists induce rotational bias by altering the coupling between ipsi- and contralateral hindlimbs, and between forelimbs. In straight walking, however, the gait of 6-OHDA lesion animals reflected normal, coupled hindlimb stepping as controlled by spinal pattern generators. The data suggest that the unilateral rat model of PD resembles key features of human parkinsonian gait, and that asymmetric descending input may underlie the observed changes in gait patterns.

  17. Effects of Cultured Adrenal Chromaffin Cell Implants on Hindlimb Reflexes of the 6-OHDA Lesioned Rat

    PubMed Central

    Pulford, Bruce E.; Mihajlov, Andrea R.; Nornes, Howard O.; Whalen, L. Ray

    1994-01-01

    The effects of implantation of cultured adrenal medullary cells on the recovery of neurotransmitter specific reflex activity were studied in the rat spinal cord using electrophysiological testing methods. Cell suspensions of cultured neonatal adrenal medullary chromaffin (AM) cells (which produce catecholamines), or Schwann (Sc) cells (controls) were implanted into the lumbar region of the spinal cord 2 weeks after catecholamine (CA) denervation by intracisternal injection of 6-hydroxydopamine (6-OHDA). All cells were taken from 7 day neonates and cultured for 10 days in the presence of nerve growth factor (NGF). Three months after implantation, the extent of implant-associated recovery of reflex activity was determined by measuring electromyogram (EMG) activity and force associated with the long latency component of the hindlimb withdrawal reflex (which is CA modulated). After the electrophysiological testing, rats were anesthetized, and the spinal cords were rapidly removed and frozen. Spinal cords were sectioned longitudinally, and implanted cells were visualized using glyoxylic acid techniques. Labelled sections were examined to determine cell survival. Results indicate that 1) chromaffin cells survive for 3 months in the segments of the cord into which they have been implanted and 2) rats implanted with AM cells have significantly more forceful withdrawal reflexes than those that received Sc cells or received no implant after lesioning. PMID:7703294

  18. Dynamic of neurochemical alterations in striatum, hippocampus and cortex after the 6-OHDA mesostriatal lesion.

    PubMed

    Zhang, Sheng; Gui, Xue-Hong; Xue, Zhong-Feng; Huang, Li-Ping; Fang, Ruo-Ming; Ke, Xue-Hong; Li, Ling; Fang, Yong-Qi

    2014-08-01

    Immediate neurochemical alterations produced by 6-OHDA could explain the general toxic pattern in the central nervous system. However, no evidences describe the effects of 6-OHDA on early changes of neurotransmitters in rats' striatum, cortex and hippocampus. In our study, unilateral 6-OHDA injection into medial forebrain bundle (MFB) was used in rats, then five neurotransmitters were analyzed at 3, 6, 12, 24, 48 and 72 h, respectively. Results showed that 6-OHDA injection caused a sharp decline of striatal dopamine (DA) levels in the first 12h followed by a further reduction between 12 and 48 h. However, striatal levels of homovanillic acid (HVA) were stable in the first 12h and showed a marked reduction between 12 and 24h. Striatal levels of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) decreased linearly for 72 h, whereas levels of norepinephrine (NE) showed a slight reduction in the first 48 h, and returned back to normal afterwards. Striatal HVA/DA ratio increased significantly in the first 12h, but 5-HIAA/5-HT ratio showed a sharp increase between 12 and 72 h. Besides, neurochemical alterations were also found in hippocampus and cortex, and the correlations of neurotransmitters were analyzed. Our study indicated that NE system had little influence in the early phase of 6-OHDA injection, moreover, early neurochemical alterations were involved with striatum, hippocampus and cortex.

  19. Progressive impairment in motor skill learning at 12 and 20 weeks post 6-OHDA- SNc lesion in rats.

    PubMed

    Gambhir, Hardeep; Mathur, Rashmi; Behari, Madhuri

    2011-07-01

    Deficiency in skilled motor activity is primarily attributed to the loss of dopaminergic neurons in the pars compacta of substantia nigra (SNc), which can be detected by performance of the rotarod test. Previous reports have demonstrated impaired skilled motor behavior in rats during the pre-motor stage of Parkinson's disease (PD) (3-8 weeks post 6-OHDA lesion of striatum). We studied skilled motor learning in 6-hydroxydopamine (6-OHDA) SNc lesion rats at 12 and 20 weeks by rotarod task after providing sufficient training to give allowance for ageing (3 sessions/day for 14 consecutive days). On each day, the stay duration on rotarod was noted and compared between the groups (Group 1 = Control, Group 2 = Post lesion (PL) week 12, Group 3 = PL week 20). In Group 2 rats, the duration of stay on rotarod gradually increased from day 1 through 7 {day 7 = 193.1 (81.8-247.4) vs. control group day 7 = 202.1 (87.7-279.8), p = 0.771} and declined thereafter. While, the stay duration in Group 3 rats remained lower {day 7 = 32.5 (20.4-52.1), p = 0.011} than that of the control rats throughout the study period. The results of our study suggest a slower brief learning of skilled motor tasks at post lesion week 12 whereas no learning at all at post-lesion week 20.

  20. Valproic Acid Neuroprotection in the 6-OHDA Model of Parkinson's Disease Is Possibly Related to Its Anti-Inflammatory and HDAC Inhibitory Properties

    PubMed Central

    Ximenes, José Christian Machado; Neves, Kelly Rose Tavares; Leal, Luzia Kalyne A. M.; do Carmo, Marta Regina Santos; Brito, Gerly Anne de Castro; Naffah-Mazzacoratti, Maria da Graça; Cavalheiro, Ésper Abrão; Viana, Glauce Socorro de Barros

    2015-01-01

    Parkinson's disease is a neurodegenerative disorder where the main hallmark is the dopaminergic neuronal loss. Besides motor symptoms, PD also causes cognitive decline. Although current therapies focus on the restoration of dopamine levels in the striatum, prevention or disease-modifying therapies are urgently needed. Valproic acid (VA) is a wide spectrum antiepileptic drug, exerting many biochemical and physiological effects. It has been shown to inhibit histone deacetylase which seems to be associated with the drug neuroprotective action. The objectives were to study the neuroprotective properties of VA in a model of Parkinson's disease, consisting in the unilateral striatal injection of the neurotoxin 6-OHDA. For that, male Wistar rats (250 g) were divided into the groups: sham-operated (SO), untreated 6-OHDA-lesioned, and 6-OHDA-lesioned treated with VA (25 or 50 mg/kg). Oral treatments started 24 h after the stereotaxic surgery and continued daily for 2 weeks, when the animals were subjected to behavioral evaluations (apomorphine-induced rotations and open-field tests). Then, they were sacrificed and had their mesencephalon, striatum, and hippocampus dissected for neurochemical (DA and DOPAC determinations), histological (Fluoro-Jade staining), and immunohistochemistry evaluations (TH, OX-42, GFAP, TNF-alpha, and HDAC). The results showed that VA partly reversed behavioral and neurochemical alterations observed in the untreated 6-OHDA-lesioned rats. Besides, VA also decreased neuron degeneration in the striatum and reversed the TH depletion observed in the mesencephalon of the untreated 6-OHDA groups. This neurotoxin increased the OX-42 and GFAP immunoreactivities in the mesencephalon, indicating increased microglia and astrocyte reactivities, respectively, which were reversed by VA. In addition, the immunostainings for TNF-alpha and HDAC demonstrated in the untreated 6-OHDA-lesioned rats were also decreased after VA treatments. These results were

  1. Depressive-like behaviors alterations induced by intranigral MPTP, 6-OHDA, LPS and rotenone models of Parkinson's disease are predominantly associated with serotonin and dopamine.

    PubMed

    Santiago, Ronise M; Barbieiro, Janaína; Lima, Marcelo M S; Dombrowski, Patrícia A; Andreatini, Roberto; Vital, Maria A B F

    2010-08-16

    Depression is a frequently encountered non-motor feature of Parkinson's disease (PD) and it can have a significant impact on patient's quality of life. Considering the differential pathophysiology of depression in PD, it prompts the idea that a degenerated nigrostriatal system plays a role in depressive-like behaviors, whilst animal models of PD are employed. Therefore, we addressed the question of whether dopamine (DA) depletion, promoted by the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), lipopolysaccharide (LPS) and rotenone are able to induce depressive-like behaviors and neurotransmitters alterations similarly that encountered in PD. To test this rationale, we performed intranigral injections of each neurotoxin, followed by motor behavior, depressive-like behaviors, histological and neurochemical tests. After the motor recovery period, MPTP, 6-OHDA and rotenone were able to produce anhedonia and behavioral despair. These altered behavioral responses were accompanied by reductions of striatal DA, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) restricted to the 6-OHDA group. Additionally, decreases on the hippocampal serotonin (5-HT) content were detected for the MPTP, 6-OHDA and rotenone groups. Notably, strong correlations were detected among the groups when 5-HT and DA were correlated with swimming (r=+0.97; P=0.001) and immobility (r=-0.90; P=0.012), respectively. Our data indicate that MPTP, 6-OHDA and rotenone, but not LPS were able to produce depressive-like behaviors accompanied primarily by hippocampal 5-HT reductions. Moreover, DA and 5-HT strongly correlated with "emotional" impairments suggesting an important participation of these neurotransmitters in anhedonia and behavioral despair after nigral lesions promoted by the neurotoxins.

  2. Neuroprotective Properties of the Standardized Extract from Camellia sinensis (Green Tea) and Its Main Bioactive Components, Epicatechin and Epigallocatechin Gallate, in the 6-OHDA Model of Parkinson's Disease

    PubMed Central

    Bitu Pinto, Natália; da Silva Alexandre, Bruno; Neves, Kelly Rose Tavares; Silva, Aline Holanda; Leal, Luzia Kalyne A. M.; Viana, Glauce S. B.

    2015-01-01

    Camellia sinensis (green tea) is largely consumed, mainly in Asia. It possesses several biological effects such as antioxidant and anti-inflammatory properties. The objectives were to investigate the neuroprotective actions of the standardized extract (CS), epicatechin (EC) and epigallocatechin gallate (EGCG), on a model of Parkinson's disease. Male Wistar rats were divided into SO (sham-operated controls), untreated 6-OHDA-lesioned and 6-OHDA-lesioned treated for 2 weeks with CS (25, 50, or 100 mg/kg), EC (10 mg/kg), or EGCG (10 mg/kg) groups. One hour after the last administration, animals were submitted to behavioral tests and euthanized and their striata and hippocampi were dissected for neurochemical (DA, DOPAC, and HVA) and antioxidant activity determinations, as well as immunohistochemistry evaluations (TH, COX-2, and iNOS). The results showed that CS and catechins reverted behavioral changes, indicating neuroprotection manifested as decreased rotational behavior, increased locomotor activity, antidepressive effects, and improvement of cognitive dysfunction, as compared to the untreated 6-OHDA-lesioned group. Besides, CS, EP, and EGCG reversed the striatal oxidative stress and immunohistochemistry alterations. These results show that the neuroprotective effects of CS and its catechins are probably and in great part due to its powerful antioxidant and anti-inflammatory properties, pointing out their potential for the prevention and treatment of PD. PMID:26167188

  3. Behavioral and Neurochemical Effects of Alpha-Lipoic Acid in the Model of Parkinson's Disease Induced by Unilateral Stereotaxic Injection of 6-Ohda in Rat

    PubMed Central

    de Araújo, Dayane Pessoa; De Sousa, Caren Nádia Soares; Araújo, Paulo Victor Pontes; Menezes, Carlos Eduardo de Souza; Sousa Rodrigues, Francisca Taciana; Escudeiro, Sarah Souza; Lima, Nicole Brito Cortez; Patrocínio, Manoel Claúdio Azevedo; Aguiar, Lissiana Magna Vasconcelos; Viana, Glauce Socorro de Barros; Vasconcelos, Silvânia Maria Mendes

    2013-01-01

    This study aimed to investigate behavioral and neurochemical effects of α-lipoic acid (100 mg/kg or 200 mg/kg) alone or associated with L-DOPA using an animal model of Parkinson's disease induced by stereotaxic injection of 6-hydroxydopamine (6-OHDA) in rat striatum. Motor behavior was assessed by monitoring body rotations induced by apomorphine, open field test and cylinder test. Oxidative stress was accessed by determination of lipid peroxidation using the TBARS method, concentration of nitrite and evaluation of catalase activity. α-Lipoic acid decreased body rotations induced by apomorphine, as well as caused an improvement in motor performance by increasing locomotor activity in the open field test and use of contralateral paw (in the opposite side of the lesion produced by 6-OHDA) at cylinder test. α-lipoic acid showed antioxidant effects, decreasing lipid peroxidation and nitrite levels and interacting with antioxidant system by decreasing of endogenous catalase activity. Therefore, α-lipoic acid prevented the damage induced by 6-OHDA or by chronic use of L-DOPA in dopaminergic neurons, suggesting that α-lipoic could be a new therapeutic target for Parkinson's disease prevention and treatment. PMID:24023579

  4. High correlation between in vivo [123I]β-CIT SPECT/CT imaging and post-mortem immunohistochemical findings in the evaluation of lesions induced by 6-OHDA in rats

    PubMed Central

    2013-01-01

    Background 6-Hydroxydopamine (6-OHDA) is widely used in pre-clinical animal studies to induce degeneration of midbrain dopamine neurons to create animal models of Parkinson's disease. The aim of our study was to evaluate the potential of combined single-photon emission computed tomography/computed tomography (SPECT/CT) for the detection of differences in 6-OHDA-induced partial lesions in a dose- and time-dependent manner using the dopamine transporter (DAT) ligand 2β-carbomethoxy-3β-(4-[123I]iodophenyl)tropane ([123I]β-CIT). Methods Rats were unilaterally lesioned with intrastriatal injections of 8 or 2 × 10 μg 6-OHDA. At 2 or 4 weeks post-lesion, 40 to 50 MBq [123I]β-CIT was administered intravenously and rats were imaged with small-animal SPECT/CT under isoflurane anesthesia. The striatum was delineated and mean striatal activity in the lesioned side was compared to the intact side. After the [123I]β-CIT SPECT/CT scan, the rats were tested for amphetamine-induced rotation asymmetry, and their brains were immunohistochemically stained for DAT and tyrosine hydroxylase (TH). The fiber density of DAT- and TH-stained striata was estimated, and TH-immunoreactive cells in the rat substantia nigra pars compacta (SNpc) were stereologically counted. Results The striatal uptake of [123I]β-CIT differed significantly between the lesion groups and the results were highly correlated to both striatal DAT- and TH-immunoreactive fiber densities and to TH-immunoreactive cell numbers in the rat SNpc. No clear progression of the lesion could be seen. Conclusions [123I]β-CIT SPECT/CT is a valuable tool in predicting the condition of the rat midbrain dopaminergic pathway in the unilateral partial 6-OHDA lesion model of Parkinson's disease and it offers many advantages, allowing repeated non-invasive analysis of living animals. PMID:23758882

  5. (6aR)-11-amino-N-propyl-noraporphine, a new dopamine D2 and serotonin 5-HT1A dual agonist, elicits potent antiparkinsonian action and attenuates levodopa-induced dyskinesia in a 6-OHDA-lesioned rat model of Parkinson's disease.

    PubMed

    Zhao, Rui; Lu, Weijian; Fang, Xing; Guo, Lin; Yang, Zhi; Ye, Na; Zhao, Jiahao; Liu, Zhili; Jia, Jia; Zheng, Longtai; Zhao, Bin; Zhang, Ao; Zhen, Xuechu

    2014-09-01

    Parkinson's disease (PD) drug therapy remains a challenge. Dual modulation of dopamine and 5-HT receptors has emerged as a promising approach in anti-PD drug development. Taking advantage of the newly discovered aporphine analogue(s), (6aR)-11-amino-N-propyl-noraporphine (SOMCL-171), which exhibited dual D2/5-HT1A receptor agonistic activity, we studied the effects of the compound on levodopa-induced dyskinesia (LID) in a PD animal model. The results demonstrated that SOMCL-171 elicited a potent anti-PD effect in a 6-OHDA-lesioned rat model. Chronic use of SOMCL-171 reduced LID without compromising the antiparkinsonian efficacy. Furthermore, we found that the antidyskinesia effect of SOMCL-171 is associated with its 5-HT1A agonistic activity and the up-regulation of the striatal 5-HT1A receptor. The present data indicated that chronic SOMCL-171 alone produced potent antiparkinsonian effects with weak dyskinesia, compared with that of levodopa. In addition, chronic SOMCL-171 application attenuated the development of levodopa-induced LID at no expense to the antiparkinsonian efficacy. Taken together, our data suggested that dual modulation of D2/5-HT1A receptors may provide a novel approach for drug development in PD and LID.

  6. The CB1 cannabinoid receptor agonist reduces L-DOPA-induced motor fluctuation and ERK1/2 phosphorylation in 6-OHDA-lesioned rats.

    PubMed

    Song, Lu; Yang, Xinxin; Ma, Yaping; Wu, Na; Liu, Zhenguo

    2014-01-01

    The dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) has been used as an effective drug for treating dopamine depletion-induced Parkinson's disease (PD). However, long-term administration of L-DOPA produces motor complications. L-DOPA has also been found to modify the two key signaling cascades, protein kinase A/dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) and extracellular signal-regulated kinases 1 and 2 (ERK1/2), in striatal neurons, which are thought to play a pivotal role in forming motor complications. In the present study, we tested the possible effect of a CB1 cannabinoid receptor agonist on L-DOPA-stimulated abnormal behavioral and signaling responses in vivo. Intermittent L-DOPA administration for 3 weeks induced motor fluctuation in a rat model of PD induced by intrastriatal infusion of dopamine-depleting neurotoxin 6-hydroxydopamine (6-OHDA). A single injection of a CB1 cannabinoid receptor agonist WIN-55,212-2 had no effect on L-DOPA-induced motor fluctuation. However, chronic injections of WIN-55,212-2 significantly attenuated abnormal behavioral responses to L-DOPA in 6-OHDA-lesioned rats. Similarly, chronic injections of WIN-55,212-2 influence the L-DOPA-induced alteration of DARPP-32 and ERK1/2 phosphorylation status in striatal neurons. These data provide evidence for the active involvement of CB1 cannabinoid receptors in the regulation of L-DOPA action during PD therapy.

  7. Use of [18F]FDOPA-PET for in vivo evaluation of dopaminergic dysfunction in unilaterally 6-OHDA-lesioned rats

    PubMed Central

    2011-01-01

    Background We evaluated the utility of L-3,4-dihydroxy-6-[18F]fluoro-phenylalanine ([18F]FDOPA) positron emission tomography (PET) as a method for assessing the severity of dopaminergic dysfunction in unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats by comparing it with quantitative biochemical, immunohistochemical, and behavioral measurements. Methods Different doses of 6-OHDA (0, 7, 14, and 28 μg) were unilaterally injected into the right striatum of male Sprague-Dawley rats. Dopaminergic functional activity in the striatum was assessed by [18F]FDOPA-PET, measurement of striatal dopamine (DA) and DA metabolite levels, tyrosine hydroxylase (TH) immunostaining, and methamphetamine-induced rotational testing. Results Accumulation of [18F]FDOPA in the bilateral striatum was observed in rats pretreated with both aromatic L-amino acid decarboxylase and catechol-O-methyltransferase (COMT) inhibitors. Unilateral intrastriatal injection of 6-OHDA produced a significant site-specific reduction in [18F]FDOPA accumulation. The topological distribution pattern of [18F]FDOPA accumulation in the ipsilateral striatum agreed well with the pattern in TH-stained corresponding sections. A significant positive relationship was found between Patlak plot Ki values and striatal levels of DA and its metabolites (r = 0.958). A significant negative correlation was found between both Ki values (r = -0.639) and levels of DA and its metabolites (r = -0.719) and the number of methamphetamine-induced rotations. Conclusions Ki values determined using [18F]FDOPA-PET correlated significantly with the severity of dopaminergic dysfunction. [18F]FDOPA-PET makes it possible to perform longitudinal evaluation of dopaminergic function in 6-OHDA-lesioned rats, which is useful in the development of new drugs and therapies for Parkinson's disease (PD). PMID:22214344

  8. Differential induction of dyskinesia and neuroinflammation by pulsatile versus continuous l-DOPA delivery in the 6-OHDA model of Parkinson's disease.

    PubMed

    Mulas, Giovanna; Espa, Elena; Fenu, Sandro; Spiga, Saturnino; Cossu, Giovanni; Pillai, Elisabetta; Carboni, Ezio; Simbula, Gabriella; Jadžić, Dragana; Angius, Fabrizio; Spolitu, Stefano; Batetta, Barbara; Lecca, Daniela; Giuffrida, Andrea; Carta, Anna R

    2016-12-01

    Neuroinflammation is associated with l-DOPA treatment in Parkinson's disease (PD), suggesting a role in l-DOPA-induced dyskinesia (LID), however it is unclear whether increased inflammation is specifically related to the dyskinetic outcome of l-DOPA treatment. Diversely from oral l-DOPA, continuous intrajejunal l-DOPA infusion is associated with very low dyskinetic outcome in PD patients. We reproduced these regimens of administration in 6-OHDA-lesioned hemiparkinsonian rats, where dyskinetic responses and striatal neuroinflammation induced by chronic pulsatile (DOPAp) or continuous (DOPAc) l-DOPA were compared. Moreover, we investigated the contribution of a peripheral inflammatory challenge with lipopolysaccharide (LPS), to DOPAp-induced dyskinetic and neuroinflammatory responses. Rats 6-OHDA-infused in the medial forebrain bundle received two weeks treatment with DOPAp, DOPAc via subcutaneous osmotic minipumps, or DOPAp followed by DOPAc. l-DOPA plasma levels were measured in all experimental groups. An independent group of rats received one peripheral dose of LPS 24h before DOPAp treatment. Abnormal involuntary movements (AIMs) were evaluated as a rat model of LID. Immunoreactivity (IR) for OX-42, microglial and neuronal TNF-α, iNOS and GFAP was quantified in denervated and contralateral striatum. In addition, serum TNF-α was measured. The 6-OHDA denervation induced a mild microgliosis in the striatum two weeks after neurotoxin infusion, and increased TNF-α IR in microglia. Rats receiving the DOPAp treatment developed AIMs and displayed increased striatal OX-42, microglial TNF-α, iNOS and GFAP. Moreover, TNF-α IR was also increased in a subpopulation of striatal neurons. Conversely, DOPAc did not induce AIMs or inflammatory responses in either drug-naïve animals or rats that were previously dyskinetic when exposed to DOPAp. Serum TNF-α was not altered by any l-DOPA treatment. LPS pre-treatment increased the degree of DOPAp-induced AIMs and striatal IR

  9. Induction and expression of abnormal involuntary movements is related to the duration of dopaminergic stimulation in 6-OHDA-lesioned rats.

    PubMed

    Papathanou, Maria; Rose, Sarah; McCreary, Andrew; Jenner, Peter

    2011-06-01

    Dyskinesia induction in Parkinson's disease (PD) appears less marked with long-acting dopamine agonists than with short-acting L-Dopa, but the relationship to duration of drug action is unknown. It is also unclear whether the duration of drug action affects the expression of established dyskinesia. This study compared the ability of L-Dopa and four dopamine agonists of different duration of action to induce abnormal involuntary movements (AIMs) in 6-hydroxydopamine (6-OHDA)-lesioned rats, and their ability to express established AIMs following prior exposure to L-Dopa. 6-OHDA-lesioned rats were treated with saline, L-Dopa/benserazide, apomorphine, ropinirole, pramipexole or pergolide once daily for 15 days. Repeated administration of the short-acting dopamine agonists, apomorphine (duration 80 min) and ropinirole (duration 90 min) induced marked axial, limb and orolingual AIMs at peak effect. L-Dopa (duration 100 min) produced moderate AIMs at peak effect, while administration of the long-acting dopamine agonists, pramipexole (duration 150 min) and pergolide (duration 240 min) resulted in mild AIMs. In rats primed to exhibit severe AIMs following repeated L-Dopa administration, acute administration of apomorphine, ropinirole and L-Dopa induced severe AIMs. By contrast, pramipexole and pergolide evoked only mild-moderate AIMs. Again, there was a negative correlation between duration of effect and the severity of AIMs expressed. These studies show that both the induction and expression of AIMs in 6-OHDA-lesioned rats are related to the duration of action of dopaminergic drugs. These findings suggest that continuous dopaminergic stimulation could be used both to avoid dyskinesia induction and to improve motor function in late-stage PD when troublesome dyskinesia is evident.

  10. 6-OHDA injections into A8-A9 dopaminergic neurons modelling early stages of Parkinson's disease increase the harmaline-induced tremor in rats.

    PubMed

    Kolasiewicz, Wacław; Kuter, Katarzyna; Berghauzen, Klemencja; Nowak, Przemysław; Schulze, Gert; Ossowska, Krystyna

    2012-10-05

    The aim of the present study was to examine the influence of a unilateral 6-hydroxydopamine (6-OHDA)-induced partial lesion of both the substantia nigra pars compacta (SNc, A9) and retrorubral field (RRF, A8) on the tremor evoked by harmaline. 6-OHDA (8μg/2μl) was injected unilaterally into the region of the posterior part of the SNc and RRF. Harmaline was administered in a dose of 7.5mg/kg ip on the eighth day after the operation and tremor of forelimbs, head and trunk was measured. We found that the lesion increased intensity of the tremor induced by harmaline but did not influence its character. Stereological examination of the lesion extent revealed losses of dopaminergic (tyrosine hydroxylase-immunoreactive) neurons in the anterior (30%) and posterior (72%) SNc, as well as in RRF (72% on the average). Levels of dopamine and all its metabolites, as well as noradrenaline concentrations, were ipsilaterally moderately decreased in the caudate-putamen in the lesioned animals, however, dopamine and DOPAC in the anterior cerebellum were increased. In the caudate-putamen, the ipsi/contra ratio of dopamine level correlated negatively, while that of dopamine turnover positively with the tremor intensity. However, in the anterior cerebellum an inverse relationship was found. Moreover, this symptom correlated positively with the serotonin level and negatively with the 5-HIAA/serotonin ratio on the contralateral side of the posterior cerebellum. The present results seem to indicate that the modulation of dopaminergic and serotonergic transmissions by the lesion modelling early stages of Parkinson's disease may influence tremor triggered in the cerebellum.

  11. Dopaminergic neurotoxicant 6-OHDA induces oxidative damage through proteolytic activation of PKC{delta} in cell culture and animal models of Parkinson's disease

    SciTech Connect

    Latchoumycandane, Calivarathan; Anantharam, Vellareddy; Jin, Huajun; Kanthasamy, Anumantha; Kanthasamy, Arthi

    2011-11-15

    The neurotoxicant 6-hydroxydopamine (6-OHDA) is used to investigate the cellular and molecular mechanisms underlying selective degeneration of dopaminergic neurons in Parkinson's disease (PD). Oxidative stress and caspase activation contribute to the 6-OHDA-induced apoptotic cell death of dopaminergic neurons. In the present study, we sought to systematically characterize the key downstream signaling molecule involved in 6-OHDA-induced dopaminergic degeneration in cell culture and animal models of PD. Treatment of mesencephalic dopaminergic neuronal N27 cells with 6-OHDA (100 {mu}M) for 24 h significantly reduced mitochondrial activity and increased cytosolic cytochrome c, followed by sequential activation of caspase-9 and caspase-3. Co-treatment with the free radical scavenger MnTBAP (10 {mu}M) significantly attenuated 6-OHDA-induced caspase activities. Interestingly, 6-OHDA induced proteolytic cleavage and activation of protein kinase C delta (PKC{delta}) was completely suppressed by treatment with a caspase-3-specific inhibitor, Z-DEVD-FMK (50 {mu}M). Furthermore, expression of caspase-3 cleavage site-resistant mutant PKC{delta}{sup D327A} and kinase dead PKC{delta}{sup K376R} or siRNA-mediated knockdown of PKC{delta} protected against 6-OHDA-induced neuronal cell death, suggesting that caspase-3-dependent PKC{delta} promotes oxidative stress-induced dopaminergic degeneration. Suppression of PKC{delta} expression by siRNA also effectively protected N27 cells from 6-OHDA-induced apoptotic cell death. PKC{delta} cleavage was also observed in the substantia nigra of 6-OHDA-injected C57 black mice but not in control animals. Viral-mediated delivery of PKC{delta}{sup D327A} protein protected against 6-OHDA-induced PKC{delta} activation in mouse substantia nigra. Collectively, these results strongly suggest that proteolytic activation of PKC{delta} is a key downstream event in dopaminergic degeneration, and these results may have important translational value for

  12. Catechin attenuates behavioral neurotoxicity induced by 6-OHDA in rats.

    PubMed

    Teixeira, M D A; Souza, C M; Menezes, A P F; Carmo, M R S; Fonteles, A A; Gurgel, J P; Lima, F A V; Viana, G S B; Andrade, G M

    2013-09-01

    This study was designed to investigate the beneficial effect of catechin in a model of Parkinson's disease. Unilateral, intrastriatal 6-hydroxydopamine (6-OHDA)-lesioned rats were pretreated with catechin (10 and 30 mg/kg) by intraperitoneal (i.p.) injection 2h before surgery and for 14 days afterwards. After treatments, apomorphine-induced rotations, locomotor activity, working memory and early and late aversive memories were evaluated. The mesencephalon was used to determine the levels of monoamines and measurement of glutathione (GSH). Immunohistochemical staining was also used to evaluate the expression of tyrosine hydroxylase (TH) in mesencephalic and striatal tissues. Catechin administration attenuated the increase in rotational behavior and the decrease in locomotor activity observed in lesioned rats. Although catechin did not rescue the impairment of late aversive memory, it protected the animals against 6-OHDA-induced working memory deficits. Furthermore, catechin treatment restored GSH levels, and significantly increased dopamine and DOPAC content, and TH-immunoreactivity in 6-OHDA-lesioned rats. Catechin protected 6-OHDA-lesioned rats due to its antioxidant action, indicating that it could be useful as an adjunctive therapy for the treatment of Parkinson's disease.

  13. The H3 receptor agonist immepip does not affect l-dopa-induced abnormal involuntary movements in 6-OHDA-lesioned rats.

    PubMed

    Papathanou, Maria; Jenner, Peter; Iravani, Mahmoud; Jackson, Michael; Stockwell, Kim; Strang, Isabel; Zeng, Bai-Yun; McCreary, Andrew C; Rose, Sarah

    2014-10-15

    The treatment of dyskinesia in Parkinson׳s disease remains poor but H3 receptor agonists have been suggested as a novel pharmacological approach. We examined the effects of the H3 agonist, immepip, in 6-OHDA-lesioned rats exhibiting AIMs (abnormal involuntary movements), a rat analogue of dyskinesia, in response to l-dopa compared to the known anti-dyskinetic agents amantadine, MK-801 and 8-OHDPAT. We then attempted to extend these studies in to dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated common marmosets. Amantadine, MK-801 and 8-OHDPAT all dose-dependently reduced l-dopa-induced axial, lingual and oral (ALO) AIMs in 6-OHDA-lesioned animals accompanied by a reduction in contralateral rotation with higher doses of amantadine and MK-801. By contrast, immepip had no effect on AIMs expression or contralateral rotation. In the MPTP-treated common marmoset exhibiting dyskinesia to l-dopa, immepip alone induced retching and in combination with l-dopa administered subcutaneously or orally induced the rapid onset of retching and vomiting which was not controlled by pretreatment with domperidone. Administration of the unrelated H3 agonist, imetit had the same effect. Despite causing negative side-effects, it appears that both agonists reduced the antiparkinsonian response to l-dopa resulting in reduced dyskinesia. H3 agonists appear unlikely candidates for the treatment of dyskinesia in PD based on lack of evidence of efficacy and potential adverse effects.

  14. Pentoxifylline Neuroprotective Effects Are Possibly Related to Its Anti-Inflammatory and TNF-Alpha Inhibitory Properties, in the 6-OHDA Model of Parkinson's Disease.

    PubMed

    Neves, Kelly Rose Tavares; Nobre, Hélio Vitoriano; Leal, Luzia Kalyne A M; de Andrade, Geanne Matos; Brito, Gerly Anne de Castro; Viana, Glauce Socorro de Barros

    2015-01-01

    Pentoxifylline (PTX) is a phosphodiesterase inhibitor with anti-TNF-alpha activity, associated with its anti-inflammatory action. Considering Parkinson's disease (PD) as a neuroinflammatory disorder, the objectives were to evaluate PTX neuroprotective properties, in a model of PD. Male Wistar rats, divided into sham-operated (SO), untreated 6-OHDA, and 6-OHDA treated with PTX (10, 25, and 50 mg/kg) groups, received a unilateral 6-OHDA injection, except the SO group administered with saline. Treatments started 24 h after surgery and continued for 15 days when the animals were submitted to apomorphine-induced rotations, open field, and forced swimming tests. At the next day, they were euthanized and their striata processed for neurochemical (DA and DOPAC determinations), histological, and immunohistochemical (Fluoro-Jade, TH, DAT, OX-42, TNF-alpha, COX-2, and iNOS) studies. PTX reversed the behavioral changes observed in the untreated 6-OHDA animals. Furthermore, PTX partially reversed the decrease in DA contents and improved neuronal viability. In addition, decreases in immunostaining for TH and dopamine transporter (DAT) were reversed. The untreated 6-OHDA group showed intense OX-42, TNF-alpha, COX-2, and iNOS immunoreactivities, which were attenuated by PTX. In conclusion, we demonstrated a neuroprotective effect of PTX, possibly related to its anti-inflammatory and antioxidant actions, indicating its potential as an adjunct treatment for PD.

  15. Coherence of neuronal firing of the entopeduncular nucleus with motor cortex oscillatory activity in the 6-OHDA rat model of Parkinson's disease with levodopa-induced dyskinesias.

    PubMed

    Jin, Xingxing; Schwabe, Kerstin; Krauss, Joachim K; Alam, Mesbah

    2016-04-01

    The pathophysiological mechanisms leading to dyskinesias in Parkinson's disease (PD) after long-term treatment with levodopa remain unclear. This study investigates the neuronal firing characteristics of the entopeduncular nucleus (EPN), the rat equivalent of the human globus pallidus internus and output nucleus of the basal ganglia, and its coherence with the motor cortex (MCx) field potentials in the unilateral 6-OHDA rat model of PD with and without levodopa-induced dyskinesias (LID). 6-hydroxydopamine-lesioned hemiparkinsonian (HP) rats, 6-OHDA-lesioned HP rats with LID (HP-LID) rats, and naïve controls were used for recording of single-unit activity under urethane (1.4 g/kg, i.p) anesthesia in the EPN "on" and "off" levodopa. Over the MCx, the electrocorticogram output was recorded. Analysis of single-unit activity in the EPN showed enhanced firing rates, burst activity, and irregularity compared to naïve controls, which did not differ between drug-naïve HP and HP-LID rats. Analysis of EPN spike coherence and phase-locked ratio with MCx field potentials showed a shift of low (12-19 Hz) and high (19-30 Hz) beta oscillatory activity between HP and HP-LID groups. EPN theta phase-locked ratio was only enhanced in HP-LID compared to HP rats. Overall, levodopa injection had no stronger effect in HP-LID rats than in HP rats. Altered coherence and changes in the phase lock ratio of spike and local field potentials in the beta range may play a role for the development of LID.

  16. Dimethyl fumarate attenuates 6-OHDA-induced neurotoxicity in SH-SY5Y cells and in animal model of Parkinson's disease by enhancing Nrf2 activity.

    PubMed

    Jing, X; Shi, H; Zhang, C; Ren, M; Han, M; Wei, X; Zhang, X; Lou, H

    2015-02-12

    Oxidative stress is central to the pathology of several neurodegenerative diseases, including Parkinson's disease (PD), and therapeutics designed to enhance antioxidant potential could have clinical value. In this study, we investigated whether dimethyl fumarate (DMF) has therapeutic effects in cellular and animal model of PD, and explore the role of nuclear transcription factor related to NF-E2 (Nrf2) in this process. Treatment of animals and dopaminergic SH-SY5Y cells with DMF resulted in increased nuclear levels of active Nrf2, with subsequent upregulation of antioxidant target genes. The cytotoxicity of 6-hydroxydopamine (6-OHDA) was reduced by pre-treatment with DMF in SH-SY5Y cells. The increase in the reactive oxygen species caused by 6-OHDA treatment was also attenuated by DMF in SH-SY5Y cells. The neuroprotective effects of DMF against 6-OHDA neurotoxicity were dependent on Nrf2, since treatment with Nrf2 siRNA failed to block against 6-OHDA neurotoxicity and induce Nrf2-dependent cytoprotective genes in SH-SY5Y cells. In vivo, DMF oral administration was shown to upregulate mRNA and protein levels of Nrf2 and Nrf2-regulated cytoprotective genes, attenuate 6-OHDA induced striatal oxidative stress and inflammation in C57BL/6 mice. Moreover, DMF ameliorated dopaminergic neurotoxicity in 6-OHDA-induced PD animal models as evidenced by amelioration of locomotor dysfunction, loss in striatal dopamine, and reductions in dopaminergic neurons in the substantia nigra and striatum. Taken together, these data strongly suggest that DMF may be beneficial for the treatment of neurodegenerative diseases like PD.

  17. Levodopa/benserazide microsphere (LBM) prevents L-dopa induced dyskinesia by inactivation of the DR1/PKA/P-tau pathway in 6-OHDA-lesioned Parkinson's rats.

    PubMed

    Xie, Cheng-long; Wang, Wen-Wen; Zhang, Su-fang; Yuan, Ming-Lu; Che, Jun-Yi; Gan, Jing; Song, Lu; Yuan, Wei-En; Liu, Zhen-Guo

    2014-12-16

    L-3, 4-dihydroxyphenylalanine (L-dopa) is the gold standard for symptomatic treatment of Parkinson's disease (PD), but long-term therapy is associated with the emergence of L-dopa-induced dyskinesia (LID). In the present study, L-dopa and benserazide were loaded by poly (lactic-co-glycolic acid) microspheres (LBM), which can release levodopa and benserazide in a sustained manner in order to continuous stimulate dopaminergic receptors. We investigated the role of striatal DR1/PKA/P-tau signal transduction in the molecular event underlying LID in the 6-OHDA-lesioned rat model of PD. We found that animals rendered dyskinetic by L-dopa treatment, administration of LBM prevented the severity of AIM score, as well as improvement in motor function. Moreover, we also showed L-dopa elicits profound alterations in the activity of three LID molecular markers, namely DR1/PKA/P-tau (ser396). These modifications are totally prevented by LBM treatment, a similar way to achieve continuous dopaminergic delivery (CDD). In conclusion, our experiments provided evidence that intermittent administration of L-dopa, but not continuous delivery, and DR1/PKA/p-tau (ser396) activation played a critical role in the molecular and behavioural induction of LID in 6-OHDA-lesioned rats. In addition, LBM treatment prevented the development of LID by inhibiting the expression of DR1/PKA/p-tau, as well as PPEB mRNA in dyskintic rats.

  18. The majority of newly generated cells in the adult mouse substantia nigra express low levels of Doublecortin, but their proliferation is unaffected by 6-OHDA-induced nigral lesion or Minocycline-mediated inhibition of neuroinflammation.

    PubMed

    Worlitzer, Maik M A; Viel, Thomas; Jacobs, Andreas H; Schwamborn, Jens C

    2013-09-01

    Parkinson's disease is characterized by a selective loss of dopaminergic neurons in the substantia nigra (SN). However, whether regenerative endogenous neurogenesis is taking place in the mammalian SN of parkinsonian and non-parkinsonian brains remains of debate. Here, we tested whether proliferating cells in the SN and their neurogenic potential would be affected by anti-inflammatory treatment under physiological conditions and in the 6-hydroxy-dopamine (6-OHDA) Parkinson's disease mouse model. We report that the majority of newly generated nigral cells are positive for Doublecortin (Dcx), which is an often used marker for neural progenitor cells. Yet, Dcx expression levels in these cells were much lower than in neural progenitor cells of the subventricular zone and the dentate gyrus neural progenitor cells. Furthermore, these newly generated nigral cells are negative for neuronal lineage markers such as TuJ1 and NeuN. Therefore, their neuronal commitment is questionable. Instead, we found evidence for oligodendrogenesis and astrogliosis in the SN. Finally, neither short-term nor long-term inhibition of neuroinflammation by Minocycline- or 6-OHDA-induced lesion affected the numbers of newly generated cells in our disease paradigm. Our findings of adult generated Dcx(+) cells in the SN add important data for understanding the cellular composition and consequently the regenerative capacity of the SN.

  19. Genetic, temporal and diurnal influences on L-dopa-induced dyskinesia in the 6-OHDA model.

    PubMed

    Monville, Christelle; Torres, Eduardo M; Pekarik, Vladimir; Lane, Emma L; Dunnett, Stephen B

    2009-03-16

    Current treatments for Parkinson's disease rely on a dopamine replacement strategy and are reasonably effective, particularly in the early stages of the disease. However, chronic dopaminergic therapy is limited by the development of a range of side effects, including the onset of abnormal movements ('dyskinesia'). The neural mechanisms that underlie dyskinesia are far from clear but they have been associated with pulsatile stimulation of dopamine receptors, downstream changes in proteins and genes, and abnormalities in non-dopamine transmitter systems. However, there has been no pathophysiological explanation for the worsening motor symptoms in the afternoon and evening reported by Parkinsonian patients in long-term L-dopa therapy, and no direct relationship has been found with the pharmacokinetics of the drug. Moreover, there continues to be a debate about whether the development of dyskinesias in patients is dependent upon the duration of L-dopa treatment or on the degree of denervation/advanced stage of the disease, both factors that are difficult to resolve experimentally in the human disease. The objective of this study was to characterise, in an animal model, factors that predispose some individuals to develop dyskinesia after a prolonged treatment with L-dopa, whereas others continue to exhibit symptom alleviation without the side effects. We report that none of the parameters studied--genetic variation within and between strains, delay of treatment onset after lesion, or time of day of the drug treatment--were found to influence directly the formation of dyskinesias after L-dopa treatment. We conclude that a complex combination of individual factors are likely to interact to regulate the onset and development of abnormal movements in some animals but not others.

  20. A Novel Immunosuppressor, (5R)-5-Hydroxytriptolide, Alleviates Movement Disorder and Neuroinflammation in a 6-OHDA Hemiparkinsonian Rat Model

    PubMed Central

    Su, Ruijun; Sun, Min; Wang, Wei; Zhang, Jianliang; Zhang, Li; Zhen, Junli; Qian, Yanjing; Zheng, Yan; Wang, Xiaomin

    2017-01-01

    Parkinson’s disease (PD) is one of the most common age-related neurodegenerative diseases. Promising therapies for PD still need to be explored. Immune dysfunction has been found to be involved in PD pathogenesis. Here, a novel immunosuppressor, (5R)-5-hydroxytriptolide (LLDT8), was used to treat 6-hydroxydopamine (6-OHDA)-induced hemiparkinson rats. We found that oral administration of LLDT8 significantly alleviated apomorphine-induced rotations at a dose of 125 µg/kg, and improved performance in cylinder and rotarod tests at a lower dose of 31.25 µg/kg, in 6-OHDA hemiparkinsonian rats. Moreover, loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the 6-OHDA rat was attenuated in response to LLDT8 treatment in a dose-dependent manner. In addition, inflammatory factors IL-1β, IL-6 and TNF-α, were significantly inhibited in LLDT8-treated hemiparkisonian rats, compared with vehicle. Notably, the level of dopamine (DA) in the striatum of PD rats was restored by LLDT8 treatment. Furthermore, we also detected that the disequilibrium of peripheral lymphocytes was reversed by LLDT8 administration. Taken together, the results imply that the immunosuppressor, LLDT8, can rescue dopaminergic neurodegeneration in 6-OHDA hemiparkinsonian rats, thus providing a potential therapeutic strategy for PD. PMID:28203480

  1. A Novel Immunosuppressor, (5R)-5-Hydroxytriptolide, Alleviates Movement Disorder and Neuroinflammation in a 6-OHDA Hemiparkinsonian Rat Model.

    PubMed

    Su, Ruijun; Sun, Min; Wang, Wei; Zhang, Jianliang; Zhang, Li; Zhen, Junli; Qian, Yanjing; Zheng, Yan; Wang, Xiaomin

    2017-02-01

    Parkinson's disease (PD) is one of the most common age-related neurodegenerative diseases. Promising therapies for PD still need to be explored. Immune dysfunction has been found to be involved in PD pathogenesis. Here, a novel immunosuppressor, (5R)-5-hydroxytriptolide (LLDT8), was used to treat 6-hydroxydopamine (6-OHDA)-induced hemiparkinson rats. We found that oral administration of LLDT8 significantly alleviated apomorphine-induced rotations at a dose of 125 µg/kg, and improved performance in cylinder and rotarod tests at a lower dose of 31.25 µg/kg, in 6-OHDA hemiparkinsonian rats. Moreover, loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the 6-OHDA rat was attenuated in response to LLDT8 treatment in a dose-dependent manner. In addition, inflammatory factors IL-1β, IL-6 and TNF-α, were significantly inhibited in LLDT8-treated hemiparkisonian rats, compared with vehicle. Notably, the level of dopamine (DA) in the striatum of PD rats was restored by LLDT8 treatment. Furthermore, we also detected that the disequilibrium of peripheral lymphocytes was reversed by LLDT8 administration. Taken together, the results imply that the immunosuppressor, LLDT8, can rescue dopaminergic neurodegeneration in 6-OHDA hemiparkinsonian rats, thus providing a potential therapeutic strategy for PD.

  2. Behavioral and biochemical correlates of the dyskinetic potential of dopaminergic agonists in the 6-OHDA lesioned rat.

    PubMed

    Carta, Anna R; Frau, Lucia; Lucia, Frau; Pinna, Annalisa; Annalisa, Pinna; Pontis, Silvia; Silvia, Pontis; Simola, Nicola; Nicola, Simola; Schintu, Nicoletta; Nicoletta, Schintu; Morelli, Micaela; Micaela, Morelli

    2008-07-01

    Prolonged treatment with L-DOPA induces highly disabling dyskinesia in Parkinson's disease (PD) patients. In contrast, dopaminergic agonists display variably dyskinetic outcome, depending on pharmacokinetic/pharmacodynamic profile. The present study was aimed at assessing behavioral and biochemical correlates of intense or mild dyskinesia displayed by the different dopamine (DA) receptors stimulation in a rat model of PD. The effect of subchronic stimulation of the D(1) receptor by SKF38393, and the D(2)/D(3) receptor by ropinirole was evaluated in unilaterally 6-hydroxyDA-lesioned rats. Sensitization of contralateral turning (SCT) behavior and abnormal involuntary movements (AIMs) were assessed as behavioral correlates of dyskinetic responses. Opioid peptides mRNA in the dorsolateral striatum (dlStr) and glutamic acid decarboxylase (GAD67) mRNA content in globus pallidus (GP), were evaluated as an index of neuroadaptive changes occurring in the direct and indirect basal ganglia pathways. Subchronic SKF38393 caused AIMs and SCT whereas ropinirole elicited SCT only, indicating that both drugs induced some dyskinetic response, albeit of different type. Peptides mRNA evaluation in dlStr, showed that SKF38393 subchronic treatment was associated to an overexpression of both dynorphin (DYN) and enkephalin (ENK) mRNAs, in the direct and indirect striatal pathway respectively. In contrast, a decrease in DYN mRNA levels only was observed after treatment with ropinirole. Analysis of GAD67 mRNA levels in the GP showed an increase after both D(1) and D(2)/D(3) agonist treatments. Results suggest that presence of SCT alone or SCT plus AIMs might represent correlates of the differential severity of dyskinetic movements induced by treatment with low (ropinirole) or high (SKF38393) dyskinetic potential. Neuroadaptive increases in opioid peptide expression in both direct and indirect striatal pathways were associated to the appearance of AIMs alone. In contrast, increase of GAD67 m

  3. Characterisation of spatial neglect induced by unilateral 6-OHDA lesions on a choice reaction time task in rats.

    PubMed

    Heuer, Andreas; Dunnett, Stephen B

    2013-01-15

    Unilateral dopamine depletion and excitotoxic lesions of the striatum have been shown to induce a contralateral neglect when rats have to respond in a choice reaction time setting. Whereas, in a lateralised setting when response options are to either side of the animal's head all contralateral responding is impaired, testing animals only on one side of the head per day but with a near and far response option, rats are able to correctly respond to contralateral stimuli, but rather bias their responses towards the near hole. Here, we further investigated the nature of the contralateral neglect in egocentric space coding in more detail. Firstly, we tested the effects of near-complete unilateral dopamine depletion on this type of task. Secondly, previous observations suggested that lesioned rats shifted their response strategy which resulted in a response bias towards the most proximal location in contralateral space. In order to "encourage" dopamine depleted rats to respond to the neglected response location we implemented an error correction procedure to the task. Near-complete unilateral dopamine depletion, via 6-hydroxydopamine infusions into the medial forebrain bundle of female Lister Hood rats, resulted in a reduction of usable trials, a near hole bias when animals were tested on the side contralateral to the lesion, as well as increased reaction and movement time latencies. The introduction of an error-correction procedure had no effect on the animals' response bias towards the near contralateral location. Probe trials showed that the bias is most likely the result of responses being misdirected when in a choice situation. The findings further highlight the role of dopamine and an intact striatum to code responses into egocentrically defined space.

  4. Antioxidant effect of Spirulina (Arthrospira) maxima in a neurotoxic model caused by 6-OHDA in the rat striatum.

    PubMed

    Tobón-Velasco, J C; Palafox-Sánchez, Victoria; Mendieta, Liliana; García, E; Santamaría, A; Chamorro-Cevallos, G; Limón, I Daniel

    2013-08-01

    There is evidence to support that an impaired energy metabolism and the excessive generation of reactive oxygen species (ROS) contribute to brain injury in neurodegenerative disorders such as Parkinson's disease (PD), whereas diets enriched in foods with an antioxidant action may modulate its progression. Several studies have proved that the antioxidant components produced by Spirulina, a microscopic blue-green alga, might prevent cell death by decreasing free radicals, inhibiting lipoperoxidation and upregulating the antioxidant enzyme systems. In our study, we investigated the protective effect of the Spirulina maxima (S. maxima) against the 6-OHDA-caused toxicity in the rat striatum. The S. maxima (700 mg/kg/day, vo) was administered for 40 days before and 20 days after a single injection of 6-OHDA (16 μg/2 μL) into the dorsal striatum. At 20-day postsurgery, the brain was removed and the striatum was obtained to evaluate the indicators of toxicity, such as nitric oxide levels, ROS formation, lipoperoxidation, and mitochondrial activity. These variables were found significantly stimulated in 6-OHDA-treated rats and were accompanied by declines in dopamine levels and motor activity. In contrast, the animals that received the chronic treatment with S. maxima had a restored locomotor activity, which is associated with the decreased levels of nitric oxide, ROS, and lipoperoxidation in the striatum, although mitochondrial functions and dopamine levels remained preserved. These findings suggest that supplementation with antioxidant phytochemicals (such as contained in S. maxima) represents an effective neuroprotective strategy against 6-OHDA-caused neurotoxicity vía free radical production to preserve striatal dopaminergic neurotransmission in vivo.

  5. The mitochondria-targeted anti-oxidant MitoQ reduces aspects of mitochondrial fission in the 6-OHDA cell model of Parkinson's disease.

    PubMed

    Solesio, María E; Prime, Tracy A; Logan, Angela; Murphy, Michael P; Del Mar Arroyo-Jimenez, María; Jordán, Joaquín; Galindo, María F

    2013-01-01

    Parkinson's disease (PD) is a neurodegenerative disorder for which available treatments provide symptom relief but do not stop disease progression. Mitochondria, and in particular mitochondrial dynamics, have been postulated as plausible pharmacological targets. Mitochondria-targeted antioxidants have been developed to prevent mitochondrial oxidative damage, and to alter the involvement of reactive oxygen species (ROS) in signaling pathways. In this study, we have dissected the effect of MitoQ, which is produced by covalent attachment of ubiquinone to a triphenylphosphonium lipophilic cation by a ten carbon alkyl chain. MitoQ was tested in an in vitro PD model which involves addition of 6-hydroxydopamine (6-OHDA) to SH-SY5Y cell cultures. At sublethal concentrations of 50μM, 6-OHDA did not induce increases in protein carbonyl, mitochondrial lipid peroxidation or mitochondrial DNA damage. However, after 3h of treatment, 6-OHDA disrupts the mitochondrial morphology and activates the machinery of mitochondrial fission, but not fusion. Addition of 6-OHDA did not increase the levels of fission 1, mitofusins 1 and 2 or optic atrophy 1 proteins, but does lead to the translocation of dynamin related protein 1 from the cytosol to the mitochondria. Pre-treatment with MitoQ (50nM, 30min) results in the inhibition of the mitochondrial translocation of Drp1. Furthermore, MitoQ also inhibited the translocation of the pro-apoptotic protein Bax to the mitochondria. These findings provide mechanistic evidence for a role for redox events contributing to mitochondrial fission and suggest the potential of mitochondria-targeted therapeutics in diseases that involve mitochondrial fragmentation due to oxidative stress.

  6. Adenosine A2A Receptor Gene Knockout Prevents l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia by Downregulation of Striatal GAD67 in 6-OHDA-Lesioned Parkinson’s Mice

    PubMed Central

    Yin, Su-bing; Zhang, Xiao-guang; Chen, Shuang; Yang, Wen-ting; Zheng, Xia-wei; Zheng, Guo-qing

    2017-01-01

    l-3,4-Dihydroxyphenylalanine (l-DOPA) remains the primary pharmacological agent for the symptomatic treatment of Parkinson’s disease (PD). However, the development of l-DOPA-induced dyskinesia (LID) limits the long-term use of l-DOPA for PD patients. Some data have reported that adenosine A2A receptor (A2AR) antagonists prevented LID in animal model of PD. However, the mechanism in which adenosine A2AR blockade alleviates the symptoms of LID has not been fully clarified. Here, we determined to knock out (KO) the gene of A2AR and explored the possible underlying mechanisms implicated in development of LID in a mouse model of PD. A2AR gene KO mice were unilaterally injected into the striatum with 6-hydroxydopamine (6-OHDA) in order to damage dopamine neurons on one side of the brain. 6-OHDA-lesioned mice were then injected once daily for 21 days with l-DOPA. Abnormal involuntary movements (AIMs) were evaluated on days 3, 8, 13, and 18 after l-DOPA administration, and real-time polymerase chain reaction and immunohistochemistry for glutamic acid decarboxylase (GAD) 65 and GAD67 were performed. We found that A2AR gene KO was effective in reducing AIM scores and accompanied with decrease of striatal GAD67, rather than GAD65. These results demonstrated that the possible mechanism involved in alleviation of AIM symptoms by A2AR gene KO might be through reducing the expression of striatal GAD67. PMID:28377741

  7. Effects of prolonged neuronal nitric oxide synthase inhibition on the development and expression of L-DOPA-induced dyskinesia in 6-OHDA-lesioned rats.

    PubMed

    Padovan-Neto, Fernando Eduardo; Cavalcanti-Kiwiatkoviski, Roberta; Carolino, Ruither Oliveira Gomes; Anselmo-Franci, Janete; Del Bel, Elaine

    2015-02-01

    It is well known that nitric oxide (NO) interacts with dopamine (DA) within the striatal circuitry. The anti-dyskinetic properties of NO synthase (NOS) inhibitors demonstrate the importance of NO in L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID). Here, we investigated the ability of a daily co-treatment of the preferential neuronal NOS (nNOS) inhibitor, 7-nitroindazole (7-NI, 30 mg/kg), with L-DOPA (30 mg/kg) to counteract LID in unilaterally 6-OHDA-lesioned rats. We analyzed striatal nNOS-expressing interneurons, DA and 5-HT neurochemistry in the striatum and alterations of the Fos-B/ΔFosB expression in the corticostriatal, nigrostriatal and mesolimbic pathways. Prolonged administration of 7-NI inhibited the manifestation of chronic L-DOPA treatment-induced abnormal involuntary movements (AIMs). LID was associated with an up-regulation in the number of nNOS-expressing interneurons in the lateral but not medial striatum. nNOS inhibition reduced the number of nNOS-expressing interneurons. The anti-dyskinetic effects of 7-NI correlated with a reduction in DA and 5-HT turnover in the striatum. At postsynaptic striatal sites, 7-NI prevented L-DOPA-induced Fos-B/ΔFosB up-regulation in the motor cortex, nucleus accumbens and striatum. Finally, 7-NI blocked Fos-B/ΔFosB expression in nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d)-positive interneurons in the striatum. These results provide further evidence of the molecular mechanisms by which NOS-inhibiting compounds attenuate LID. The involvement of NO with DA and 5-HT neurochemistry may contribute to the understanding of this new, non-dopaminergic therapy for the management of LID.

  8. Dual effects of intermittent or continuous L-DOPA administration on gene expression in the globus pallidus and subthalamic nucleus of adult rats with a unilateral 6-OHDA lesion.

    PubMed

    Nielsen, Kirsten M; Soghomonian, Jean-Jacques

    2003-09-15

    Intermittent oral doses of levodopa (L-DOPA) are routinely used to treat Parkinson's disease, but with prolonged use can result in adverse motor complications, such as dyskinesia. Continuous administration of L-DOPA achieves therapeutic efficacy without producing this effect, yet the molecular mechanisms are unclear. This study examined, by in situ hybridization histochemistry, the effects of continuous or intermittent L-DOPA administration on gene expression in the globus pallidus and subthalamic nucleus of adult rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway. Results were compared to 6-OHDA-treated rats receiving vehicle. Our results provide original evidence that continuous L-DOPA normalizes the 6-OHDA-lesion-induced increase in mRNA levels encoding for the 67 kDa isoform of glutamate decarboxylase in neurons of the globus pallidus and cytochrome oxidase subunit I mRNA levels in the subthalamic nucleus. The extent of normalization did not differ between the continuous and intermittent groups. In addition, intermittent L-DOPA induced an increase in the mRNA levels encoding for the 65 kDa isoform of glutamate decarboxylase in globus pallidus neurons ipsilateral to the lesion and a bilateral increase in c-fos mRNA expression in the subthalamic nucleus. These results suggest that continuous L-DOPA tends to normalize the 6-OHDA-lesion-induced alterations in cell signaling in the pallido-subthalamic loop. On the other hand, we propose that chronic intermittent L-DOPA exerts a dual effect by normalizing cell signaling in a subpopulation of neurons in the globus pallidus and subthalamic nucleus while inducing abnormal signaling in another subpopulation.

  9. Squamosamide derivative FLZ protected dopaminergic neuron by activating Akt signaling pathway in 6-OHDA-induced in vivo and in vitro Parkinson's disease models.

    PubMed

    Bao, Xiu-Qi; Kong, Xiang-Chen; Kong, Li-Bing; Wu, Liang-Yu; Sun, Hua; Zhang, Dan

    2014-02-14

    Parkinson's disease (PD) is a neurodegenerative disease affecting up to 80% of dopaminergic neurons in the nigrostriatal pathway. FLZ, a novel synthetic squamosamide derivative from a Chinese herb, has been shown to have neuroprotective effects in experimental PD models. In this study, we carried out a set of in vitro and in vivo experiments to address the neuroprotective effect of FLZ and related mechanism. The results showed that FLZ significantly improved motor dysfunction and dopaminergic neuronal loss of rats injured by 6-hydroxydopamine (6-OHDA). The beneficial effects of FLZ attributed to the elevation of dopaminergic neuron number, dopamine level and tyrosine hydroxylase (TH) activity. Mechanistic study showed that FLZ protected TH activity and dopaminergic neurons through decreasing α-synuclein (α-Syn) expression and the interaction between α-Syn and TH. Further studies indicated the involvement of phosphoinositide 3-kinases (PI3K)/Akt signaling pathway in the protective effect of FLZ since it showed that blocking PI3K/Akt signaling pathway prevented the expression of α-Syn and attenuated the neuroprotection of FLZ. In addition, FLZ treatment reduced the expression of RTP801, an important protein involved in the pathogenesis of PD. Taken together, these results revealed that FLZ suppressed α-Syn expression and elevated TH activity in dopaminergic neuron through activating Akt survival pathway in 6-OHDA-induced PD models. The data also provided evidence that FLZ had potent neuroprotecive effects and might become a new promising agent for PD treatment.

  10. Anti-dyskinetic mechanisms of amantadine and dextromethorphan in the 6-OHDA rat model of Parkinson's disease: role of NMDA vs. 5-HT1A receptors.

    PubMed

    Paquette, Melanie A; Martinez, Alex A; Macheda, Teresa; Meshul, Charles K; Johnson, Steven W; Berger, S Paul; Giuffrida, Andrea

    2012-11-01

    Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia (LID) in patients with Parkinson's disease (PD) and abnormal involuntary movements (AIMs) in the unilateral 6-hydroxydopamine (6-OHDA) rat model. These effects have been attributed to N-methyl-d-aspartate (NMDA) antagonism. However, amantadine and dextromethorphan are also thought to block serotonin (5-HT) uptake and cause 5-HT overflow, leading to stimulation of 5-HT(1A) receptors, which has been shown to reduce LID. We undertook a study in 6-OHDA rats to determine whether the anti-dyskinetic effects of these two compounds are mediated by NMDA antagonism and/or 5-HT(1A) agonism. In addition, we assessed the sensorimotor effects of these drugs using the Vibrissae-Stimulated Forelimb Placement and Cylinder tests. Our data show that the AIM-suppressing effect of amantadine was not affected by the 5-HT(1A) antagonist WAY-100635, but was partially reversed by the NMDA agonist d-cycloserine. Conversely, the AIM-suppressing effect of dextromethorphan was prevented by WAY-100635 but not by d-cycloserine. Neither amantadine nor dextromethorphan affected the therapeutic effects of L-DOPA in sensorimotor tests. We conclude that the anti-dyskinetic effect of amantadine is partially dependent on NMDA antagonism, while dextromethorphan suppresses AIMs via indirect 5-HT(1A) agonism. Combined with previous work from our group, our results support the investigation of 5-HT(1A) agonists as pharmacotherapies for LID in PD patients.

  11. L-DOPA-induced dyskinesia in adult rats with a unilateral 6-OHDA lesion of dopamine neurons is paralleled by increased c-fos gene expression in the subthalamic nucleus.

    PubMed

    Soghomonian, Jean-Jacques

    2006-05-01

    Levodopa (L-DOPA), the metabolic precursor of dopamine, is widely used as a pharmacological agent for the symptomatic treatment of Parkinson's disease. However, long-term L-DOPA use results in abnormal involuntary movements such as dyskinesias. There is evidence that abnormal cell signaling in the basal ganglia is involved in L-DOPA-induced dyskinesia. The subthalamic nucleus (STN) plays a key role in the circuitry of the basal ganglia and in the pathophysiology of Parkinson's disease. However, the contribution of the STN to L-DOPA-induced dyskinesias remains unclear. The objective of this work was to study the effects of acute or chronic systemic administration of L-DOPA to adult rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of dopamine neurons on c-fos expression in the STN and test the hypothesis that these effects correlate with L-DOPA-induced dyskinesias. c-fos mRNA expression was measured in the STN by in situ hybridization histochemistry at the single cell level. Our results confirm earlier evidence that the chronic administration of L-DOPA to rats with a unilateral 6-OHDA lesion increases c-fos expression in the STN. We also report that c-fos expression can be increased following an acute injection of L-DOPA to 6-OHDA-lesioned rats but not following a chronic injection of L-DOPA to sham-operated, unlesioned rats. Finally, we provide evidence that the occurrence and severity of dyskinesia is correlated with c-fos mRNA levels in the ipsilateral STN. These results suggest that altered cell signaling in the STN is involved in some of the behavioral effects induced by systemic L-DOPA administration.

  12. Reduction of GABAergic transmission and alterations in behavior after 6-OHDA treatment of rats.

    PubMed

    Podkletnova, I; Raevsky, V; Alho, H

    1996-07-20

    We studied the effects of neonatal administration of 6-hydroxydopamine (6-OHDA) upon gamma-aminobutyric acid (GABA) and noradrenergic neurotransmission in the developing rat brain. After 6-OHDA administration tyrosine hydroxylase (TH) immunolabelling revealed more than 70% loss of catecholaminergic terminals in cortex. Glutamic acid decarboxylase (GAD) immunolabelling showed that the intensity of staining and the density of labelled terminals were decreased by approximately 50% in the prefrontal cortex of 6-OHDA treated animals, but in visual and somatosensory zones there was no difference between lesioned and control cortex. The open field test revealed an altered development of the searching activity after neonatal 6-OHDA injections. A significant difference was found between 6-OHDA treated and control rats in searching, orienting and skills performance. Our results indicate that the behavioral changes observed in young rats after 6-OHDA treatment may be reflections not only of reduced catecholaminergic transmission but also of GABAergic disturbance, occurring in the frontal cortex.

  13. Disrupted brain metabolic connectivity in a 6-OHDA-induced mouse model of Parkinson’s disease examined using persistent homology-based analysis

    PubMed Central

    Im, Hyung-Jun; Hahm, Jarang; Kang, Hyejin; Choi, Hongyoon; Lee, Hyekyoung; Hwang, Do Won; Kim, E. Edmund; Chung, June-Key; Lee, Dong Soo

    2016-01-01

    Movement impairments in Parkinson’s disease (PD) are caused by the degeneration of dopaminergic neurons and the consequent disruption of connectivity in the cortico-striatal-thalamic loop. This study evaluated brain metabolic connectivity in a 6-Hydroxydopamine (6-OHDA)-induced mouse model of PD using 18F-fluorodeoxy glucose positron emission tomography (FDG PET). Fourteen PD-model mice and ten control mice were used for the analysis. Voxel-wise t-tests on FDG PET results yielded no significant regional metabolic differences between the PD and control groups. However, the PD group showed lower correlations between the right caudoputamen and the left caudoputamen and right visual cortex. Further network analyses based on the threshold-free persistent homology framework revealed that brain networks were globally disrupted in the PD group, especially between the right auditory cortex and bilateral cortical structures and the left caudoputamen. In conclusion, regional glucose metabolism of PD was preserved, but the metabolic connectivity of the cortico-striatal-thalamic loop was globally impaired in PD. PMID:27650055

  14. The Effects of Crocin on 6-OHDA-Induced Oxidative/Nitrosative Damage and Motor Behaviour in Hemiparkinsonian Rats

    PubMed Central

    Hosseini, Maryam; Rajaei, Ziba; Alaei, Hojjatallah; Tajadini, Mohamadhasan

    2016-01-01

    Background Crocin is considered to prevent oxidative stress-related diseases, such as ischemia and Alzheimer’s. The aim of the present investigation was to evaluate the effects of crocin on motor behaviour and 6-OHDA-induced oxidative/nitrosative damage to the striatum in an experimental model of Parkinson’s disease. Methods Left medial forebrain bundle was lesioned by microinjection of 6-OHDA (16μg in 0.2% ascorbate-saline). Crocin (30 and 60 mg/kg) was injected intraperitoneally three days before surgery until six weeks. Rotational behaviour and biochemical analysis were used to evaluate the effect of crocin in a unilateral 6-OHDA-induced model of Parkinson’s disease. Results The contralateral rotations induced by apomorphine in 6-OHDA lesioned group were highly significant (P < 0.001) as compared to the sham group. Moreover, chronic administration of crocin at doses of 30 and 60 mg/kg over six weeks did not change the rotations. The TBARS and nitrite levels in the striatum were also significantly (P < 0.05) increased in lesioned group. Treatment with crocin at a dose of 60 mg/kg significantly decreased the nitrite levels (P < 0.05) in the striatum. Conclusion Crocin at a dose of 60 mg/kg could be effective in preventing the nitrosative damage in the striatum. Further investigations using higher doses of crocin is suggested to get the full neuroprotective effects of crocin in Parkinson’s disease. PMID:28090177

  15. Enhanced Efficacy of the CDNF/MANF Family by Combined Intranigral Overexpression in the 6-OHDA Rat Model of Parkinson's Disease

    PubMed Central

    Cordero-Llana, Óscar; Houghton, Benjamin C; Rinaldi, Federica; Taylor, Hannah; Yáñez-Muñoz, Rafael J; Uney, James B; Wong, Liang-Fong; Caldwell, Maeve A

    2015-01-01

    Cerebral Dopamine Neurotrophic Factor (CDNF) and Mesencephalic Astrocyte-derived Neurotrophic factor (MANF) are members of a recently discovered family of neurotrophic factors (NTFs). Here, we used intranigral or intrastriatal lentiviral vector-mediated expression to evaluate their efficacy at protecting dopaminergic function in the 6-OHDA model of Parkinson's disease (PD). In contrast to the well-studied Glial-Derived Neurotrophic Factor (GDNF), no beneficial effects were demonstrated by striatal overexpression of either protein. Interestingly, nigral overexpression of CDNF decreased amphetamine-induced rotations and increased tyroxine hydroxylase (TH) striatal fiber density but had no effect on numbers of TH+ cells in the SN. Nigral MANF overexpression had no effect on amphetamine-induced rotations or TH striatal fiber density but resulted in a significant preservation of TH+ cells. Combined nigral overexpression of both factors led to a robust reduction in amphetamine-induced rotations, greater increase in striatal TH-fiber density and significant protection of TH+ cells in the SN. We conclude that nigral CDNF and MANF delivery is more efficacious than striatal delivery. This is also the first study to demonstrate that combined NTF can have synergistic effects that result in enhanced neuroprotection, suggesting that multiple NTF delivery may be more efficacious for the treatment of PD than the single NTF approaches attempted so far. PMID:25369767

  16. Intrastriatal Grafting of Chromospheres: Survival and Functional Effects in the 6-OHDA Rat Model of Parkinson's Disease.

    PubMed

    Boronat-García, Alejandra; Palomero-Rivero, Marcela; Guerra-Crespo, Magdalena; Millán-Aldaco, Diana; Drucker-Colín, René

    2016-01-01

    Cell replacement therapy in Parkinson's disease (PD) aims at re-establishing dopamine neurotransmission in the striatum by grafting dopamine-releasing cells. Chromaffin cell (CC) grafts produce some transitory improvements of functional motor deficits in PD animal models, and have the advantage of allowing autologous transplantation. However, CC grafts have exhibited low survival, poor functional effects and dopamine release compared to other cell types. Recently, chromaffin progenitor-like cells were isolated from bovine and human adult adrenal medulla. Under low-attachment conditions, these cells aggregate and grow as spheres, named chromospheres. Here, we found that bovine-derived chromosphere-cell cultures exhibit a greater fraction of cells with a dopaminergic phenotype and higher dopamine release than CC. Chromospheres grafted in a rat model of PD survived in 57% of the total grafted animals. Behavioral tests showed that surviving chromosphere cells induce a reduction in motor alterations for at least 3 months after grafting. Finally, we found that compared with CC, chromosphere grafts survive more and produce more robust and consistent motor improvements. However, further experiments would be necessary to determine whether the functional benefits induced by chromosphere grafts can be improved, and also to elucidate the mechanisms underlying the functional effects of the grafts.

  17. Intrastriatal Grafting of Chromospheres: Survival and Functional Effects in the 6-OHDA Rat Model of Parkinson's Disease

    PubMed Central

    Boronat-García, Alejandra; Palomero-Rivero, Marcela; Guerra-Crespo, Magdalena; Millán-Aldaco, Diana; Drucker-Colín, René

    2016-01-01

    Cell replacement therapy in Parkinson’s disease (PD) aims at re-establishing dopamine neurotransmission in the striatum by grafting dopamine-releasing cells. Chromaffin cell (CC) grafts produce some transitory improvements of functional motor deficits in PD animal models, and have the advantage of allowing autologous transplantation. However, CC grafts have exhibited low survival, poor functional effects and dopamine release compared to other cell types. Recently, chromaffin progenitor-like cells were isolated from bovine and human adult adrenal medulla. Under low-attachment conditions, these cells aggregate and grow as spheres, named chromospheres. Here, we found that bovine-derived chromosphere-cell cultures exhibit a greater fraction of cells with a dopaminergic phenotype and higher dopamine release than CC. Chromospheres grafted in a rat model of PD survived in 57% of the total grafted animals. Behavioral tests showed that surviving chromosphere cells induce a reduction in motor alterations for at least 3 months after grafting. Finally, we found that compared with CC, chromosphere grafts survive more and produce more robust and consistent motor improvements. However, further experiments would be necessary to determine whether the functional benefits induced by chromosphere grafts can be improved, and also to elucidate the mechanisms underlying the functional effects of the grafts. PMID:27525967

  18. High frequency electro-acupuncture enhances striatum DAT and D1 receptor expression, but decreases D2 receptor level in 6-OHDA lesioned rats.

    PubMed

    Rui, Gao; Guangjian, Zhang; Yong, Wang; Jie, Feng; Yanchao, Cui; Xi, Jia; Fen, Li

    2013-01-15

    The direct effects of electro-acupuncture (EA) on the dopaminergic neurotransmitter system in Parkinson's disease (PD) patients remain elusive. In the present study, 0, 2 or 100Hz EA was applied to acupoints Sanyinjiao (SP6), Yanglingquan (GB34) and Zusanli (ST36) in a rat model unilaterally lesioned by 6-hydroxydopamine. Rotational behavior tests were performed and the animals were then decapitated. Levels of striatal dopamine (DA), dopamine transporter, and D1- and D2-like DA receptors were subsequently evaluated. EA at 100 Hz was shown to significantly enhance survival of dopaminergic neurons in the substantia nigra (52.10 ± 11.41% of the level on the non-lesioned rats vs. 21.22 ± 5.52% in the non-EA group, P<0.05) and reduce motor deficits (207.80 ± 31.14 vs. 476.11 ± 68.80 turns/30 min, P<0.05), whereas it only slightly restored the 6-hydroxydopamine-induced loss of striatal DA (P>0.05 vs. the non-EA group). There was a 253.78% increase in dopamine transporter protein expression in the striatum in the 100 Hz EA group (P<0.05 vs. the non-EA group). Moreover, high frequency EA induced increases in striatal D1-like receptor mRNA and protein levels of 81.88% and 62.62%, respectively (P<0.001 and P<0.05 vs. the non-EA group). However, the D2-like DA receptor up-regulation observed in the non-EA group was suppressed in high frequency group (P>0.05 vs. the sham operation group). These findings suggest that high-frequency EA might work by acting on presynaptic dopamine transporter and postsynaptic dopamine receptors simultaneously to achieve a therapeutic effect in PD patients and models. This might shed some light on the mechanism by which EA affects the DA neurotransmitter system.

  19. RETRACTED: 6-OHDA-induced apoptosis and mitochondrial dysfunction are mediated by early modulation of intracellular signals and interaction of Nrf2 and NF-κB factors.

    PubMed

    Tobón-Velasco, Julio C; Limón-Pacheco, Jorge H; Orozco-Ibarra, Marisol; Macías-Silva, Marina; Vázquez-Victorio, Genaro; Cuevas, Elvis; Ali, Syed F; Cuadrado, Antonio; Pedraza-Chaverrí, José; Santamaría, Abel

    2013-02-08

    6-Hydroxydopamine (6-OHDA) is a neurotoxin that generates an experimental model of Parkinson's disease in rodents and is commonly employed to induce a lesion in dopaminergic pathways. The characterization of those molecular mechanisms linked to 6-OHDA-induced early toxicity is needed to better understand the cellular events further leading to neurodegeneration. The present work explored how 6-OHDA triggers early downstream signaling pathways that activate neurotoxicity in the rat striatum. Mitochondrial function, caspases-dependent apoptosis, kinases signaling (Akt, ERK 1/2, SAP/JNK and p38) and crosstalk between nuclear factor kappa B (NF-κB) and nuclear factor-erythroid-2-related factor 2 (Nrf2) were evaluated at early times post-lesion. We found that 6-OHDA initiates cell damage via mitochondrial complex I inhibition, cytochrome c and apoptosis-inducing factor (AIF) release, as well as activation of caspases 9 and 3 to induce apoptosis, kinase signaling modulation and NF-κB-mediated inflammatory responses, accompanied by inhibition of antioxidant systems regulated by the Nrf2 pathway. Our results suggest that kinases SAP/JNK and p38 up-regulation may play a role in the early stages of 6-OHDA toxicity to trigger intrinsic pathways for apoptosis and enhanced NF-κB activation. In turn, these cellular events inhibit the activation of cytoprotective mechanisms, thereby leading to a condition of general damage.

  20. Neuroprotective potential of atorvastatin and simvastatin (HMG-CoA reductase inhibitors) against 6-hydroxydopamine (6-OHDA) induced Parkinson-like symptoms.

    PubMed

    Kumar, Anil; Sharma, Neha; Gupta, Amit; Kalonia, Harikesh; Mishra, Jitendriya

    2012-08-30

    Neuro-inflammation and oxidative stress plays a key role in the pathophysiology of Parkinson's disease (PD). Studies demonstrated that neuro-inflammation and associated infiltration of inflammatory cells into central nervous system are inhibited by 3-hydroxy-3-methyl glutaryl co-enzyme A (HMG-CoA) reductase inhibitors. Based on these experimental evidences, the present study has been designed to evaluate the neuroprotective effect of HMG-CoA reductase inhibitors (atorvastatin and simvastatin) against 6-hydroxydopamine (6-OHDA) induced unilateral lesion model of PD. In the present study, the animals were divided into nine groups (n=15 per group). Group I: Naive (without treatment); Group II: Sham (surgery performed, vehicle administered); Group III: Atorvastatin (20mg/kg); Group IV: Simvastatin (30 mg/kg); Group V: Control [Intrastriatal 6-OHDA (20 μg; single unilateral injection)]; Groups VI and VII: 6-OHDA (20 μg)+atorvastatin (10mg/kg and 20mg/kg) respectively; Groups VIII and IX: 6-OHDA (20 μg)+simvastatin (15 mg/kg and 30 mg/kg) respectively. Intrastriatal administration of 6-OHDA (20 μg; 4 μl of 5 μg/μl) significantly caused impairment in body weight, locomotor activity, rota-rod performance, oxidative defense and mitochondrial enzyme complex activity, and increase in the inflammatory cytokine levels (TNF-α and IL-6) as compared to naive animals. Atorvastatin (20mg/kg) and simvastatin (30 mg/kg) drug treatment significantly improved these behavioral and biochemical alterations restored mitochondrial enzyme complex activities and attenuated neuroinflammatory markers in 6-OHDA (20 μg) treated animals as compared to control group. The findings of the present study demonstrate the neuroprotective potential of statins in experimental model of 6-OHDA induced Parkinson like symptoms.

  1. Carbidopa-based modulation of the functional effect of the AAV2-hAADC gene therapy in 6-OHDA lesioned rats.

    PubMed

    Ciesielska, Agnieszka; Sharma, Nitasha; Beyer, Janine; Forsayeth, John; Bankiewicz, Krystof

    2015-01-01

    Progressively blunted response to L-DOPA in Parkinson's disease (PD) is a critical factor that complicates long-term pharmacotherapy in view of the central importance of this drug in management of the PD-related motor disturbance. This phenomenon is likely due to progressive loss of one of the key enzymes involved in the biosynthetic pathway for dopamine in the basal ganglia: aromatic L-amino acid decarboxylase (AADC). We have developed a gene therapy based on an adeno-associated virus encoding human AADC (AAV2-hAADC) infused into the Parkinsonian striatum. Although no adverse clinical effects of the AAV2-hAADC gene therapy have been observed so far, the ability to more precisely regulate transgene expression or transgene product activity could be an important long-term safety feature. The present study was designed to define pharmacological regulation of the functional activity of AAV2-hAADC transgene product by manipulating L-DOPA and carbidopa (AADC inhibitor) administration in hemi-parkinsonian rats. Thirty days after unilateral striatal infusion of AAV2-hAADC, animals displayed circling behavior and acceleration of dopamine metabolism in the lesioned striatum after administration of a low dose of L-DOPA (5 mg/kg) co-administered with 1.25 mg/kg of carbidopa. This phenomenon was not observed in control AAV2-GFP-treated rats. Withdrawal of carbidopa from a daily L-DOPA regimen decreased the peripheral L-DOPA pool, resulting in almost total loss of L-DOPA-induced behavioral response in AAV2-hAADC rats and a significant decline in striatal dopamine turnover. The serum L-DOPA level correlated with the magnitude of circling behavior in AAV2-hAADC rats. Additionally, AADC activity in homogenates of lesioned striata transduced by AAV2-AADC was 10-fold higher when compared with AAV2-GFP-treated control striata, confirming functional transduction. Our data suggests that the pharmacological regulation of circulating L-DOPA might be effective in the controlling of

  2. Inhibition of Endoplasmic Reticulum Stress is Involved in the Neuroprotective Effect of bFGF in the 6-OHDA-Induced Parkinson’s Disease Model

    PubMed Central

    Cai, Pingtao; Ye, Jingjing; Zhu, Jingjing; Liu, Dan; Chen, Daqing; Wei, Xiaojie; Johnson, Noah R.; Wang, Zhouguang; Zhang, Hongyu; Cao, Guodong; Xiao, Jian; Ye, Junming; Lin, Li

    2016-01-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder with complicated pathophysiologic mechanisms. Endoplasmic reticulum (ER) stress appears to play a critical role in the progression of PD. We demonstrated that basic fibroblast growth factor (bFGF), as a neurotropic factor, inhibited ER stress-induced neuronal cell apoptosis and that 6-hydroxydopamine (6-OHDA)-induced ER stress was involved in the progression of PD in rats. bFGF administration improved motor function recovery, increased tyrosine hydroxylase (TH)-positive neuron survival, and upregulated the levels of neurotransmitters in PD rats. The 6-OHDA-induced ER stress response proteins were inhibited by bFGF treatment. Meanwhile, bFGF also increased expression of TH. The administration of bFGF activated the downstream signals PI3K/Akt and Erk1/2 in vivo and in vitro. Inhibition of the PI3K/Akt and Erk1/2 pathways by specific inhibitors partially reduced the protective effect of bFGF. This study provides new insight towards bFGF translational drug development for PD involving the regulation of ER stress. PMID:27493838

  3. Tetramethylpyrazine Analogue CXC195 Protects Against Dopaminergic Neuronal Apoptosis via Activation of PI3K/Akt/GSK3β Signaling Pathway in 6-OHDA-Induced Parkinson's Disease Mice.

    PubMed

    Chen, Lin; Cheng, Li; Wei, Xinbing; Yuan, Zheng; Wu, Yanmei; Wang, Shuaishuai; Ren, Zhiping; Liu, Xinyong; Liu, Huiqing

    2016-12-22

    Parkinson's disease (PD) is a progressive neurodegenerative disorder and characterized by motor system disorders resulting in loss of dopaminergic (DA) neurons. CXC195, a novel tetramethylpyrazine derivative, has been shown strongest neuroprotective effects due to its anti-apoptotic activity. However, whether CXC195 protects against DA neuronal damage in PD and the mechanisms underlying its beneficial effects are unknown. The purpose of our study was to investigate the potential neuroprotective role of CXC195 and to elucidate its mechanism of action against 6-hydroxydopamine (6-OHDA)-induced mouse model of PD. CXC195 administration improved DA neurodegeneration in PD mice induced by 6-OHDA. Our further findings confirmed treatment of CXC195 at the dose of 10 mg/kg significantly inhibited the apoptosis by decreasing the level of cleaved caspase-3 and Bax, and increasing the level of Bcl-2 in 6-OHDA-lesioned mice. Meanwhile, 6-OHDA also decreased the amount of phosphorylated Akt while increased GSK-3β activity (the amount of phosphorylated GSK-3β at Ser9 was decreased) which was prevented by CXC195. Wortmannin, a specific PI3K inhibitor, dramatically abolished the changes induced by CXC195. Our study firstly demonstrated that CXC195 protected against DA neurodegeneration in 6-OHDA-induced PD model by its anti-apoptotic properties and PI3K/Akt/GSK3β signaling pathway was involved in it.

  4. A novel therapeutic approach to 6-OHDA-induced Parkinson's disease in rats via supplementation of PTD-conjugated tyrosine hydroxylase

    SciTech Connect

    Wu Shaoping; Fu Ailing; Wang Yuxia; Yu Leiping; Jia Peiyuan; Li Qian; Jin Guozhang; Sun Manji . E-mail: Sunmj@nic.bmi.ac.cn

    2006-07-21

    The present study aimed to evaluate whether the protein transduction domain (PTD)-conjugated human tyrosine hydroxylase (TH) fusion protein was effective on the 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD) model rats. An expression vector pET-PTD-TH harbouring the PTD-TH gene was constructed and transformed to the Escherichia coli BL21 cells for expression. The expressed recombinant PTD-TH with a molecular weight of 61 kD was successfully transduced (1 {mu}M) into the dopaminergic SH-sy5y human neuroblastoma cells in vitro and visualized by immunohistochemical assay. An in vivo experiment in rats showed that the iv administered PTD-TH protein (8 mg/kg) permeated across the blood-brain barrier, penetrated into the striatum and midbrain, and peaked at 5-8 h after the injection. The behavioral effects of PTD-TH on the apomorphine-induced rotations in the PD model rats 8 weeks after the 6-OHDA lesion showed that a single bolus of PTD-TH (8 mg/kg) iv injection caused a decrement of 60% of the contralateral turns on day 1 and 40% on days 5-17. The results imply that iv delivery of PTD-TH is therapeutically effective on the 6-OHDA-induced PD in rats, the PTD-mediated human TH treatment opening a promising therapeutic direction in treatment of PD.

  5. Effect of antidepressant drugs on 6-OHDA-treated mice in the FST.

    PubMed

    Chenu, F; Dailly, E; Bourin, M

    2007-02-01

    There is growing evidence suggesting that dopamine could be indirectly involved in the appearance of behavioural effects of antidepressants. In this study, we induced a partial (over 70%) and non-reversible depletion of dopamine-containing neurons in mice by i.c.v. infusion of 6-OHDA. Then, we compared the antidepressant-like effect of drugs (citalopram, paroxetine, desipramine and imipramine) with or without dopamine depletion in the mice forced swimming test. Our results clearly show that lesion with 6-OHDA does not modify the response of mice to desipramine and imipramine, whereas dopamine depletion abolished the antidepressant-like effect of citalopram and paroxetine. It could then be suggested that antidepressant-like effect of selective serotonin reuptake inhibitors (paroxetine and citalopram) in the mice FST requires the activation of dopaminergic pathways to occur.

  6. Peripheral administration of the selective inhibitor of soluble Tumor Necrosis Factor (TNF) XPro®1595 attenuates nigral cell loss and glial activation in 6-OHDA hemiparkinsonian rats

    PubMed Central

    Barnum, Christopher J.; Chen, Xi; Chung, Jaegwon; Chang, Jianjun; Williams, Martha; Grigoryan, Nelly; Tesi, Raymond J.; Tansey, Malú G.

    2014-01-01

    BACKGROUND Parkinson's disease (PD) is a complex multi-system age-related neurodegenerative disorder. Targeting the ongoing neuroinflammation in PD patients is one strategy postulated to slow down or halt disease progression. Proof-of-concept studies from our group demonstrated that selective inhibition of soluble Tumor Necrosis Factor (solTNF) by intranigral delivery of dominant negative TNF (DN-TNF) inhibitors reduced neuroinflammation and nigral dopamine (DA) neuron loss in endotoxin and neurotoxin rat models of nigral degeneration. OBJECTIVE As a next step toward human clinical trials, we aimed to determine the extent to which peripherally administered DN-TNF inhibitor XPro®1595 could: i) cross the blood-brain-barrier in therapeutically relevant concentrations, ii) attenuate neuroinflammation (microglia and astrocyte), and iii) mitigate loss of nigral DA neurons in rats receiving a unilateral 6-hydroxydopamine (6-OHDA) striatal lesion. METHODS Rats received unilateral 6-OHDA (20 μg into the right striatum). Three or 14 days after lesion, rats were dosed with XPro®1595 (10 mg/kg in saline, subcutaneous) every third day for 35 days. Forelimb asymmetry was used to assess motor deficits after the lesion; brains were harvested 35 days after the lesion for analysis of XPro®1595 levels, glial activation, and nigral DA neuron number. RESULTS Peripheral subcutaneous dosing of XPro®1595 achieved plasma levels of 1–8 μg/mL and CSF levels of 1–6 ng/mL depending on the time the rats were killed after final XPro®1595 injection. Irrespective of start date, XPro®1595 significantly reduced microglia and astrocyte number in SNpc whereas loss of nigral DA neurons was attenuated when drug was started 3, but not 14 days after the 6-OHDA lesion. CONCLUSIONS Our data suggest that systemically administered XPro®1595 may have disease-modifying potential in PD patients where inflammation is part of their pathology. PMID:25061061

  7. Rho kinase inhibition by fasudil in the striatal 6-hydroxydopamine lesion mouse model of Parkinson disease.

    PubMed

    Tatenhorst, Lars; Tönges, Lars; Saal, Kim-Ann; Koch, Jan C; Szegő, Éva M; Bähr, Mathias; Lingor, Paul

    2014-08-01

    Chronic degeneration of nigrostriatal projections, followed by nigral dopaminergic cell death, is a key feature of Parkinson disease (PD). This study examines the neuroprotective potential of the rho kinase inhibitor fasudil in the 6-hydroxydopamine (6-OHDA) mouse model of PD in vivo. C57Bl/6 mice were lesioned by striatal stereotactic injections with 4 μg of 6-OHDA and treated with fasudil 30 or 100 mg/kg body weight via drinking water. Motor behavior was tested biweekly; histologic and biochemical analyses were performed at 4 and 12 weeks after lesion. Motor behavior was severely impaired after 6-OHDA lesion and was not improved by fasudil treatment. Fasudil 100 mg/kg did not significantly increase the number of dopaminergic cells in the substantia nigra after 12 weeks versus lesion controls. Interestingly, however, high-performance liquid chromatography analysis of dopamine metabolites revealed that striatal levels of 3,4-dihydroxyphenylacetic acid were significantly increased after 12 weeks, suggesting a regenerative response. In contrast to recent findings in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin model, fasudil effects seem limited in this severe 6-OHDA model of PD. Nevertheless, high therapeutic concentrations of fasudil are suggestive of a proregenerative potential for dopaminergic neurons, making further evaluations of rho kinase inhibition as a proregenerative therapeutic strategy in PD promising.

  8. Chemoreflex and baroreflex alterations in Parkinsonism induced by 6-OHDA in unanesthetized rats.

    PubMed

    Ariza, Deborah; Lopes, Fernanda Novi Cortegoso; Crestani, Carlos Cesar; Martins-Pinge, Marli Cardoso

    2015-10-21

    Parkinson's disease (PD) is mainly characterized by motor signals. However, non-motor signals also affect and decrease the quality of life of PD patients. Among these non-motor signs are cardiovascular disorders as orthostatic hypotension, postprandial hypotension and cardiac arrhythmias, which may be due to the involvement of both central nervous system and peripheral autonomic nervous system. In the present study we investigated the cardiovascular function, evaluating cardiovascular reflexes (chemoreflex and baroreflex), in an animal model of Parkinsonism induced by bilateral infusion of the toxin 6-hydroxydopamine (6-OHDA), in the substantia nigra pars compacta (SNpc). The results showed that the animals induced to Parkinsonism had lower arterial pressure (AP) and heart rate HR) compared to control animals. We showed that after activation of the baroreceptors by phenylephrine (Phe) and sodium nitroprusside (SNP), the baroreflex sensitivity index was not changed between the groups. However, there was a greater increase in the AP when stimulated with Phe and greater tachycardia when stimulated with SNP in 6-OHDA animals. After activation of the peripheral chemoreceptors through KCN injection (cytotoxic hypoxia), there was a higher increase in pressor and bradycardic response in injured animals with bilateral 6-OHDA. These changes in the cardiovascular reflexes may be important adjustments mechanisms to maintain the cerebral blood flow in those animals, and may be a result of denervation supersensitivity to catecholamines in autonomic targets.

  9. Protein Kinase D1 (PKD1) Phosphorylation Promotes Dopaminergic Neuronal Survival during 6-OHDA-Induced Oxidative Stress

    PubMed Central

    Asaithambi, Arunkumar; Ay, Muhammet; Jin, Huajun; Gosh, Anamitra; Anantharam, Vellareddy; Kanthasamy, Arthi; Kanthasamy, Anumantha G.

    2014-01-01

    Oxidative stress is a major pathophysiological mediator of degenerative processes in many neurodegenerative diseases including Parkinson’s disease (PD). Aberrant cell signaling governed by protein phosphorylation has been linked to oxidative damage of dopaminergic neurons in PD. Although several studies have associated activation of certain protein kinases with apoptotic cell death in PD, very little is known about protein kinase regulation of cell survival and protection against oxidative damage and degeneration in dopaminergic neurons. Here, we characterized the PKD1-mediated protective pathway against oxidative damage in cell culture models of PD. Dopaminergic neurotoxicant 6-hydroxy dopamine (6-OHDA) was used to induce oxidative stress in the N27 dopaminergic cell model and in primary mesencephalic neurons. Our results indicated that 6-OHDA induced the PKD1 activation loop (PKD1S744/S748) phosphorylation during early stages of oxidative stress and that PKD1 activation preceded cell death. We also found that 6-OHDA rapidly increased phosphorylation of the C-terminal S916 in PKD1, which is required for PKD1 activation loop (PKD1S744/748) phosphorylation. Interestingly, negative modulation of PKD1 activation by RNAi knockdown or by the pharmacological inhibition of PKD1 by kbNB-14270 augmented 6-OHDA-induced apoptosis, while positive modulation of PKD1 by the overexpression of full length PKD1 (PKD1WT) or constitutively active PKD1 (PKD1S744E/S748E) attenuated 6-OHDA-induced apoptosis, suggesting an anti-apoptotic role for PKD1 during oxidative neuronal injury. Collectively, our results demonstrate that PKD1 signaling plays a cell survival role during early stages of oxidative stress in dopaminergic neurons and therefore, positive modulation of the PKD1-mediated signal transduction pathway can provide a novel neuroprotective strategy against PD. PMID:24806360

  10. Prostaglandin receptor EP2 protects dopaminergic neurons against 6-OHDA-mediated low oxidative stress

    PubMed Central

    Carrasco, Emilce; Werner, Peter; Casper, Diana

    2008-01-01

    Dopaminergic neurons in the substantia nigra (SN) selectively die in Parkinson’s disease (PD), but it is unclear how and why this occurs. Recent findings implicate prostaglandin E2 (PGE2) and two of its four receptors, namely EP1 and EP2, as mediators of degenerative and protective events in situations of acute and chronic neuronal death. EP1 activation can exacerbate excitotoxic damage in stroke models and our recent study showed that EP1 activation may explain the selective sensitivity of dopaminergic neurons to oxidative stress. Conversely, EP2 activation may be neuroprotective, although toxic effects have also been demonstrated. Here we investigated if and how EP2 activation might alter the survival of dopaminergic neurons following selective low-level oxidative injury evoked by the neurotoxin 6-hydroxydopamine (6-OHDA) in primary neuronal cultures prepared from embryonic rat midbrain. We found that cultured dopaminergic neurons displayed EP2 receptors. Butaprost, a selective EP2 agonist, significantly reduced 6-OHDA neurotoxicity. EP2 receptors are coupled to stimulatory G-proteins (Gs), which activate adenylate cyclase, increasing cAMP synthesis, which then activates protein kinase A (PKA). Both dibutyryl cAMP and forskolin reduced dopaminergic cell loss after 6-OHDA exposure. Conversely, KT5720 and H-89, two structurally distinct high-affinity PKA inhibitors, abolished the protective effect of butaprost, implicating cAMP-dependent PKA activity in the neuroprotection by EP2 activation. Finally, we show that melanized dopaminergic neurons in the human SN express EP2. This pathway warrants consideration as a neuroprotective strategy for PD. PMID:18597941

  11. Prostaglandin receptor EP2 protects dopaminergic neurons against 6-OHDA-mediated low oxidative stress.

    PubMed

    Carrasco, Emilce; Werner, Peter; Casper, Diana

    2008-08-15

    Dopaminergic neurons in the substantia nigra (SN) selectively die in Parkinson's disease (PD), but it is unclear how and why this occurs. Recent findings implicate prostaglandin E(2) (PGE(2)) and two of its four receptors, namely EP1 and EP2, as mediators of degenerative and protective events in situations of acute and chronic neuronal death. EP1 activation can exacerbate excitotoxic damage in stroke models and our recent study showed that EP1 activation may explain the selective sensitivity of dopaminergic neurons to oxidative stress. Conversely, EP2 activation may be neuroprotective, although toxic effects have also been demonstrated. Here we investigated if and how EP2 activation might alter the survival of dopaminergic neurons following selective low-level oxidative injury evoked by the neurotoxin 6-hydroxydopamine (6-OHDA) in primary neuronal cultures prepared from embryonic rat midbrain. We found that cultured dopaminergic neurons displayed EP2 receptors. Butaprost, a selective EP2 agonist, significantly reduced 6-OHDA neurotoxicity. EP2 receptors are coupled to stimulatory G-proteins (Gs), which activate adenylate cyclase, increasing cAMP synthesis, which then activates protein kinase A (PKA). Both dibutyryl cAMP and forskolin reduced dopaminergic cell loss after 6-OHDA exposure. Conversely, KT5720 and H-89, two structurally distinct high-affinity PKA inhibitors, abolished the protective effect of butaprost, implicating cAMP-dependent PKA activity in the neuroprotection by EP2 activation. Finally, we show that melanized dopaminergic neurons in the human SN express EP2. This pathway warrants consideration as a neuroprotective strategy for PD.

  12. Palmitoylethanolamide protects mice against 6-OHDA-induced neurotoxicity and endoplasmic reticulum stress: In vivo and in vitro evidence.

    PubMed

    Avagliano, Carmen; Russo, Roberto; De Caro, Carmen; Cristiano, Claudia; La Rana, Giovanna; Piegari, Giuseppe; Paciello, Orlando; Citraro, Rita; Russo, Emilio; De Sarro, Giovambattista; Meli, Rosaria; Mattace Raso, Giuseppina; Calignano, Antonio

    2016-11-01

    Several pathogenetic factors have been involved in the onset and progression of Parkinson's disease (PD), including inflammation, oxidative stress, unfolded protein accumulation, and apoptosis. Palmitoylethanolamide (PEA), an endogenous N-acylethanolamine, has been shown to be a neuroprotective and anti-inflammatory molecule, acting as a peroxisome proliferator activated receptor (PPAR)-α agonist. In this study we investigated the effects of PEA on behavioral alterations and the underlying pathogenic mechanisms in the 6-hydroxydopamine (6-OHDA)-induced model of PD in male mice. Additionally, we showed the involvement of PPAR-α in PEA protective effect on SH-SY5Y neuroblastoma against 6-OHDA damage. Here, we report that PEA (3-30mg/kg/days.c.) improved behavioral impairments induced by unilateral intrastriatal injection of 6-OHDA. This effect was accompanied by a significant increase in tyrosine hydroxylase expression at striatal level, indicating PEA preserving effect on dopaminergic neurons. Moreover, we found a reduction in the expression of pro-inflammatory enzymes, i.e. inducible nitric oxide synthase and cyclooxygenase-2, a modulation between pro- and anti-apoptotic markers, suggestive of PEA capability in controlling neuroinflammation and cell death. Interestingly, PEA also showed protective scavenging effect, through superoxide dismutase induction, and dampened unfolding protein response, interfering on glucose-regulated protein 78 expression and PERK-eIF2α pathway. Similar data were found in in vitro studies, where PEA treatment was found to rescue SH-SY5Y neuroblastoma cells from 6-OHDA-induced damage and death, partly by inhibiting endoplasmic reticulum stress detrimental response. Therefore, PEA, counteracting the pathogenetic aspects involved in the development of PD, showed its therapeutic potential, possibly integrating current treatments correcting dopaminergic deficits and motor dysfunction.

  13. Lesioning of the Striatum Reverses Motor Asymmetry in the 6-Hydroxydopamine Rodent Model of Parkinsonism

    PubMed Central

    Friehs, G. M.; Parker, R. G.; He, L. S.; Haines, S. J.; Turner, D. A.; Ebner, T. J.

    1991-01-01

    In the rat several paradigms of grafting of adrenal medulla into the striatum were studied following the induction of a parkinsonian model, using a unilateral 6-hydroxydopamine (6-OHDA) lesion of the substantia nigra . Direct autologous grafting of adrenal medulla into the caudate-putamen complex, a radiofrequency lesion of the striatum alone, and a radiofrequency lesion followed by delayed grafting of adrenal medulla were compared by analyzing rotational behavior. Direct grafting of adrenal medulla produced an overall reduction in apomorphine induced turning behavior by 43.5% when compared with controls. Radiofrequency lesioning of the striatum without graft showed the best improvement over control animals with a 92% reduction in the total number of rotations induced by apomorphine. Delayed grafting into the caudate lesion cavity also produced a dramatic reduction in motor asymmetry but did not improve the behavioral outcome over that of the lesion alone. Animals receiving only radiofrequency lesions exhibited a band of increased tyrosine hydroxylase like immunoreactivity bordering the lesion cavity. Graft survival was limited in the nonlesioned animals but appeared enhanced in the animals whose striatum was previously lesioned. Lesion location within the striatum influenced the behavioral outcome. Large reductions in apomorphine-induced rotations could result from small lesions of the dorso-lateral striatum. These findings indicate that selective destruction of the caudate-putamen complex without tissue transplantation produces a dramatic reduction in the motor asymmetry of 6-OHDA treated rats. Suggested explanations for the decrease in induced rotational behavior with radiofrequency lesions include a decrease in the number of striatal dopamine receptors following cell destruction and lesioninduced recovery of host dopaminergic afferents. Striatal damage in critical areas can reverse some of the motor behavior associated with the 6-OHDA model and needs to be

  14. Characterization of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in rat partial and full nigral 6-hydroxydopamine lesion models of Parkinson's disease.

    PubMed

    Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille; Mikkelsen, Jens D; Jelsing, Jacob; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-09-01

    Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, have been demonstrated to promote neuroprotection in the rat 6-hydroxydopamine (6-OHDA) neurotoxin model of Parkinson's disease (PD), a neurodegenerative disorder characterized by progressive nigrostriatal dopaminergic neuron loss. In this report, we characterized the effect of a long-acting GLP-1 receptor agonist, liraglutide (500µg/kg/day, s.c.) in the context of a partial or advanced (full) 6-OHDA induced nigral lesion in the rat. Rats received a low (3µg, partial lesion) or high (13.5µg, full lesion) 6-OHDA dose stereotaxically injected into the right medial forebrain bundle (n=17-20 rats per experimental group). Six weeks after induction of a partial nigral dopaminergic lesion, vehicle or liraglutide was administered for four weeks. In the full lesion model, vehicle dosing or liraglutide treatment was applied for a total of six weeks starting three weeks pre-lesion, or administered for three weeks starting on the lesion day. Quantitative stereology was applied to assess the total number of midbrain tyrosine hydroxylase (TH) positive dopaminergic neurons. As compared to vehicle controls, liraglutide had no effect on the rotational responsiveness to d-amphetamine or apomorphine, respectively. In correspondence, while numbers of TH-positive nigral neurons were significantly reduced in the lesion side (partial lesion ≈55%; full lesion ≈90%) liraglutide administration had no influence dopaminergic neuronal loss in either PD model setting. In conclusion, liraglutide showed no neuroprotective effects in the context of moderate or substantial midbrain dopaminergic neuronal loss and associated functional motor deficits in the rat 6-OHDA lesion model of PD.

  15. RING finger protein 11 (RNF11) modulates susceptibility to 6-OHDA-induced nigral degeneration and behavioral deficits through NF-κB signaling in dopaminergic cells.

    PubMed

    Pranski, Elaine L; Dalal, Nirjari V; Sanford, Carson Van; Herskowitz, Jeremy H; Gearing, Marla; Lazo, Carlos; Miller, Gary W; Lah, James J; Levey, Allan I; Betarbet, Ranjita S

    2013-06-01

    Chronic activation of the NF-κB pathway is associated with progressive neurodegeneration in Parkinson's disease (PD). Given the role of neuronal RING finger protein 11 (RNF11) as a negative regulator of the NF-κB pathway, in this report we investigated the function of RNF11 in dopaminergic cells in PD-associated neurodegeneration. We found that RNF11 knockdown in an in vitro model of PD mediated protection against 6-OHDA-induced toxicity. In converse, over-expression of RNF11 enhanced 6-OHDA-induced dopaminergic cell death. Furthermore, by directly manipulating NF-κB signaling, we showed that the observed RNF11-enhanced 6-OHDA toxicity is mediated through inhibition of NF-κB-dependent transcription of TNF-α, antioxidants GSS and SOD1, and anti-apoptotic factor BCL2. Experiments in an in vivo 6-OHDA rat model of PD recapitulated the in vitro results. In vivo targeted RNF11 over-expression in nigral neurons enhanced 6-OHDA toxicity, as evident by increased amphetamine-induced rotations and loss of nigral dopaminergic neurons as compared to controls. This enhanced toxicity was coupled with the downregulation of NF-κB transcribed GSS, SOD1, BCL2, and neurotrophic factor BDNF mRNA levels, in addition to decreased TNF-α mRNA levels in ventral mesenchephalon samples. In converse, knockdown of RNF11 was associated with protective phenotypes and increased expression of above-mentioned NF-κB transcribed genes. Collectively, our in vitro and in vivo data suggest that RNF11-mediated inhibition of NF-κB in dopaminergic cells exaggerates 6-OHDA toxicity by inhibiting neuroprotective responses while loss of RNF11 inhibition on NF-κB activity promotes neuronal survival. The decreased expression of RNF11 in surviving cortical and nigral tissue detected in PD patients, thus implies a compensatory response in the diseased brain to PD-associated insults. In summary, our findings demonstrate that RNF11 in neurons can modulate susceptibility to 6-OHDA toxicity through NF

  16. Blockade of RyRs in the ER Attenuates 6-OHDA-Induced Calcium Overload, Cellular Hypo-Excitability and Apoptosis in Dopaminergic Neurons

    PubMed Central

    Huang, Lu; Xue, Ying; Feng, DaYun; Yang, RuiXin; Nie, Tiejian; Zhu, Gang; Tao, Kai; Gao, GuoDong; Yang, Qian

    2017-01-01

    Calcium (Ca2+) dyshomeostasis induced by endoplasmic reticulum (ER) stress is an important molecular mechanism of selective dopaminergic (DA) neuron loss in Parkinson’s disease (PD). Inositol 1,4,5-triphosphate receptors (IP3Rs) and ryanodine receptors (RyRs), which are located on the ER surface, are the main endogenous Ca2+ release channels and play crucial roles in regulating Ca2+ homeostasis. However, the roles of these endogenous Ca2+ release channels in PD and their effects on the function and survival of DA neurons remain unknown. In this study, using a 6-hydroxydopamine (6-OHDA)-induced in vitro PD model (SN4741 Cell line), we found that 6-OHDA significantly increased cytoplasmic Ca2+ levels ([Ca2+]i), which was attenuated by pretreatment with 4-phenyl butyric acid (4-PBA; an ER stress inhibitor) or ryanodine (a RyRs blocker). In addition, in acute midbrain slices of male Sprague-Dawley rats, we found that 6-OHDA reduced the spike number and rheobase of DA neurons, which were also reversed by pretreatment with 4-PBA and ryanodine. TUNEL staining and MTT assays also showed that 4-PBA and ryanodine obviously alleviated 6-OHDA-induced cell apoptosis and devitalization. Interestingly, a IP3Rs blocker had little effect on the above 6-OHDA-induced neurotoxicity in DA neurons. In conclusion, our findings provide evidence of the different roles of IP3Rs and RyRs in the regulation of endogenous Ca2+ homeostasis, neuronal excitability, and viability in DA neurons, and suggest a potential therapeutic strategy for PD by inhibiting the RyRs Ca2+ channels in the ER. PMID:28316566

  17. Monoaminergic PET imaging and histopathological correlation in unilateral and bilateral 6-hydroxydopamine lesioned rat models of Parkinson's disease: a longitudinal in-vivo study.

    PubMed

    Molinet-Dronda, Francisco; Gago, Belén; Quiroga-Varela, Ana; Juri, Carlos; Collantes, María; Delgado, Mercedes; Prieto, Elena; Ecay, Margarita; Iglesias, Elena; Marín, Concepció; Peñuelas, Iván; Obeso, José A

    2015-05-01

    Carbon-11 labeled dihydrotetrabenazine ((11)C-DTBZ) binds to the vesicular monoamine transporter 2 and has been used to assess nigro-striatal integrity in animal models and patients with Parkinson's disease. Here, we applied (11)C-DTBZ positron emission tomography (PET) to obtain longitudinally in-vivo assessment of striatal dopaminergic loss in the classic unilateral and in a novel bilateral 6-hydroxydopamine (6-OHDA) lesion rat model. Forty-four Sprague-Dawley rats were divided into 3 sub-groups: 1. 6-OHDA-induced unilateral lesion in the medial forebrain bundle, 2. bilateral lesion by injection of 6-OHDA in the third ventricle, and 3. vehicle injection in either site. (11)C-DTBZ PET studies were investigated in the same animals successively at baseline, 1, 3 and 6weeks after lesion using an anatomically standardized volumes-of-interest approach. Additionally, 12 rats had PET and Magnetic Resonance Imaging to construct a new (11)C-DTBZ PET template. Behavior was characterized by rotational, catalepsy and limb-use asymmetry tests and dopaminergic striatal denervation was validated post-mortem by immunostaining of the dopamine transporter (DAT). (11)C-DTBZ PET showed a significant decrease of striatal binding (SB) values one week after the unilateral lesion. At this point, there was a 60% reduction in SB in the affected hemisphere compared with baseline values in 6-OHDA unilaterally lesioned animals. A 46% symmetric reduction over baseline SB values was found in bilaterally lesioned rats at the first week after lesion. SB values remained constant in unilaterally lesioned rats whereas animals with bilateral lesions showed a modest (22%) increase in binding values at the 3rd and 6th weeks post-lesion. The degree of striatal dopaminergic denervation was corroborated histologically by DAT immunostaining. Statistical analysis revealed a high correlation between (11)C-DTBZ PET SB and striatal DAT immunostaining values (r=0.95, p<0.001). The data presented here indicate

  18. Caffeine and CSC, adenosine A2A antagonists, offer neuroprotection against 6-OHDA-induced neurotoxicity in rat mesencephalic cells.

    PubMed

    Nobre, Hélio Vitoriano; Cunha, Geanne Matos de Andrade; de Vasconcelos, Lissiana Magna; Magalhães, Hemerson Iury Ferreira; Oliveira Neto, Raimundo Nogueira; Maia, Flávio Damasceno; de Moraes, Manoel Odorico; Leal, L Kalyne A Moreira; Viana, Glauce Socorro de Barros

    2010-01-01

    In this study, the cytoprotective effects of caffeine (CAF) and 8-(3-chlorostyryl)-caffeine (CSC), A(2A) receptor antagonists, were tested against 6-OHDA-induced cytotoxicity, in rat mesencephalic cells. Both drugs significantly increased the number of viable cells, after their exposure to 6-OHDA, as measured by the MTT assay. While nitrite levels in the cells were drastically increased by 6-OHDA, their concentrations were brought toward normality after CAF or CSC, indicating that both drugs block 6-OHDA-induced oxidative stress which leads to free radicals generation. A complete blockade of 6-OHDA-induced lipid peroxidation, considered as a major source of DNA damage, was observed after cells treatment with CAF or CSC. 6-OHDA decreased the number of normal cells while increasing the number of apoptotic cells. In the CAF plus 6-OHDA group, a significant recover in the number of viable cells and a decrease in the number of apoptotic cells were seen, as compared to the group treated with 6-OHDA alone. A similar effect was observed after cells exposure to CSC in the presence of 6-OHDA. Unexpectedly, while a significant lower number of activated microglia was observed after cells exposure to CAF plus 6-OHDA, this was not the case after cells exposure to CSC under the same conditions. While CAF lowered the percentage of reactive astrocytes increased by 6-OHDA, CSC presented no effect. The effects of these drugs were also examined on the releases of myeloperoxidase (MPO), an inflammatory marker, and lactate dehydrogenase (LDH), a marker for cytotoxicity, in human neutrophils, in vitro. CSC and CAF (0.1, 1 and 10 microg/ml) produced inhibitions of the MPO release from PMA-stimulated cells, ranging from 45 to 83%. In addition, CSC and CAF (5, 50 and 100 microg/ml) did not show any cytotoxicity in the range of concentrations used, as determined by the LDH assay. All together, our results showed a strong neuroptrotection afforded by caffeine or CSC, on rat mesencephalic

  19. Atomoxetine blocks motor hyperactivity in neonatal 6-hydroxydopamine-lesioned rats: implications for treatment of attention-deficit hyperactivity disorder.

    PubMed

    Moran-Gates, Taylor; Zhang, Kehong; Baldessarini, Ross J; Tarazi, Frank I

    2005-09-01

    We recently reported that selective inhibitors of neuronal transport of norepinephrine (NE), desipramine and nisoxetine, reversed motor hyperactivity in an animal model of attention-deficit hyperactivity disorder (ADHD). In this study, we examined behavioural effects of atomoxetine, a potent new NE reuptake blocker, in juvenile male rats with neonatal 6-hydroxydopamine (6-OHDA) lesions of dopamine projections to the forebrain. 6-OHDA (100 microg) was administered intracisternally on postnatal day (PD) 5 following desipramine (25 mg/kg s.c.) pretreatment to protect noradrenergic neurons. Atomoxetine (1 mg/kg) was given intraperitoneally before recording motor activity for 90 min at PD 23-26 in a novel environment. Atomoxetine greatly reduced motor hyperactivity in 6-OHDA-lesioned rats while exhibiting transient sedative effects in sham controls. The observed effects in this animal model for ADHD are consistent with the emerging clinical use of atomoxetine as a novel, non-stimulant treatment for ADHD.

  20. Intranasal Administration of GDNF Protects Against Neural Apoptosis in a Rat Model of Parkinson's Disease Through PI3K/Akt/GSK3β Pathway.

    PubMed

    Yue, Peijian; Gao, Lin; Wang, Xuejing; Ding, Xuebing; Teng, Junfang

    2017-02-28

    Glial cell line-derived neurotrophic factor (GDNF) plays important roles in protecting the damaged or dying dopamine neurons in the animal models of Parkinson's disease (PD). This study was to determine the effect and mechanisms of GDNF on the apoptosis of neurons in 6-hydroxydopamine (6-OHDA) induced Parkinson's disease model of rats. Healthy male Sprague-Dawley rats (220-240 g) were randomly divided into six groups (n = 10). 6-OHDA was used to establish the PD rat model. Tyrosine hydroxylase (TH) immunohistochemistry was used to assess the neuron loss in 6-OHDA-lesioned rats. TUNEL and western blot were used to identify the effects and mechanisms of GDNF in the rat model of PD. The numbers of TH-positive neurons in the 6-OHDA-injected lesioned substantia nigra (SN) decreased significantly compared with the Sham group. GDNF treatment effectively ameliorated the apoptosis of neuronal cells in SN induced by 6-OHDA. In addition, GDNF significantly increased serine protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK3β) phosphorylation induced by 6-OHDA. In contrast, application of LY294002 or triciribine reversed the roles of GDNF in PD models. The results implicated that the anti-apoptosis effects of GDNF in neurons might be mediated through PI3K/Akt/GSK3β pathway. Therefore, GDNF may be a promising agent for PD treatment.

  1. Naringin treatment induces neuroprotective effects in a mouse model of Parkinson's disease in vivo, but not enough to restore the lesioned dopaminergic system.

    PubMed

    Kim, Heung Deok; Jeong, Kyoung Hoon; Jung, Un Ju; Kim, Sang Ryong

    2016-02-01

    We recently reported that treatment with naringin, a major flavonoid found in grapefruit and citrus fruits, attenuated neurodegeneration in a rat model of Parkinson's disease (PD) in vivo. In order to investigate whether its effects are universally applied to a different model of PD and whether its treatment induces restorative effects on the lesioned nigrostriatal dopaminergic (DA) projection, we observed the effects of pre-treatment or post-treatment with naringin in a mouse model of PD. For neuroprotective effects, 6-hydroxydopamine (6-OHDA) was unilaterally injected into the striatum of mouse brains for a neurotoxin model of PD in the presence or absence of naringin by daily intraperitoneal injection. Our results showed that naringin protected the nigrostriatal DA projection from 6-OHDA-induced neurotoxicity. Moreover, similar to the effects in rat brains, this treatment induced the activation of mammalian target of rapamycin complex 1 (mTORC1), which is well known as an important survival factor for DA neurons, and inhibited microglial activation in the substantia nigra (SN) of mouse brains treated with 6-OHDA. However, there was no significant change of DA phenotypes in the SN and striatum post-treated with naringin compared with 6-OHDA-lesioned mice, despite the treatment being continued for 12 weeks. These results suggest that post-treatment with naringin alone may not be enough to restore the nigrostriatal DA projection in a mouse model of PD. However, our results apparently suggest that naringin is a beneficial natural product to prevent DA degeneration, which is involved in PD.

  2. Troxerutin exerts neuroprotection in 6-hydroxydopamine lesion rat model of Parkinson's disease: Possible involvement of PI3K/ERβ signaling.

    PubMed

    Baluchnejadmojarad, Tourandokht; Jamali-Raeufy, Nida; Zabihnejad, Sedigheh; Rabiee, Nafiseh; Roghani, Mehrdad

    2017-04-15

    Parkinson's disease (PD) is a neurodegenerative disease with progressive loss of mesencephalic dopaminergic neurons of the substantia nigra and with multiple incapacitating motor and non-motor symptoms. Troxerutin is a natural bioflavonoid with nephro- and hepato-protective, antioxidant, and anti-inflammatory properties. In this study, we evaluated its possible neuroprotective effect in 6-hydroxydopamine (6-OHDA) rat model of PD. Intrastriatal 6-OHDA-lesioned rats were pretreated with troxerutin at a dose of 150mg/kg/day for 1 week. Results showed that troxerutin mitigates apomorphine-induced motor asymmetry and lowered the latency to initiate and the total time in the narrow beam task and this beneficial effect was lost following central application of estrogen receptor β (ERβ) antagonist or phosphatidylinositol 3-kinase (PI3K) inhibitor. In addition, troxerutin reduced striatal malondialdehyde (MDA) as an index of lipid peroxidation, reactive oxygen species, glial fibrillary acid protein (GFAP) as a marker of astrogliosis, and DNA fragmentation as an apoptotic marker with no significant alteration of catalase activity and nitrite level. Meanwhile, troxerutin was capable to prevent loss of nigral tyrosine hydroxylase (TH)-positive neurons. These findings indicate neuroprotective potential of troxerutin in 6-OHDA rat model of PD through mitigation of apoptosis, astrogliosis, and oxidative stress and part of its effect is dependent on PI3K/ERβ signaling.

  3. Calcitriol promotes augmented dopamine release in the lesioned striatum of 6-hydroxydopamine treated rats

    PubMed Central

    Cass, Wayne A.; Peters, Laura E.; Fletcher, Anita M.; Yurek, David M.

    2014-01-01

    Current therapies for Parkinson's disease (PD) offer symptomatic relief but do not provide a cure or slow the disease process. Treatments that could halt progression of the disease or help restore function to damaged neurons would be of substantial benefit. Calcitriol, the active metabolite of vitamin D, has been shown to have significant effects on the brain. These effects include upregulating trophic factor levels, and reducing the severity of some central nervous system lesions. While previous studies have shown that calcitriol can be neuroprotective in 6-hydroxydopamine (6-OHDA) rodent models of PD, the present experiments were designed to examine the ability of calcitriol to promote restoration of extracellular DA levels and tissue content of DA in animals previously lesioned with 6-OHDA. Male Fischer-344 rats were given a single injection of 12 µg 6-OHDA into the right striatum. Four weeks later the animals were administered vehicle or calcitriol (0.3 or 1.0 µg/kg, s.c.) once a day for eight consecutive days. Three weeks after the calcitriol treatments in vivo microdialysis experiments were conducted to measure potassium and amphetamine evoked overflow of DA from both the left and right striata. In control animals treated with 6-OHDA and vehicle there were significant reductions in both potassium and amphetamine evoked overflow of DA on the lesioned side of the brain compared to the contralateral side. In animals treated with 6-OHDA followed by calcitriol there was significantly greater potassium and amphetamine evoked overflow of DA from the lesioned striatum compared to that from the control animals. The calcitriol treatments also led to increases in postmortem tissue levels of DA in the striatum and substantia nigra. These results suggest that calcitriol may help promote recovery of dopaminergic functioning in injured nigrostriatal neurons. PMID:24858239

  4. Striatal mRNA expression patterns underlying peak dose L-DOPA-induced dyskinesia in the 6-OHDA hemiparkinsonian rat.

    PubMed

    Smith, L M; Parr-Brownlie, L C; Duncan, E J; Black, M A; Gemmell, N J; Dearden, P K; Reynolds, J N J

    2016-06-02

    L-DOPA is the primary pharmacological treatment for relief of the motor symptoms of Parkinson's disease (PD). With prolonged treatment (⩾5 years) the majority of patients will develop abnormal involuntary movements as a result of L-DOPA treatment, known as L-DOPA-induced dyskinesia. Understanding the underlying mechanisms of dyskinesia is a crucial step toward developing treatments for this debilitating side effect. We used the 6-hydroxydopamine (6-OHDA) rat model of PD treated with a three-week dosing regimen of L-DOPA plus the dopa decarboxylase inhibitor benserazide (4 mg/kg and 7.5 mg/kgs.c., respectively) to induce dyskinesia in 50% of individuals. We then used RNA-seq to investigate the differences in mRNA expression in the striatum of dyskinetic animals, non-dyskinetic animals, and untreated parkinsonian controls at the peak of dyskinesia expression, 60 min after L-DOPA administration. Overall, 255 genes were differentially expressed; with significant differences in mRNA expression observed between all three groups. In dyskinetic animals 129 genes were more highly expressed and 14 less highly expressed when compared with non-dyskinetic and untreated parkinsonian controls. In L-DOPA treated animals 42 genes were more highly expressed and 95 less highly expressed when compared with untreated parkinsonian controls. Gene set cluster analysis revealed an increase in expression of genes associated with the cytoskeleton and phosphoproteins in dyskinetic animals compared with non-dyskinetic animals, which is consistent with recent studies documenting an increase in synapses in dyskinetic animals. These genes may be potential targets for drugs to ameliorate L-DOPA-induced dyskinesia or as an adjunct treatment to prevent their occurrence.

  5. Botanical Drug Puerarin Attenuates 6-Hydroxydopamine (6-OHDA)-Induced Neurotoxicity via Upregulating Mitochondrial Enzyme Arginase-2.

    PubMed

    Zhao, Jia; Cheng, Yuanyuan; Yang, Chuanbin; Lau, Sam; Lao, Lixing; Shuai, Bo; Cai, Jing; Rong, Jianhui

    2016-05-01

    Inhibition of nitric oxide synthases (NOSs) shows promise to halt the progression of neurodegenerative diseases. The present study was designed to explore whether botanical isoflavone puerarin could attenuate nitric oxide (NO)-mediated neurotoxicity via modulating the enzymes in the L-arginine-NO pathway. Neurotoxin 6-hydroxydopamine (6-OHDA) is well known to induce neurodegeneration via a NO-dependent mechanism. We first validated that puerarin protected rat dopamingeric PC12 cells against 6-OHDA-induced neurotoxicity in a concentration-dependent manner. We subsequently profiled the cellular responses to puerarin by a proteomic response fingerprinting approach. A total of 16 protein spots with >1.5-fold change of intensity were selected and identified by mass spectrometry. As one of puerarin-upregulated proteins, mitochondrial arginase-2 hydrolyzes L-arginine to L-ornithine, thereby competing with neuronal NOS for substrate L-arginine in mitochondria. Thus, we hypothesize that puerain may attenuate nitric oxide (NO)-mediated mitochondrial injury via increasing arginase-2 expression. Western blot and reverse transcription polymerase chain reaction (RT-PCR) analyses confirmed that puerarin increased arginase-2 expression in a concentration- and time-dependent manner. Accordingly, puerarin suppressed 6-OHDA-induced NO production and neurotoxicity in PC12 cells and primary rat midbrain neurons. Arginase inhibitor BEC diminished the effect of puerarin on 6-OHDA-induced NO production and neurotoxicity. The activation of arginase-2 by puerarin represents an endogenous mechanism for specific control of NO-mediated mitochondrial damage. Thus, puerarin is a useful lead for suppressing NO-mediated neurotoxicity in neurodegenerative diseases. Graphical Abstract Arginase-2 dependent mechanism underlying the neuroprotective activity of puerarin.

  6. Circadian distribution of motor-activity in unilaterally 6-hydroxy-dopamine lesioned rats.

    PubMed

    Baier, Paul Christian; Branisa, Pablo; Koch, Reinhard; Schindehütte, Jan; Paulus, Walter; Trenkwalder, Claudia

    2006-02-01

    Sleep abnormalities in idiopathic Parkinson's disease (PD) frequently consist in a reduction of total sleep time and efficacy and subsequent excessive daytime sleepiness. As it remains unclear whether these phenomena are part of the disease itself or result from pharmacological treatment, animal models for investigating the pathophysiology of sleep alterations in PD may add knowledge to this research area. In the present study, we investigate whether changes in circadian motor activity occur in 6-OHDA-lesioning model for PD, and allow a screening for disturbed sleep-waking behaviour. Activity measurements of six male Wistar rats with 6-OHDA-lesions in the medial forebrain bundle and six controls were carried out in two consecutive 12:12 h light-dark (LD) cycles. A computer-based video-analysis system, recording the animals' movement tracks was used. Distance travelled and number of transitions between movement periods and resting periods were determined. Although 6-OHDA-lesioned animals show a reduced locomotor activity compared to non-lesioned rats, the circadian distribution basically remained intact. However, some lesioning effects were more pronounced in the resting phase than in the activity phase, possibly paralleling nocturnal akinesia in PD. In order to further elucidate the described phenomena, it will be necessary to perform studies combining sleep recordings with locomotor activity measurements.

  7. Phloroglucinol attenuates motor functional deficits in an animal model of Parkinson's disease by enhancing Nrf2 activity.

    PubMed

    Ryu, Junghwa; Zhang, Rui; Hong, Bo-Hyun; Yang, Eun-Jung; Kang, Kyoung Ah; Choi, Moonseok; Kim, Ki Cheon; Noh, Su-Jin; Kim, Hee Soo; Lee, Nam-Ho; Hyun, Jin Won; Kim, Hye-Sun

    2013-01-01

    In this study, we investigated whether phloroglucinol (1,3,5-trihydroxybenzene) has therapeutic effects in cellular and animal model of Parkinson's disease (PD). PD is the second most common, chronic and progressive neurodegenerative disease, and is clinically characterized with motor dysfunctions such as bradykinesia, rigidity, postural instability, gait impairment, and resting tremor. In the brains of PD patients, dopaminergic neuronal loss is observed in the Substantia nigra. Although the exact mechanisms underlying PD are largely unknown, mitochondrial dysfunction and oxidative stress are thought to be critical factors that induce the onset of the disease. Here, phloroglucinol administration was shown to attenuate motor functional deficits evaluated with rota-rod and apomorphine-induced rotation tests in 6-hydroxydopamine (6-OHDA)-induced PD animal models. Moreover, phloroglucinol ameliorated the loss of synapses as assessed with protein levels and immunoreactivity against synaptophysin in the midbrain region of the 6-OHDA-lesioned rats. In addition, in SH-SY5Y cultures, the cytotoxicity of 6-OHDA was reduced by pre-treatment with phloroglucinol. The increase in the reactive oxygen species, lipid peroxidation, protein carbonyl formation and 8-hydroxyguanine caused by treatment with 6-OHDA was attenuated by phloroglucinol in SH-SY5Y cells. Furthermore, phloroglucinol treatment rescued the reduced levels of nuclear Nrf2, antioxidant enzymes, i.e., catalase and glutathione peroxidase, in 6-OHDA-treated cells. Taken together, phloroglucinol has a therapeutic potential for treatment of PD.

  8. Phloroglucinol Attenuates Motor Functional Deficits in an Animal Model of Parkinson's Disease by Enhancing Nrf2 Activity

    PubMed Central

    Hong, Bo-Hyun; Yang, Eun-Jung; Kang, Kyoung Ah; Choi, Moonseok; Kim, Ki Cheon; Noh, Su-Jin; Kim, Hee Soo; Lee, Nam-Ho; Hyun, Jin Won; Kim, Hye-Sun

    2013-01-01

    In this study, we investigated whether phloroglucinol (1, 3, 5 - trihydroxybenzene) has therapeutic effects in cellular and animal model of Parkinson's disease (PD). PD is the second most common, chronic and progressive neurodegenerative disease, and is clinically characterized with motor dysfunctions such as bradykinesia, rigidity, postural instability, gait impairment, and resting tremor. In the brains of PD patients, dopaminergic neuronal loss is observed in the Substantia nigra. Although the exact mechanisms underlying PD are largely unknown, mitochondrial dysfunction and oxidative stress are thought to be critical factors that induce the onset of the disease. Here, phloroglucinol administration was shown to attenuate motor functional deficits evaluated with rota-rod and apomorphine-induced rotation tests in 6-hydroxydopamine (6-OHDA)-induced PD animal models. Moreover, phloroglucinol ameliorated the loss of synapses as assessed with protein levels and immunoreactivity against synaptophysin in the midbrain region of the 6-OHDA-lesioned rats. In addition, in SH-SY5Y cultures, the cytotoxicity of 6-OHDA was reduced by pre-treatment with phloroglucinol. The increase in the reactive oxygen species, lipid peroxidation, protein carbonyl formation and 8-hydroxyguanine caused by treatment with 6-OHDA was attenuated by phloroglucinol in SH-SY5Y cells. Furthermore, phloroglucinol treatment rescued the reduced levels of nuclear Nrf2, antioxidant enzymes, i.e., catalase and glutathione peroxidase, in 6-OHDA-treated cells. Taken together, phloroglucinol has a therapeutic potential for treatment of PD. PMID:23976995

  9. Effect of pre- and postnatal manganese exposure on brain histamine content in a rodent model of Parkinson's disease.

    PubMed

    Brus, Ryszard; Jochem, Jerzy; Nowak, Przemysław; Adwent, Marta; Boroń, Dariusz; Brus, Halina; Kostrzewa, Richard M

    2012-02-01

    Rats lesioned shortly after birth with 6-hydroxydopamine (6-OHDA; 134 μg icv) represent a near-ideal model of severe Parkinson's disease because of the near-total destruction of nigrostriatal dopaminergic fibers. There are scarce data that in Parkinson's disease, activity of the central histaminergic system is increased. The element manganese, an essential cofactor for many enzymatic reactions, itself in toxic amount, replicates some clinical features similar to those of Parkinson's disease. The aim of this study was to examine the effect of neonatal manganese exposure on 6-OHDA modeling of Parkinson's disease in rats, and to determine effects on histamine content in the brain of these rats in adulthood. Manganese (MnCl₂·4H₂O; 10,000 ppm) was included in the drinking water of pregnant Wistar rats from the time of conception until the 21st day after delivery, the age when neonatal rats were weaned. Control rats consumed tap water. Other groups of neonatal rat pups, on the 3rd day after birth, were pretreated with desipramine (20 mg/kg ip 1 h) prior to bilateral icv administration of 6-OHDA (60 or 134 μg) or its vehicle saline-ascorbic (0.1%) (control). At 2 months after birth, in rats lesioned with 60 or 134 μg 6-OHDA, endogenous striatal dopamine (DA) content was reduced, respectively, by 92 and 98% (HPLC/ED), while co-exposure of these groups to perinatal manganese did not magnify the DA depletion. However, there was prominent enhancement of histamine content in frontal cortex, hippocampus, hypothalamus, and medulla oblongata of adult rat brain after 6-OHDA (60 and 134 μg) injection on the day 3rd postnatal day. These findings indicate that histamine and the central histaminergic system are altered in the brain of rats lesioned to model Parkinson's disease, and that manganese enhances effects of 6-OHDA on histamine in brain.

  10. Inhibition of Glycogen Synthase Kinase-3β (GSK-3β) as potent therapeutic strategy to ameliorates L-dopa-induced dyskinesia in 6-OHDA parkinsonian rats

    PubMed Central

    Xie, Cheng-long; Lin, Jing-Ya; Wang, Mei-Hua; Zhang, Yu; Zhang, Su-fang; Wang, Xi-Jin; Liu, Zhen-Guo

    2016-01-01

    Levodopa (L-dopa) is the dominating therapy drug for exogenous dopaminergic substitution and can alleviate most of the manifestations of Parkinson’s disease (PD), but long-term therapy is associated with the emergence of L-dopa-induced dyskinesia (LID). Evidence points towards an involvement of Glycogen Synthase Kinase-3β (GSK-3β) in development of LID. In the present study, we found that animals rendered dyskinetic by L-dopa treatment, administration of TDZD8 (2mg/kg) obviously prevented the severity of AIM score, as well as improvement in motor function (P < 0.05). Moreover, the TDZD8-induced reduction in dyskinetic behavior correlated with a reduction in molecular correlates of LID. TDZD8 reduced the phosphorylation levels of tau, DARPP32, ERK and PKA protein, which represent molecular markers of LID, as well as reduced L-dopa-induced FosB mRNA and PPEB mRNA levels in the lesioned striatum. In addition, we found that TDZD8 antidyskinetic properties were overcome by D1 receptor, as pretreatment with SKF38393 (5 mg/kg, 10 mg/kg, reapectively), a D1 receptor agonist, blocked TDZD8 antidyskinetic actions. This study supported the hypothesis that GSK-3β played an important role in the development and expression of LID. Inhibition of GSK-3β with TDZD8 reduced the development of ALO AIM score and associated molecular changes in 6-OHDA-lesioned rats. PMID:26997328

  11. The ameliorative effect of Monascus purpureus NTU 568-fermented rice extracts on 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y cells and the rat model of Parkinson's disease.

    PubMed

    Tseng, Wei-Ting; Hsu, Ya-Wen; Pan, Tzu-Ming

    2016-02-01

    Oxidative stress and neuroinflammation underlie the major pathogenesis in Parkinson's disease (PD). Antioxidants are known to protect against the degeneration of dopaminergic neurons. Monascus purpureus-fermented rice, a traditional Chinese medicine as well as a health food, includes multifunctional metabolites. The present study was designed to investigate the effects of the antioxidant-containing M. purpureus NTU 568-fermented rice extract (extracted with 50% ethanol, so called R50E) in 6-hydrodopamine (6-OHDA)-induced neurotoxicity in vitro and in vivo. In vitro, treatment with R50E reduced 6-OHDA-induced SH-SY5Y cell death. In vivo, two doses of R50E (5.5 and 11.0 mg kg(-1)) were administered for a period of 28 days following 6-OHDA-induced lesioning. The administration of R50E reduced parkinsonian motor dysfunction and the number of tyrosine hydroxylase (TH)-immunoreactive neurons present in 6-OHDA-induced lesioned rats. Moreover, the administration of R50E reversed the elevation of reactive oxygen species (ROS) and malondialdehyde (MDA) levels and promoted the activity of antioxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione reductase, and glutathione peroxidase via down-regulation of p47 phox, NOX1, and NOX2 expression in the 6-OHDA-lesion rats. Furthermore, treatment with R50E attenuated nitric oxide (NO) and tumor necrosis factor (TNF-α) levels in the 6-OHDA-lesion rats. In conclusion, R50E may prevent neurodegeneration via anti-oxidative and anti-inflammatory mechanisms, suggesting its potential therapeutic value for PD treatment. This is the first study for evaluating the neuroprotective effects of red mold fermented products in PD models.

  12. Electroacupuncture Produces the Sustained Motor Improvement in 6-Hydroxydopamine-Lesioned Mice

    PubMed Central

    Deng, Jiahui; Sun, Min; Jia, Jun; Wang, Xiaomin

    2016-01-01

    Clinical and research evidence has shown that electroacupuncture (EA) promotes recovery of motor function in patients with Parkinson’s disease (PD). However, the “efficacy span” of EA treatment, especially the long-term effect of EA that is thought to last after the cessation of EA treatment, has not been investigated. The present study thus investigated and compared the effect of EA during and after chronic EA application on motor activity and dopamine lesions in a 6-hydroxydopamine (6-OHDA)-lesioned mouse model of PD. Chronic EA treatment (30 min a day, 6 days a week for 2 or 4 weeks) significantly attenuated motor deficiency and reduced dopamine neuron degeneration. Remarkably, EA showed a long-lasting effect after the cessation of EA stimulation. At 2 and 4 weeks after the termination of EA, EA continued to improve motor function in 6-OHDA-lesioned mice. Consistent with sustained behavioral effects, EA induced an enduring increase in the dopamine turnover ratio in the striatum 2 weeks after the cessation of EA treatment. Here we demonstrated that the therapeutic effect of EA outlasted the duration of EA application. During a relatively long period of time after the completion of EA treatment, EA is able to continue to improve motor function and enhance dopamine availability in 6-OHDA-lesioned PD mice. PMID:26894437

  13. Effects of (-)-sesamin on 6-hydroxydopamine-induced neurotoxicity in PC12 cells and dopaminergic neuronal cells of Parkinson's disease rat models.

    PubMed

    Park, Hyun Jin; Zhao, Ting Ting; Lee, Kyung Sook; Lee, Seung Ho; Shin, Keon Sung; Park, Keun Hong; Choi, Hyun Sook; Lee, Myung Koo

    2015-01-01

    The present study investigated the effects of (-)-sesamin on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity using PC12 cells and dopaminergic neuronal cells of 6-OHDA-lesioned rat model of Parkinson's disease (PD). In PC12 cells, treatment with (-)-sesamin (25 µM) reduced 6-OHDA (100 µM)-induced cell death and induced transient extracellular signal-regulated kinase (ERK1/2) phosphorylation and Bad phosphorylation at Ser112 (BadSer112). In contrast, sustained ERK1/2 phosphorylation, p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK1/2) phosphorylation, and cleaved-caspase-3 activity, all of which were induced by 6-OHDA (100 µM), were inhibited by treatment with (-)-sesamin (25 µM). Furthermore, co-treatment with (-)-sesamin (30 mg/kg, p.o.) once a day for 28 days significantly increased the number of tyrosine hydroxylase-immunopositive neuronal cells and the levels of dopamine, norepinephrine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the substantia nigra-striatum of 6-OHDA-lesioned rat model of PD with or without L-DOPA treatment. These results suggest that (-)-sesamin protects 6-OHDA-induced cytotoxicity via the activation of transient ERK1/2-BadSer112 system and the inhibition of sustained ERK-p38MAPK-JNK1/2-caspase-3 system in PC12 cells. (-)-Sesamin also shows protective effects on long-term L-DOPA therapy in dopaminergic neuronal cells of PD rat models. (-)-Sesamin may serve as adjuvant therapeutics in PD.

  14. [Effects of hypothalamic microinjections of 6-hydroxydopamine (6-OHDA) on estral cycle and morphology of the genital tract in the female rat (author's transl)].

    PubMed

    Sala, M A; Oteui, J T; Benedetti, W I

    1975-01-01

    To determine whether central catecholaminergic pathways are involved in the neural contral of gonadotrophin secretion, they were interrupted at the hypothalamic level by microinjections of 6-hydroxydopamine (6-OHDA). The effects on ovulation, estral cycle and ovarian and uterine histology were studied. Microinjections of 50 mug of 6-OHDA hydrobromyde were made bilaterally into the anterolateral hypothalamus in a group of rats. Another group was injected with 25 mug of 6-OHDA, while a control group recieved an equivalent volume (5 mul) of saline with ascorbic acid. Animals injected with 50 mug of 6-OHDA showed blockade of ovulation, vaginal cytology characteristics of persistent estrous, polyfollicular ovaries and enlarged uteri with hypertrophic endometrial glands. In the group injected with 25 mug, similiar effects were demonstrated, but the number of affected animals was smaller than that in the 50 mug group. Control animals dit not show modifications, either in estral cycle or in ovarian and uterine histology. These results suggest that 6-OHDA injected into the anterolateral hypothalmus interferes with catecholaminergic pathways that participate in the neural control of ovulation.

  15. Partial dopaminergic denervation-induced impairment in stimulus discrimination acquisition in parkinsonian rats: a model for early Parkinson's disease.

    PubMed

    Eagle, Andrew L; Olumolade, Oluyemi O; Otani, Hajime

    2015-03-01

    Parkinson's disease (PD) produces progressive nigrostriatal dopamine (DA) denervation resulting in cognitive and motor impairment. However, it is unknown whether cognitive impairments, such as instrumental learning deficits, are associated with the early stage PD-induced mild DA denervation. The current study sought to model early PD-induced instrumental learning impairments by assessing the effects of low dose (5.5μg), bilateral 6OHDA-induced striatal DA denervation on acquisition of instrumental stimulus discrimination in rats. 6OHDA (n=20) or sham (n=10) lesioned rats were tested for stimulus discrimination acquisition either 1 or 2 weeks post surgical lesion. Stimulus discrimination acquisition across 10 daily sessions was used to assess discriminative accuracy, or a probability measure of the shift toward reinforced responding under one stimulus condition (Sd) away from extinction, when reinforcement was withheld, under another (S(d) phase). Striatal DA denervation was assayed by tyrosine hydroxylase (TH) staining intensity. Results indicated that 6OHDA lesions produced significant loss of dorsal striatal TH staining intensity and marked impairment in discrimination acquisition, without inducing akinetic motor deficits. Rather 6OHDA-induced impairment was associated with perseveration during extinction (S(Δ) phase). These findings suggest that partial, bilateral striatal DA denervation produces instrumental learning deficits, prior to the onset of gross motor impairment, and suggest that the current model is useful for investigating mild nigrostriatal DA denervation associated with early stage clinical PD.

  16. Effect of adenosine A(2A) receptor antagonists and L-DOPA on hydroxyl radical, glutamate and dopamine in the striatum of 6-OHDA-treated rats.

    PubMed

    Gołembiowska, Krystyna; Dziubina, Anna

    2012-02-01

    A(2A) adenosine receptor antagonists have been proposed as a new therapy of PD. Since oxidative stress plays an important role in the pathogenesis of PD, we studied the effect of the selective A(2A) adenosine receptor antagonists 8-(-3-chlorostyryl)caffeine (CSC) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) on hydroxyl radical generation, and glutamate (GLU) and dopamine (DA) extracellular level using a microdialysis in the striatum of 6-OHDA-treated rats. CSC (1 mg/kg) and ZM 241385 (3 mg/kg) given repeatedly for 14 days decreased the production of hydroxyl radical and extracellular GLU level, both enhanced by prior 6-OHDA treatment in dialysates from the rat striatum. CSC and ZM 241385 did not affect DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) extracellular levels in the striatum of 6-OHDA-treated rats. L-DOPA (6 mg/kg) given twice daily for two weeks in the presence of benserazide (3 mg/kg) decreased striatal hydroxyl radical and glutamate extracellular level in 6-OHDA-treated rats. At the same time, L-DOPA slightly but significantly increased the extracellular levels of DOPAC and HVA. A combined repeated administration of L-DOPA and CSC or ZM 241385 did not change the effect of L-DOPA on hydroxyl radical production and glutamate extracellular level in spite of an enhancement of extracellular DA level by CSC and elevation of extracellular level of DOPAC and HVA by ZM 241385. The data suggest that the 6-OHDA-induced damage of nigrostriatal DA-terminals is related to oxidative stress and excessive release of glutamate. Administration of L-DOPA in combination with CSC or ZM 241385, by restoring striatal DA-glutamate balance, suppressed 6-OHDA-induced overproduction of hydroxyl radical.

  17. Involvement of activation of the Nrf2/ARE pathway in protection against 6-OHDA-induced SH-SY5Y cell death by α-iso-cubebenol.

    PubMed

    Park, Sun Young; Kim, Do Yeon; Kang, Jong-Koo; Park, Geuntae; Choi, Young-Whan

    2014-09-01

    Free radical-mediated neurodegeneration is one of the many causes of Parkinson's disease (PD). As part of our ongoing studies on the identification of biologically active Schisandra chinensis components, we have isolated and structurally elucidated α-iso-cubebenol. This study was carried out in an attempt to clarify the neuroprotective effect of α-iso-cubebenol on toxin-insulted dopaminergic neuronal death using 6-hydroxy-dopamine (6-OHDA)-induced dopaminergic SH-SY5Y cells. α-iso-cubebenol significantly attenuated the loss of mitochondrial function (MTT assay) and membrane integrity (lactate dehydrogenase assay) associated with 6-OHDA-induced neurotoxicity. Pretreatment of the cells with α-iso-cubebenol diminished the intracellular accumulation of reactive oxygen species (ROS) and calcium in response to 6-OHDA. Moreover, α-iso-cubebenol protected against 6-OHDA-induced neurotoxicity through inhibition of SH-SY5Y cell apoptosis. In addition, JC-1 staining, which is a well-established measure of mitochondrial damage, was decreased after treatment with α-iso-cubebenol. Notably, α-iso-cubebenol inhibited the release of mitochondrial flavoprotein apoptosis inducing factor (AIF) from the mitochondria to the cytosol and nucleus following 6-OHDA treatment. In addition, α-iso-cubebenol reduced the 6-OHDA-induced phosphorylation of ERK and induced the phosphorylation of PKA, PKB, and CREB in a dose-dependent manner. Moreover, α-iso-cubebenol stimulated the activation of Nrf2, a downstream target of CREB. Furthermore, α-iso-cubebenol stimulated the expression of multiple antioxidant response genes (NQO-1 and HO-1). Finally, CREB and Nrf2 siRNA transfection diminished α-iso-cubebenol-mediated neuroprotection.

  18. Deep brain stimulation of the pedunculopontine tegmental nucleus modulates neuronal hyperactivity and enhanced beta oscillatory activity of the subthalamic nucleus in the rat 6-hydroxydopamine model.

    PubMed

    Alam, Mesbah; Heissler, Hans E; Schwabe, Kerstin; Krauss, Joachim K

    2012-01-01

    Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) area has been introduced as a novel surgical therapy for dopamine refractory gait problems, freezing and postural instability in the late stage of Parkinson's disease (PD). Lesions of the pedunculopontine tegmental (PPTg) nucleus, the equivalent of the PPN in rodents, were shown to reduce the elevated discharge rate of the subthalamic nucleus (STN) in the 6-hydroxydopamine (6-OHDA) rat model of PD. In order to further elucidate the modulatory effect of the PPTg on the STN we examined the effect of 25 Hz low frequency PPTg stimulation on neuronal single unit activity and oscillatory local field potentials (LFPs) of the STN, and on the electrocorticogram (ECoG) of the primary motor cortex region in rats with unilateral 6-OHDA induced nigrostriatal lesions. Stimulation of the PPTg reduced the enhanced firing rate in the STN, without affecting the firing pattern or approximate entropy (ApEn). It also reduced the activity in the beta band (15-30 Hz) of the STN, which is elevated in 6-OHDA lesioned rats, without affecting beta activity in the motor cortex. We showed a modulatory effect of PPTg stimulation on altered neuronal STN activity in the PD 6-OHDA rat model, indicating that PPTg DBS may alter activity of the basal ganglia circuitry at least partially. It remains unclear, however, how these changes are exactly mediated and whether they are relevant with regard to the descending PPTg projections in the lower brainstem.

  19. Transcription factor Six2 mediates the protection of GDNF on 6-OHDA lesioned dopaminergic neurons by regulating Smurf1 expression

    PubMed Central

    Gao, J; Kang, X-y; Sun, S; Li, L; Zhang, B-l; Li, Y-q; Gao, D-s

    2016-01-01

    Glial cell line-derived neurotrophic factor (GDNF) has strong neuroprotective and neurorestorative effects on dopaminergic (DA) neurons in the substantia nigra (SN); however, the underlying molecular mechanisms remain to be fully elucidated. In this study, we found that the expression level of transcription factor Six2 was increased in damaged DA neurons after GDNF rescue in vivo and in vitro. Knockdown of Six2 resulted in decreased cell viability and increased the apoptosis of damaged DA neurons after GDNF treatment in vitro. In contrast, Six2 overexpression increased cell viability and decreased cell apoptosis. Furthermore, genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) indicated that Six2 directly bound to the promoter CAGCTG sequence of smad ubiquitylation regulatory factor 1 (Smurf1). ChIP-quantitative polymerase chain reaction (qPCR) analysis showed that Smurf1 expression was significantly upregulated after GDNF rescue. Moreover, knockdown of Six2 decreased Smurf1 expression, whereas overexpression of Six2 increased Smurf1 expression in damaged DA neurons after GDNF rescue. Meanwhile, knockdown and overexpression of Smurf1 increased and decreased p53 expression, respectively. Taken together, our results from in vitro and in vivo analysis indicate that Six2 mediates the protective effects of GDNF on damaged DA neurons by regulating Smurf1 expression, which could be useful in identifying potential drug targets for injured DA neurons. PMID:27148690

  20. Differential expression of Fos and Zif268 in the nigrostriatal system after methamphetamine administration in a rat model of Parkinson's disease.

    PubMed

    Ishida, Yasushi; Kawai, Keiichi; Magata, Yasuhiro; Ebihara, Kosuke; Takeda, Ryuichiro; Abe, Hiroshi; Yoshimoto, Mitsuyoshi; Hashiguchi, Hiroyuki; Odagiri, Kei; Matsuo, Hisae; Nishimori, Toshikazu

    2008-12-01

    The goal of this study was to examine the topological specificity of methamphetamine-induced activation of the immediate-early gene proteins, Fos and Zif268, in the nigrostriatal system in a unilateral 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease with or without intrastriatal grafts of fetal ventral mesencephalon. Methamphetamine (3 mg/kg, i.p.) induced Fos-like immunoreactivity (FLI) dominantly in the striatum and the globus pallidus (GP) on the intact side as well as in the substantia nigra pars reticulata (SNr) on the lesioned side in the 6-OHDA rats. Lower levels of methamphetamine-induced FLI in the striatum and GP on the lesioned side were restored by intrastriatal grafts which could completely suppress the methamphetamine-induced rotation. In the striatum, a similar tendency could be observed between Fos and Zif268 immunoreactivity following methamphetamine. However, sparse immunoreactivity of Zif268 could be detected in the GP and SNr on both sides in the 6-OHDA rats. Intrastriatal grafts had little influence on Zif268 expression in these two regions. The differential expression of Fos and Zif268 was observed among the three regions of the nigrostriatal system following methamphetamine in the 6-OHDA rats. This may suggest that Fos and Zif268 therefore possess gene-specific and region-specific functions in the basal ganglia nuclei.

  1. [Criteria of efficiency of transplantation of embryonic nervous tissue preparations in rats with 6-OHDA-impaired dopaminergic nigrostriatal system].

    PubMed

    Chekhonin, V P; Lebedev, S V; Dmitrieva, T B; Baklaushev, V P; Savchenko, E A; Lazarenko, I P; Gurina, O I; Belopasov, V V

    2002-01-01

    Effectiveness of transplantation of cells from embryonal nervous tissue of the ventral mesencephalon (VM ENT) and striatum (STR ENT) by apomorphin-induced motor asymmetry (APO-test), consolidation of the transplant (the degree of glyal reaction and amount of dopaminergic neurons) and blood serum levels of GFAP was studied for 3 months in Wistar rats with 6-OHDA-impaired dopaminergic nigrostriatal system. Marked therapeutic effectiveness was registered in VM ENT transplantation in the denervated striatum and in combined transplantation of VM ENT into the lateral cerebral ventricle simultaneously with STR ENT transplantation in the striatum. Separate transplantation of VM ENT in the lateral ventricle and STR ENT in the striatum had no positive effect on recovery of the dopaminergic nigrostriatal system. A correlation was found between the degree of glial reaction of ENT transplants, severity of rotation asymmetry and serum levels of gliofibrillary protein (GFAP). GFAP in the serum for lifetime assessment of transplant consolidation and prognosis of neurotransplantation efficiency was assayed.

  2. L-F001, a Multifunction ROCK Inhibitor Prevents 6-OHDA Induced Cell Death Through Activating Akt/GSK-3beta and Nrf2/HO-1 Signaling Pathway in PC12 Cells and Attenuates MPTP-Induced Dopamine Neuron Toxicity in Mice.

    PubMed

    Luo, Liting; Chen, Jingkao; Su, Dan; Chen, Meihui; Luo, Bingling; Pi, Rongbiao; Wang, Lan; Shen, Wei; Wang, Rikang

    2017-02-01

    Amounting evidences demonstrated that Rho/Rho-associated kinase (ROCK) might be a novel target for the therapy of Parkinson's disease (PD). Recently, we synthesized L-F001 and revealed it was a potent ROCK inhibitor with multifunctional effects. Here we investigated the effects of L-F001 in PD models. We found that L-F001 potently attenuated 6-OHDA-induced cytotoxicity in PC12 cells and significantly decreased intracellular reactive oxygen species (ROS), prevented the 6-OHDA-induced decline of mitochondrial membrane potential and intracellular GSH levels. In addition, L-F001 increased Akt and GSK-3beta phosphorylation and induced the nuclear Nrf2 and HO-1 expression in a time- and concentration-dependent manner. Moreover, L-F001 restored the levels of p-Akt and p-GSK-3beta (Ser9) as well as HO-1 expression reduced by 6-OHDA. Those effects were blocked by the specific PI3K inhibitor, LY294002, indicating the involvement of Akt/GSK-3beta pathway in the neuroprotective effect of L-F001. In addition, L-F001 significantly attenuated the tyrosinehydroxylase immunoreactive cell loss in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced mice PD model. Together, our findings suggest that L-F001 prevents 6-OHDA-induced cell death through activating Akt/GSK-3beta and Nrf2/HO-1 signaling pathway and attenuates MPTP-induced dopaminergic neuron toxicity in mice. L-F001 might be a promising drug candidate for PD.

  3. Androgens exacerbate motor asymmetry in male rats with unilateral 6-hydroxydopamine lesion.

    PubMed

    Cunningham, Rebecca L; Macheda, Teresa; Watts, Lora Talley; Poteet, Ethan; Singh, Meharvan; Roberts, James L; Giuffrida, Andrea

    2011-11-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopamine neuron loss in the nigrostriatal pathway that shows greater incidence in men than women. The mechanisms underlying this gender bias remain elusive, although one possibility is that androgens may increase dopamine neuronal vulnerability to oxidative stress. Motor impairment can be modeled in rats receiving a unilateral injection of 6-hydroxydopamine (6-OHDA), a neurotoxin producing nigrostriatal degeneration. To investigate the role of androgens in PD, we compared young (2 months) and aged (24 months) male rats receiving gonadectomy (GDX) and their corresponding intact controls. One month after GDX, rats were unilaterally injected with 6-OHDA, and their motor impairment and asymmetry were assessed 2 weeks later using the cylinder test and the amphetamine-induced rotation test. Plasma samples were also collected to assess the concentration of testosterone and advanced oxidation protein products, a product of oxidative stress. GDX decreased lesion-induced asymmetry along with oxidative stress and increased amphetamine-induced rotations. These results show that GDX improves motor behaviors by decreasing motor asymmetry in 6-OHDA-treated rats, an effect that may be ascribed to increased release of striatal dopamine and decreased oxidative stress. Collectively, the data support the hypothesis that androgens may underlie the gender bias observed in PD.

  4. Antioxidant and neuroprotector effect of Lepidium meyenii (maca) methanol leaf extract against 6-hydroxy dopamine (6-OHDA)-induced toxicity in PC12 cells.

    PubMed

    Rodríguez-Huamán, Ángel; Casimiro-Gonzales, Sandra; Chávez-Pérez, Jorge Antonio; Gonzales-Arimborgo, Carla; Cisneros-Fernández, Richard; Aguilar-Mendoza, Luis Ángel; Gonzales, Gustavo F

    2017-01-08

    Reactive oxygen species (ROS) are normally produced during cell metabolism, there is strong evidence to suggest that ROS produced in excess impair the cell and may be etiologically related to various neurodegenerative diseases. This study was undertaken to examine the effects of Lepidium meyenii (MACA) methanol leaf extract on neurotoxicity in PC12 cell exposed to 6-hydroxydopamine (6-OHDA). Fresh samples of "maca" leaves were processed in order to obtain foliar extracts and to evaluate the neurobiological activity on PC12 cells, subjected to the cytotoxic effect of 6-OHDA through the determination of the capacity antioxidant, cell viability and cytotoxicity assays on PC12 cells. The results of the tests of antioxidant activity, showed maximum values of 2262.37 and 1305.36 expressed in Trolox equivalents (TEAC), for the methanolic and aqueous fractions respectively. Cell viability assays at a dose of 10 μg extract showed an increase of 31% and 60% at 6 and 12 h of pretreatment, respectively. Cytotoxicity assays at the same dose and exposure time showed a 31.4% and 47.8% reduction in lactate dehydrogenase (LDH) activity and an increase in superoxide dismutase (SOD) activity. The results allow us to affirm that the methanolic foliar extract of "maca" presents in vitro neurobiological activity of antioxidant protection, increase in cell viability and reduction of cytotoxicity against oxidative stress generated by 6-OHDA. In conclusion, the present study shows a protective role for Lepidium meyenii leaf extract on 6-OHDA-induced toxicity by an antioxidant effect.

  5. PEGylated rhFGF-2 conveys long-term neuroprotection and improves neuronal function in a rat model of Parkinson's disease.

    PubMed

    Zhu, Guanghui; Chen, Ganping; Shi, Lu; Feng, Jenny; Wang, Yan; Ye, Chaohui; Feng, Wenke; Niu, Jianlou; Huang, Zhifeng

    2015-02-01

    Fibroblast growth factor 2 (FGF-2) has a neurotrophic effect on dopaminergic neurons in vitro and in vivo, and exhibits beneficial effects in animal models of neurodegenerative disorders such as Parkinson's disease (PD). The poor stability and short half-life of FGF-2, however, have hampered its clinical use for neurological diseases. In the present study, we modified native recombinant human FGF-2 (rhFGF-2) by covalently attaching polyethylene glycol (PEG) polymers, named PEGylation, to enhance its neuroprotection efficacy in 6-hydroxydopamine (6-OHDA)-induced model of PD. In vitro, PEG-rhFGF-2 performed better biostability in 6-OHDA-induced PC-12 cells than native rhFGF-2. The in vivo data showed that, compared with native rhFGF-2, PEGylated rhFGF-2 was more efficacious in preventing 6-OHDA-induced lesion upon tyrosine hydroxylase-positive neurons in the substantia nigra (SN), improving the apomorphine-induced rotational behavior and the 6-OHDA-induced decline in tissue concentration of dopamine (DA) and its metabolites. Importantly, our data showed that the superior pharmacological activity of PEGylated rhFGF-2 is probably due to its greater permeability through the blood-brain barrier and better in vivo stability compared to native rhFGF-2. The enhanced stability and bioavailability of PEGylated rhFGF-2 make this molecule a great therapeutic candidate for neurodegenerative diseases such as PD and mood disorders.

  6. Adenoviral vector-mediated GDNF gene therapy in a rodent lesion model of late stage Parkinson's disease.

    PubMed

    Lapchak, P A; Araujo, D M; Hilt, D C; Sheng, J; Jiao, S

    1997-11-28

    A recombinant adenoviral vector encoding the human glial cell line-derived neurotrophic factor (GDNF) gene (Ad-GDNF) was used to express the neurotrophic factor GDNF in the unilaterally 6-hydroxydopamine (6-OHDA) denervated substantia nigra (SN) of adult rats ten weeks following the 6-OHDA injection. 6-OHDA lesions significantly increased apomorphine-induced (contralateral) rotations and reduced striatal and nigral dopamine (DA) levels by 99% and 70%, respectively. Ad-GDNF significantly (P < 0.01) decreased (by 30-40%) apomorphine-induced rotations in lesioned rats for up to two weeks following a single injection. Locomotor activity, assessed 7 days following the Ad-GDNF injection, was also significantly (P < 0.05) increased (by 300-400%). Two weeks after the Ad-GDNF injection, locomotor activity was still significantly increased compared to the Ad-beta-gal-injected 6-OHDA lesioned (control) group. Additionally, in Ad-GDNF-injected rats, there was a significant decrease (10-13%) in weight gain which persisted for approximately two weeks following the injection. Consistent with the behavioral changes, levels of DA and the metabolite dihydroxyphenylacetic acid (DOPAC) were elevated (by 98% and 65%, respectively) in the SN, but not the striatum of Ad-GDNF-injected rats. Overall, a single Ad-GDNF injection had significant effects for 2-3 weeks following administration. These results suggest that virally delivered GDNF promotes the recovery of nigral dopaminergic tone (i.e.: increased DA and DOPAC levels) and improves behavioral performance (i.e.: decreased rotations, increased locomotion) in rodents with extensive nigrostriatal dopaminergic denervation. Moreover, our results suggest that viral delivery of trophic factors may be used eventually to treat neurodegenerative diseases such as Parkinson's disease.

  7. Enhancing effect of taurine in the rat caudate spindle. II. Effect of bilateral 6-hydroxydopamine lesions of the nigro-striatal dopamine system.

    PubMed

    Hashimoto-Kitsukawa, S; Okuyama, S; Aihara, H

    1988-10-01

    Bilateral injections of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle of rats resulted in destruction of dopamine (DA) nerve terminals in the striatum. DA contents decreased to 16.8, 15.0 and 13.7% of control values on 3, 5 and 7 days after the lesions, respectively. The time course of the effect of 6-OHDA lesions on apomorphine (0.5 mg/kg, IV)-induced stereotypy was investigated as the index of the development of supersensitivity. Stereotypy was unchanged on 3 days, but was enhanced 5 and 7 days after 6-OHDA lesions. Therefore, the sensitivity of postsynaptic DA receptors for apomorphine did not change 3 days after 6-OHDA lesions, although the striatal DA was depleted. The effects of bilateral injections of taurine into the striatum on the rat caudate spindle were determined 3 days after 6-OHDA lesions. Taurine, at a dose of 30 micrograms, enhanced the spindle in sham-operated rats, but this enhancement was not seen after 6-OHDA lesions. Intravenous administration of apomorphine (0.5 mg/kg) to lesioned rats suppressed the spindle, and this effect was prevented by a lower dose (3 micrograms) of taurine. These results provide further evidence that taurine enhances the spindle, possibly by decreasing the activity of the nigro-striatal DA system at the pre- and postsynaptic sites.

  8. Reduced ability of calcitriol to promote augmented dopamine release in the lesioned striatum of aged rats.

    PubMed

    Cass, Wayne A; Peters, Laura E

    2017-04-05

    Parkinson's disease (PD) is a progressive and debilitating neurodegenerative disorder that affects over one million people in the United States. Previous studies, carried out in young adult rats, have shown that calcitriol, the active metabolite of vitamin D, can be neuroprotective in 6-hydroxydopamine (6-OHDA) models of PD. However, as PD usually affects older individuals, the ability of calcitriol to promote dopaminergic recovery was examined in lesioned young adult (4 month old), middle-aged (14 month old) and aged (22 month old) rats. Animals were given a single injection of 12 μg 6-OHDA into the right striatum. Four weeks later they were administered vehicle or calcitriol (1.0 μg/kg, s.c.) once a day for eight consecutive days. In vivo microdialysis experiments were carried out three weeks after the calcitriol or vehicle treatments to measure potassium and amphetamine evoked overflow of DA from both the left and right striata. In control animals treated with 6-OHDA and vehicle there were significant reductions in evoked overflow of DA on the lesioned side of the brain compared to the contralateral side. The calcitriol treatments significantly increased evoked overflow of DA from the lesioned striatum in both the young adult and middle-aged rats. However, the calcitriol treatments did not significantly augment DA overflow in the aged rats. Postmortem tissue levels of striatal DA were also increased in the young and middle-aged animals, but not in the aged animals. In the substantia nigra, the calcitriol treatments led to increased levels of DA in all three age groups. Thus, the effects of calcitriol were similar in the young adult and middle-aged animals, but in the aged animals the effects of calcitriol were diminished. These results suggest that calcitriol may help promote recovery of dopaminergic functioning in injured nigrostriatal neurons; however, the effectiveness of calcitriol may be reduced in aging.

  9. Neuronal Entropy-Rate Feature of Entopeduncular Nucleus in Rat Model of Parkinson's Disease.

    PubMed

    Darbin, Olivier; Jin, Xingxing; Von Wrangel, Christof; Schwabe, Kerstin; Nambu, Atsushi; Naritoku, Dean K; Krauss, Joachim K; Alam, Mesbah

    2016-03-01

    The function of the nigro-striatal pathway on neuronal entropy in the basal ganglia (BG) output nucleus, i.e. the entopeduncular nucleus (EPN) was investigated in the unilaterally 6-hyroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD). In both control subjects and subjects with 6-OHDA lesion of dopamine (DA) the nigro-striatal pathway, a histological hallmark for parkinsonism, neuronal entropy in EPN was maximal in neurons with firing rates ranging between 15 and 25 Hz. In 6-OHDA lesioned rats, neuronal entropy in the EPN was specifically higher in neurons with firing rates above 25 Hz. Our data establishes that the nigro-striatal pathway controls neuronal entropy in motor circuitry and that the parkinsonian condition is associated with abnormal relationship between firing rate and neuronal entropy in BG output nuclei. The neuronal firing rates and entropy relationship provide putative relevant electrophysiological information to investigate the sensory-motor processing in normal condition and conditions such as movement disorders.

  10. Effects of L-DOPA and STN-HFS dyskinesiogenic treatments on NR2B regulation in basal ganglia in the rat model of Parkinson's disease.

    PubMed

    Quintana, Adrien; Sgambato-Faure, Véronique; Savasta, Marc

    2012-12-01

    Dyskinesia is a major side effect of chronic levodopa (L-DOPA) administration, the reference treatment for Parkinson's disease (PD). High-frequency stimulation of the subthalamic nucleus (STN-HFS) alleviates parkinsonian motor symptoms and indirectly improves dyskinesia by decreasing L-DOPA requirement. However, inadequate stimulation can also trigger dyskinetic movements in PD patients and animal models. Here, we investigated the possible association between L-DOPA- and STN-HFS-induced dyskinesia and regulation of the NR2B subunit of NMDA receptors in the rodent model of PD. We subjected 6-OHDA-lesioned rats to HFS for 1h, at an intensity triggering forelimb dyskinesia. Other 6-OHDA-lesioned rats were treated with chronic high doses of L-DOPA for ten days, to induce abnormal involuntary movements. The 6-OHDA lesion regulated NR2B only in the SNr, where the activation of NR2B was observed (as assessed by phosphorylation of the Tyr1472 residue). Both STN-HFS and L-DOPA dyskinesiogenic treatments induced NR2B activation in the STN and EP, but only L-DOPA triggered NR2B hyperphosphorylation in the striatum. Finally, the use of CP-101,606 exacerbated L-DOPA-induced motor behavior and associated NR2B hyperphosphorylation in the striatum, STN and EP. Thus, NR2B activation in basal ganglia structures is correlated with dyskinesia.

  11. Neuroprotective Effect of Thymoquinone, the Nigella Sativa Bioactive Compound, in 6-Hydroxydopamine-Induced Hemi-Parkinsonian Rat Model

    PubMed Central

    Sedaghat, Reza; Roghani, Mehrdad; Khalili, Mohsen

    2014-01-01

    Parkinson disease (PD) is the most common movement disorder with progressive degeneration of midbrain dopaminergic neurons for which current treatments afford symptomatic relief with no-prevention of disease progression. Due to the neuroprotective property of the Nigella sativa bioactive compound thymoquinone (TQ), this study was undertaken to evaluate whether TQ could improve behavioral and cellular abnormalities and markers of oxidative stress in an experimental model of early PD in rat. Unilateral intrastriatal 6-hydroxydopamine (6-OHDA)-lesioned rats were daily pretreated p.o. with TQ at doses of 5 and/or 10 mg/Kg three times at an interval of 24 h. After 1 week, apomorphine caused contralateral rotations, a reduction in the number of neurons on the left side of the substantia nigra pars compacta (SNC) was observed, malondialdehyde (MDA) and nitrite level in midbrain homogenate increased and activity of superoxide dismutase (SOD) reduced in the 6-OHDA lesion group. TQ pretreatment significantly improved turning behavior, prevented loss of SNC neurons, and lowered level of MDA. These results suggest that TQ could afford neuroprotection against 6-OHDA neurotoxicity that is partly due to the attenuation of lipid peroxidation and this may provide benefits, along with other therapies, in neurodegenerative disorders including PD. PMID:24734075

  12. Acetyl-l-carnitine protects dopaminergic nigrostriatal pathway in 6-hydroxydopamine-induced model of Parkinson's disease in the rat.

    PubMed

    Afshin-Majd, Siamak; Bashiri, Keyhan; Kiasalari, Zahra; Baluchnejadmojarad, Tourandokht; Sedaghat, Reza; Roghani, Mehrdad

    2017-02-12

    Parkinson's disease (PD) is a movement disorder and the second most common neurodegenerative disease worldwide in which nigrostriatal dopaminergic neurons within substantia nigra pars compacta (SNC) are lost, with clinical motor and non-motor symptoms including bradykinesia, resting tremor, rigidity, stooping posture and cognitive deficits. This study was undertaken to evaluate the neuroprotective potential of acetyl-l-carnitine (ALC) against unilateral striatal 6-hydroxydopamine (6-OHDA)-induced model of PD and to explore some involved mechanisms. In this experimental study, intrastriatal 6-OHDA-lesioned rats received ALC at doses of 100 or 200mg/kg/day for 1 week. ALC (200mg/kg) lowered apomorphine-induced rotational asymmetry and reduced the latency to initiate and the total time in the narrow beam test, reduced striatal malondialdehyde (MDA), increased catalase activity and glutathione (GSH) level, prevented reduction of nigral tyrosine hydroxylase (TH)-positive neurons and striatal TH-immunoreactivity, and lowered striatal glial fibrillary acidic protein (GFAP) and its immunoreactivity as an indicator of astrogliosis, and nuclear factor NF-kappa B and Toll-like receptor 4 (TLR4) as reliable markers of neuroinflammation. Meanwhile, ALC at both doses mitigated nigral DNA fragmentation as a valuable marker of apoptosis. The results of this study clearly suggest the neuroprotective effect of ALC in 6-OHDA-induced model of PD through abrogation of neuroinflammation, apoptosis, astrogliosis, and oxidative stress and it may be put forward as an ancillary therapeutic candidate for controlling PD.

  13. Morphological Changes in a Severe Model of Parkinson's Disease and Its Suitability to Test the Therapeutic Effects of Microencapsulated Neurotrophic Factors.

    PubMed

    Requejo, C; Ruiz-Ortega, J A; Bengoetxea, H; García-Blanco, A; Herrán, E; Aristieta, A; Igartua, M; Pedraz, J L; Ugedo, L; Hernández, R M; Lafuente, J V

    2016-11-14

    The unilateral 6-hydroxydopamine (6-OHDA) lesion of medial forebrain bundle (MFB) in rats affords us to study the advanced stages of Parkinson's disease (PD). Numerous evidences suggest synergic effects when various neurotrophic factors are administered in experimental models of PD. The aim of the present work was to assess the morphological changes along the rostro-caudal axis of caudo-putamen complex and substantia nigra (SN) in the referred model in order to test the suitability of a severe model to evaluate new neurorestorative therapies. Administration of 6-OHDA into MFB in addition to a remarkable depletion of dopamine in the nigrostriatal system induced an increase of glial fibrillary acidic protein (GFAP)-positive cells in SN and an intense immunoreactivity for OX-42, vascular endothelial growth factor (VEGF), and Lycopersycum esculentum agglutinin (LEA) in striatum and SN. Tyrosine hydroxylase (TH) immunostaining revealed a significant decrease of the TH-immunopositive striatal volume in 6-OHDA group from rostral to caudal one. The loss of TH-immunoreactive (TH-ir) neurons and axodendritic network (ADN) was higher in caudal sections. Morphological recovery after the implantation of microspheres loaded with VEGF and glial cell line-derived neurotrophic factor (GDNF) in parkinsonized rats was related to the preservation of the TH-ir cell number and ADN in the caudal region of the SN. In addition, these findings support the neurorestorative role of VEGF+GDNF in the dopaminergic system and the synergistic effect between both factors. On the other hand, a topological distribution of the dopaminergic system was noticeable in the severe model, showing a selective vulnerability to 6-OHDA and recovering after treatment.

  14. Ellagic acid exerts protective effect in intrastriatal 6-hydroxydopamine rat model of Parkinson's disease: Possible involvement of ERβ/Nrf2/HO-1 signaling.

    PubMed

    Baluchnejadmojarad, Tourandokht; Rabiee, Nafiseh; Zabihnejad, Sedigheh; Roghani, Mehrdad

    2017-02-23

    Parkinson's disease (PD) is a prevalent movement disorder in the elderly with progressive loss of mesencephalic dopaminergic neurons and incapacitating motor and non-motor complications. Ellagic acid is a natural phenolic compound with potent antioxidant and anti-inflammatory properties. In this study, we investigated its possible neuroprotective effect in 6-hydroxydopamine (6-OHDA) rat model of PD. Intrastriatal 6-OHDA-lesioned rats were pretreated with ellagic acid at a dose of 50 mg/kg/day for 1 week. Results showed that ellagic acid attenuates apomorphine-induced rotational bias and lowers the latency to initiate and the total time in the narrow beam task and this beneficial effect was partially abrogated following intracerebroventricular microinjection of estrogen receptor β (ERβ) antagonist. Furthermore, ellagic acid reduced striatal malondialdehyde (MDA), reactive oxygen species (ROS), and DNA fragmentation, and improved monoamine oxidase B (MAO-B), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and heme oxygenase 1 (HO-1). Meanwhile, ellagic acid prevented loss of tyrosine hydroxylase (TH)-positive neurons within substantia nigra pars compacta (SNC). These findings indicate neuroprotective potential of ellagic acid in 6-OHDA rat model of PD via amelioration of apoptosis and oxidative stress, suppression of MAO-B, and its favorable influence is partly reliant on ERβ/Nrf2/HO-1 signaling cascade.

  15. Chronic treatment with the mGlu5R antagonist MPEP reduces the functional effects of the mGlu5R agonist CHPG in the striatum of 6-hydroxydopamine-lesioned rats: possible relevance to the effects of mGlu5R blockade in Parkinson's disease.

    PubMed

    Domenici, Maria Rosaria; Potenza, Rosa Luisa; Martire, Alberto; Coccurello, Roberto; Pèzzola, Antonella; Reggio, Rosaria; Tebano, Maria Teresa; Popoli, Patrizia

    2005-06-01

    This study was designed to test whether chronic treatment with the metabotropic glutamate receptor 5 (mGlu5R) antagonist MPEP showed antiparkinsonian effects in rats unilaterally lesioned with 6-hydroxydopamine (6-OHDA) (a "classic" model of Parkinson's disease, PD), and to evaluate whether chronic MPEP influenced the functional properties and/or the expression of striatal mGlu5Rs. Wistar rats were lesioned with 6-OHDA and then treated with MPEP (3 mg/kg/day, i.p.) or its vehicle over 2 weeks. Chronic MPEP did not induce measurable antiparkinsonian effects, since no differences were found between MPEP- and vehicle-treated animals in the pattern of L-DOPA-induced contralateral rotations. In corticostriatal slices taken from animals chronically treated with MPEP, the functional effects of the mGlu5R agonist CHPG were significantly reduced in the lesioned vs. the intact side, while no changes were found in slices taken from vehicle-treated rats. The binding of [3H]MPEP to striatal membranes showed that neither the maximal number of binding sites (Bmax) nor the dissociation constant (Kd) were changed by the lesion and/or by chronic MPEP. While chronic MPEP did not potentiate L-DOPA-induced turning in a classical model of PD, its ability to reduce mGlu5R-associated signal could help to explain the neuroprotective/antiparkinsonian effects observed in other models of PD.

  16. Exercise partly reverses the effect of maternal separation on hippocampal proteins in 6-hydroxydopamine-lesioned rat brain.

    PubMed

    Dimatelis, J J; Hendricks, S; Hsieh, J; Vlok, N M; Bugarith, K; Daniels, W M U; Russell, V A

    2013-01-01

    Animals subjected to maternal separation stress during the early stages of development display behavioural, endocrine and growth factor abnormalities that mirror the clinical findings in anxiety/depression. In addition, maternal separation has been shown to exacerbate the behavioural deficits induced by 6-hydroxydopamine (6-OHDA) in a rat model of Parkinson's disease. In contrast, voluntary exercise reduced the detrimental effects of 6-OHDA in the rat model. The beneficial effects of exercise appeared to be largely due to compensation in the non-lesioned hemisphere. The aim of the present study was to investigate whether voluntary exercise for 3 weeks could reverse the effects of maternal separation in rats challenged with the neurotoxin 6-OHDA infused into the medial forebrain bundle after 1 week of exercise, at postnatal day 60. The rats were killed 2 weeks later, at postnatal day 74. Their brains were dissected and the hippocampus rapidly removed for proteomic analysis by isobaric tagging (iTRAQ) and quantification of peptides by matrix-assisted laser desorption/ionization tandem mass spectrometry (MALDI-MS/MS). Maternal separation upregulated hippocampal proteins functionally involved in energy metabolism (nucleoside diphosphate kinase B, enolase and triosephosphate isomerase) and synaptic plasticity (α-synuclein, tenascin-R, Ba1-667, brevican and neurocan core protein) in the non-lesioned hemisphere. Exercise reversed many of these changes by downregulating the levels of hippocampal proteins functionally associated with energy metabolism (nucleoside diphosphate kinase B, enolase and triosephosphate isomerase) and synaptic plasticity (α-synuclein, tenascin-R, Ba1-667, brevican and neurocan core protein) in the non-lesioned hemisphere of rats subjected to maternal separation. Exercise and maternal separation therefore appeared to have opposing effects on the hippocampus in the non-lesioned hemisphere of the rat brain. Exercise seemed partly to reverse the

  17. Decomposition of abnormal free locomotor behavior in a rat model of Parkinson's disease

    PubMed Central

    Grieb, Benjamin; von Nicolai, Constantin; Engler, Gerhard; Sharott, Andrew; Papageorgiou, Ismini; Hamel, Wolfgang; Engel, Andreas K.; Moll, Christian K.

    2013-01-01

    Poverty of spontaneous movement, slowed execution and reduced amplitudes of movement (akinesia, brady- and hypokinesia) are cardinal motor manifestations of Parkinson's disease that can be modeled in experimental animals by brain lesions affecting midbrain dopaminergic neurons. Most behavioral investigations in experimental parkinsonism have employed short-term observation windows to assess motor impairments. We postulated that an analysis of longer-term free exploratory behavior could provide further insights into the complex fine structure of altered locomotor activity in parkinsonian animals. To this end, we video-monitored 23 h of free locomotor behavior and extracted several behavioral measures before and after the expression of a severe parkinsonian phenotype following bilateral 6-hydroxydopamine (6-OHDA) lesions of the rat dopaminergic substantia nigra. Unbiased stereological cell counting verified the degree of midbrain tyrosine hydroxylase positive cell loss in the substantia nigra and ventral tegmental area. In line with previous reports, overall covered distance and maximal motion speed of lesioned animals were found to be significantly reduced compared to controls. Before lesion surgery, exploratory rat behavior exhibited a bimodal distribution of maximal speed values obtained for single movement episodes, corresponding to a “first” and “second gear” of motion. 6-OHDA injections significantly reduced the incidence of second gear motion episodes and also resulted in an abnormal prolongation of these fast motion events. Likewise, the spatial spread of such episodes was increased in 6-OHDA rats. The increase in curvature of motion tracks was increased in both lesioned and control animals. We conclude that the discrimination of distinct modes of motion by statistical decomposition of longer-term spontaneous locomotion provides useful insights into the fine structure of fluctuating motor functions in a rat analog of Parkinson's disease. PMID:24348346

  18. Colon Preneoplastic Lesions in Animal Models

    PubMed Central

    Suzui, Masumi; Morioka, Takamitsu; Yoshimi, Naoki

    2013-01-01

    The animal model is a powerful and fundamental tool in the field of biochemical research including toxicology, carcinogenesis, cancer therapeutics and prevention. In the carcinogenesis animal model system, numerous examples of preneoplastic lesions have been isolated and investigated from various perspectives. This may indicate that several options of endpoints to evaluate carcinogenesis effect or therapeutic outcome are presently available; however, classification of preneoplastic lesions has become complicated. For instance, these lesions include aberrant crypt foci (ACF), dysplastic ACF, flat ACF, β-catenin accumulated crypts, and mucin-depleted foci. These lesions have been induced by commonly used chemical carcinogens such as azoxymethane (AOM), 1,2-dimethylhydrazine (DMH), methylnitrosourea (MUN), or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Investigators can choose any procedures or methods to examine colonic preneoplastic lesions according to their interests and the objectives of their experiments. Based on topographical, histopathological, and biological features of colon cancer preneoplastic lesions in the animal model, we summarize and discuss the character and implications of these lesions. PMID:24526805

  19. Methodology and effects of repeated intranasal delivery of DNSP-11 in a rat model of Parkinson’s disease

    PubMed Central

    Stenslik, Mallory J.; Potts, Lisa F.; Sonne, James W.H.; Cass, Wayne A.; Turchan-Cholewo, Jadwiga; Pomerleau, Francois; Huettl, Peter; Ai, Yi; Gash, Don M.; Gerhardt, Greg A.; Bradley, Luke H.

    2015-01-01

    Background To circumvent the challenges associated with delivering large compounds directly to the brain for the treatment of Parkinson’s disease (PD), non-invasive procedures utilizing smaller molecules with protective and/or restorative actions on dopaminergic neurons are needed. New Method We developed a methodology for evaluating the effects of a synthetic neuroactive peptide, DNSP-11, on the nigrostriatal system using repeated intranasal delivery in both normal and a unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of PD. Results Normal rats repeatedly administered varying doses of DNSP-11 intranasally for 3 weeks exhibited a significant increase in dopamine (DA) turnover in both the striatum and substantia nigra (SN) at 300 μg, suggestive of a stimulative effect of the dopaminergic system. Additionally, a protective effect was observed following repeated intranasal administration in 6-OHDA lesioned rats, as suggested by: a significant decrease in d-amphetamine-induced rotation at 2 weeks; a decrease in DA turnover in the lesioned striatum; and an increased sparing of tyrosine hydroxylase (TH) positive neurons in a specific sub-region of the lesioned substantia nigra pars compacta. Finally, tracer studies showed 125I-DNSP-11 distributed diffusely throughout the brain, including the striatum and SN, as quickly as 30 minutes after a single intranasal dose. Comparison with Existing Methods The results of bilateral intranasal administration of DNSP-11 are compared to our unilateral single infusion studies to the brain in rats. Conclusions These studies support that DNSP-11 can be delivered intranasally and maintain its neuroactive properties in both normal rats and in a unilateral 6-OHDA rat model of PD. PMID:25999268

  20. Increased antiparkinson efficacy of the combined administration of VEGF- and GDNF-loaded nanospheres in a partial lesion model of Parkinson’s disease

    PubMed Central

    Herrán, Enara; Requejo, Catalina; Ruiz-Ortega, Jose Angel; Aristieta, Asier; Igartua, Manoli; Bengoetxea, Harkaitz; Ugedo, Luisa; Pedraz, Jose Luis; Lafuente, Jose Vicente; Hernández, Rosa Maria

    2014-01-01

    Current research efforts are focused on the application of growth factors, such as glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF), as neuroregenerative approaches that will prevent the neurodegenerative process in Parkinson’s disease. Continuing a previous work published by our research group, and with the aim to overcome different limitations related to growth factor administration, VEGF and GDNF were encapsulated in poly(lactic-co-glycolic acid) nanospheres (NS). This strategy facilitates the combined administration of the VEGF and GDNF into the brain of 6-hydroxydopamine (6-OHDA) partially lesioned rats, resulting in a continuous and simultaneous drug release. The NS particle size was about 200 nm and the simultaneous addition of VEGF NS and GDNF NS resulted in significant protection of the PC-12 cell line against 6-OHDA in vitro. Once the poly(lactic-co-glycolic acid) NS were implanted into the striatum of 6-OHDA partially lesioned rats, the amphetamine rotation behavior test was carried out over 10 weeks, in order to check for in vivo efficacy. The results showed that VEGF NS and GDNF NS significantly decreased the number of amphetamine-induced rotations at the end of the study. In addition, tyrosine hydroxylase immunohistochemical analysis in the striatum and the external substantia nigra confirmed a significant enhancement of neurons in the VEGF NS and GDNF NS treatment group. The synergistic effect of VEGF NS and GDNF NS allows for a reduction of the dose by half, and may be a valuable neurogenerative/neuroreparative approach for treating Parkinson’s disease. PMID:24920904

  1. A glial cell line-derived neurotrophic factor-secreting clone of the Schwann cell line SCTM41 enhances survival and fiber outgrowth from embryonic nigral neurons grafted to the striatum and to the lesioned substantia nigra.

    PubMed

    Wilby, M J; Sinclair, S R; Muir, E M; Zietlow, R; Adcock, K H; Horellou, P; Rogers, J H; Dunnett, S B; Fawcett, J W

    1999-03-15

    We have developed a novel Schwann cell line, SCTM41, derived from postnatal sciatic nerve cultures and have stably transfected a clone with a rat glial cell line-derived neurotrophic factor (GDNF) construct. Coculture with this GDNF-secreting clone enhances in vitro survival and fiber growth of embryonic dopaminergic neurons. In the rat unilateral 6-OHDA lesion model of Parkinson's disease, we have therefore made cografts of these cells with embryonic day 14 ventral mesencephalic grafts and assayed for effects on dopaminergic cell survival and process outgrowth. We show that cografts of GDNF-secreting Schwann cell lines improve the survival of intrastriatal embryonic dopaminergic neuronal grafts and improve neurite outgrowth into the host neuropil but have no additional effect on amphetamine-induced rotation. We next looked to see whether bridge grafts of GDNF-secreting SCTM41 cells would promote the growth of axons to their striatal targets from dopaminergic neurons implanted orthotopically into the 6-OHDA-lesioned substantia nigra. We show that such bridge grafts increase the survival of implanted embryonic dopaminergic neurons and promote the growth of axons through the grafts to the striatum.

  2. Palmitoyl Serotonin Inhibits L-dopa-induced Abnormal Involuntary Movements in the Mouse Parkinson Model

    PubMed Central

    Park, Hye-Yeon; Ryu, Young-Kyoung; Go, Jun; Son, Eunjung

    2016-01-01

    L-3,4-dihydroxyphenylalanine (L-DOPA) is the most common treatment for patients with Parkinson's disease (PD). However, long term use of L-DOPA for PD therapy lead to abnormal involuntary movements (AIMs) known as dyskinesia. Fatty acid amide hydrolase (FAAH) is enriched protein in basal ganglia, and inhibition of the protein reduces dyskinetic behavior of mice. Palmitoyl serotonin (PA-5HT) is a hybrid molecule patterned after arachidonoyl serotonin, antagonist of FAAH. However, the effect of PA-5HT on L-DOPA-induced dyskinesia (LID) in PD have not yet been elucidated. To investigate whether PA-5HT relieve LID in PD and decrease hyperactivation of dopamine D1 receptors, we used the 6-hydroxydopomine (6-OHDA)-lesioned mouse model of PD and treated the L-DOPA (20 mg/kg) for 10 days with PA-5HT (0.3 mg/kg/day). The number of wall contacts with the forelimb in the cylinder test was significantly decreased by 6-OHDA lesion in mice and the pharmacotherapeutic effect of L-DOPA was also revealed in PA-5HT-treated mice. Moreover, in AIMs test, PA-5HT-treated mice showed significant reduction of locomotive, axial, limb, and orofacial AIMs score compared to the vehicle-treated mice. LID-induced hyper-phosphorylation of ERK1/2 and overexpression of FosB/ΔFosB was markedly decreased in 6-OHDA-lesioned striatum of PA-5HT-treated mice, indicating that PA-5HT decreased the dopamine D1 receptor-hyperactivation induced by chronic treatment of L-DOPA in dopamine-denervated striatum. These results suggest that PA-5HT effectively attenuates the development of LID and enhance of ERK1/2 phosphorylation and FosB/ΔFosB expression in the hemi-parkinsonian mouse model. PA-5HT may have beneficial effect on the LID in PD. PMID:27574484

  3. Calcified lesion modeling for excimer laser ablation

    NASA Astrophysics Data System (ADS)

    Scott, Holly A.; Archuleta, Andrew; Splinter, Robert

    2009-06-01

    Objective: Develop a representative calcium target model to evaluate penetration of calcified plaque lesions during atherectomy procedures using 308 nm Excimer laser ablation. Materials and Methods: An in-vitro model representing human calcified plaque was analyzed using Plaster-of-Paris and cement based composite materials as well as a fibrinogen model. The materials were tested for mechanical consistency. The most likely candidate(s) resulting from initial mechanical and chemical screening was submitted for ablation testing. The penetration rate of specific multi-fiber catheter designs and a single fiber probe was obtained and compared to that in human cadaver calcified plaque. The effects of lasing parameters and catheter tip design on penetration speed in a representative calcified model were verified against the results in human cadaver specimens. Results: In Plaster of Paris, the best penetration was obtained using the single fiber tip configuration operating at 100 Fluence, 120 Hz. Calcified human lesions are twice as hard, twice as elastic as and much more complex than Plaster of Paris. Penetration of human calcified specimens was highly inconsistent and varied significantly from specimen to specimen and within individual specimens. Conclusions: Although Plaster of Paris demonstrated predictable increases in penetration with higher energy density and repetition rate, it can not be considered a totally representative laser ablation model for calcified lesions. This is in part due to the more heterogeneous nature and higher density composition of cadaver intravascular human calcified occlusions. Further testing will require a more representative model of human calcified lesions.

  4. Cardiovascular dysfunction associated with neurodegeneration in an experimental model of Parkinson's disease.

    PubMed

    Falquetto, Barbara; Tuppy, Marina; Potje, Simone R; Moreira, Thiago S; Antoniali, Cristina; Takakura, Ana C

    2017-02-15

    Patients with Parkinson's disease (PD) exhibit both motor and non-motor symptoms. Among the non-motor symptoms, cardiovascular autonomic dysfunction is frequently observed. Here, we evaluated baroreflex function, vascular reactivity and neuroanatomical changes in brainstem regions involved in the neural control of circulation in the 6-hydroxydopamine (6-OHDA) model of PD. Male Wistar rats received a bilateral injection of 6-OHDA or vehicle into the striatum. After 61days, baroreflex function and vascular reactivity were assessed. The 6-OHDA and vehicle groups showed similar increases in mean arterial pressure (MAP) in response to phenylephrine (PE). However, the bradycardia observed in the vehicle group was blunted in the 6-OHDA-treated rats. Injection of sodium nitroprusside (SNP) decreased hypotension, tachycardia and vascular relaxation in 6-OHDA-treated rats. Bilateral intrastriatal 6-OHDA led to massive degeneration of tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra and to reductions in the numbers of A1/C1 and A5 catecholaminergic neurons while sparing A2 neurons within the nucleus of the solitary tract (NTS). 6-OHDA-treated rats also showed decreases in Phox2b-expressing neurons in the NTS and in choline acetyltransferase (ChAT) immunoreactivity in the nucleus ambiguus. Altogether, our data suggest that this model of PD includes neuroanatomical and functional changes that lead to cardiovascular impairment.

  5. Both Creatine and Its Product Phosphocreatine Reduce Oxidative Stress and Afford Neuroprotection in an In Vitro Parkinson’s Model

    PubMed Central

    Martín-de-Saavedra, Maria D.; Romero, Alejandro; Egea, Javier; Ludka, Fabiana K.; Tasca, Carla I.; Farina, Marcelo; Rodrigues, Ana Lúcia S.; López, Manuela G.

    2014-01-01

    Creatine is the substrate for creatine kinase in the synthesis of phosphocreatine (PCr). This energetic system is endowed of antioxidant and neuroprotective properties and plays a pivotal role in brain energy homeostasis. The purpose of this study was to investigate the neuroprotective effect of creatine and PCr against 6-hydroxydopamine (6-OHDA)-induced mitochondrial dysfunction and cell death in rat striatal slices, used as an in vitro Parkinson’s model. The possible involvement of the signaling pathway mediated by phosphatidylinositol-3 kinase (PI3K), protein kinase B (Akt), and glycogen synthase kinase-3β (GSK3β) was also evaluated. Exposure of striatal slices to 6-OHDA caused a significant disruption of the cellular homeostasis measured as 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide reduction, lactate dehydrogenase release, and tyrosine hydroxylase levels. 6-OHDA exposure increased the levels of reactive oxygen species and thiobarbituric acid reactive substances production and decreased mitochondrial membrane potential in rat striatal slices. Furthermore, 6-OHDA decreased the phosphorylation of Akt (Serine473) and GSK3β (Serine9). Coincubation with 6-OHDA and creatine or PCr reduced the effects of 6-OHDA toxicity. The protective effect afforded by creatine or PCr against 6-OHDA-induced toxicity was reversed by the PI3K inhibitor LY294002. In conclusion, creatine and PCr minimize oxidative stress in striatum to afford neuroprotection of dopaminergic neurons. PMID:25424428

  6. Both creatine and its product phosphocreatine reduce oxidative stress and afford neuroprotection in an in vitro Parkinson's model.

    PubMed

    Cunha, Mauricio Peña; Martín-de-Saavedra, Maria D; Romero, Alejandro; Egea, Javier; Ludka, Fabiana K; Tasca, Carla I; Farina, Marcelo; Rodrigues, Ana Lúcia S; López, Manuela G

    2014-01-01

    Creatine is the substrate for creatine kinase in the synthesis of phosphocreatine (PCr). This energetic system is endowed of antioxidant and neuroprotective properties and plays a pivotal role in brain energy homeostasis. The purpose of this study was to investigate the neuroprotective effect of creatine and PCr against 6-hydroxydopamine (6-OHDA)-induced mitochondrial dysfunction and cell death in rat striatal slices, used as an in vitro Parkinson's model. The possible involvement of the signaling pathway mediated by phosphatidylinositol-3 kinase (PI3K), protein kinase B (Akt), and glycogen synthase kinase-3β (GSK3β) was also evaluated. Exposure of striatal slices to 6-OHDA caused a significant disruption of the cellular homeostasis measured as 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide reduction, lactate dehydrogenase release, and tyrosine hydroxylase levels. 6-OHDA exposure increased the levels of reactive oxygen species and thiobarbituric acid reactive substances production and decreased mitochondrial membrane potential in rat striatal slices. Furthermore, 6-OHDA decreased the phosphorylation of Akt (Serine(473)) and GSK3β (Serine(9)). Coincubation with 6-OHDA and creatine or PCr reduced the effects of 6-OHDA toxicity. The protective effect afforded by creatine or PCr against 6-OHDA-induced toxicity was reversed by the PI3K inhibitor LY294002. In conclusion, creatine and PCr minimize oxidative stress in striatum to afford neuroprotection of dopaminergic neurons.

  7. Early expression of the receptor for advanced glycation end products in a toxic model produced by 6-hydroxydopamine in the rat striatum.

    PubMed

    Serratos, Iris N; Castellanos, Pilar; Pastor, Nina; Millán-Pacheco, César; Colín-González, Ana Laura; Rembao, Daniel; Pérez-Montfort, Ruy; Cabrera, Nallely; Sánchez-García, Aurora; Gómez, Isabel; Rangel-López, Edgar; Santamaria, Abel

    2016-04-05

    The receptor for advanced glycation end products (RAGE) is commonly involved in different neurodegenerative and inflammatory disorders. The cellular signaling associated to RAGE activation may occur upon binding to different ligands. In this study we investigated whether the toxic model produced by 6-hydroxydopamine (6-OHDA) in rats comprises early noxious responses related to RAGE-mediated signaling cascades. In order to explore a possible interaction between 6-OHDA and RAGE, affinity parameters of RAGE with 6-OHDA were estimated by different means. The possible binding sites of 6-OHDA with the VC1 homodimer for both rat and human RAGE were also modeled. Our results show that the striatal infusion of 6-OHDA recruits RAGE upregulation, as evidenced by an early expression of the receptor. 6-OHDA was also found to bind the VC1 homodimer, although its affinity was moderate when compared to other ligands. This work contributes to the understanding of the role of RAGE activation for 6-OHDA-induced neurotoxicity.

  8. Expression of Tgfβ1 and Inflammatory Markers in the 6-hydroxydopamine Mouse Model of Parkinson’s Disease

    PubMed Central

    Haas, Stefan Jean-Pierre; Zhou, Xiaolai; Machado, Venissa; Wree, Andreas; Krieglstein, Kerstin; Spittau, Björn

    2016-01-01

    Parkinson’s disease (PD) is a neurodegenerative disorder that is characterized by loss of midbrain dopaminergic (mDA) neurons in the substantia nigra (SN). Microglia-mediated neuroinflammation has been described as a common hallmark of PD and is believed to further trigger the progression of neurodegenerative events. Injections of 6-hydroxydopamine (6-OHDA) are widely used to induce degeneration of mDA neurons in rodents as an attempt to mimic PD and to study neurodegeneration, neuroinflammation as well as potential therapeutic approaches. In the present study, we addressed microglia and astroglia reactivity in the SN and the caudatoputamen (CPu) after 6-OHDA injections into the medial forebrain bundle (MFB), and further analyzed the temporal and spatial expression patterns of pro-inflammatory and anti-inflammatory markers in this mouse model of PD. We provide evidence that activated microglia as well as neurons in the lesioned SN and CPu express Transforming growth factor β1 (Tgfβ1), which overlaps with the downregulation of pro-inflammatory markers Tnfα, and iNos, and upregulation of anti-inflammatory markers Ym1 and Arg1. Taken together, the data presented in this study suggest an important role for Tgfβ1 as a lesion-associated factor that might be involved in regulating microglia activation states in the 6-OHDA mouse model of PD in order to prevent degeneration of uninjured neurons by microglia-mediated release of neurotoxic factors such as Tnfα and nitric oxide (NO). PMID:26869879

  9. Environmental enrichment brings a beneficial effect on beam walking and enhances the migration of doublecortin-positive cells following striatal lesions in rats.

    PubMed

    Urakawa, S; Hida, H; Masuda, T; Misumi, S; Kim, T-S; Nishino, H

    2007-02-09

    Rats raised in an enriched environment (enriched rats) have been reported to show less motor dysfunction following brain lesions, but the neuronal correlates of this improvement have not been well clarified. The present study aimed to elucidate the effect of chemical brain lesions and environmental enrichment on motor function and lesion-induced neurogenesis. Three week-old, recently weaned rats were divided into two groups: one group was raised in an enriched environment and the other group was raised in a standard cage for 5 weeks. Striatal damage was induced at an age of 8 weeks by injection of the neuro-toxins 6-hydroxydopamine (6-OHDA) or quinolinic acid (QA) into the striatum, or by injection of 6-OHDA into the substantia nigra (SN), which depleted nigrostriatal dopaminergic innervation. Enriched rats showed better performance on beam walking compared with those raised in standard conditions, but both groups showed similar forelimb use asymmetry in a cylinder test. The number of bromodeoxyuridine-labeled proliferating cells in the subventricular zone was increased by a severe striatal lesion induced by QA injection 1 week after the lesion, but decreased by injection of 6-OHDA into the SN. Following induction of lesions by striatal injection of 6-OHDA or QA, the number of cells positive for doublecortin (DCX) was strongly increased in the striatum; however, there was no change in the number of DCX-positive cells following 6-OHDA injection into the SN. Environmental enrichment enhanced the increase of DCX-positive cells with migrating morphology in the dorsal striatum. In enriched rats, DCX-positive cells traversed the striatal parenchyma far from the corpus callosum and lateral ventricle. DCX-positive cells co-expressed an immature neuronal marker, polysialylated neural cell adhesion molecule, but were negative for a glial marker. These data suggest that environmental enrichment improves motor performance on beam walking and enhances neuronal migration toward

  10. 6-Hydroxydopamine-lesioning of the nigrostriatal pathway in rats alters basal ganglia mRNA for copper, zinc- and manganese-superoxide dismutase, but not glutathione peroxidase.

    PubMed

    Kunikowska, G; Jenner, P

    2001-12-13

    The effects of nigrostriatal pathway destruction on the mRNA levels of copper, zinc-dependent superoxide dismutase (Cu,Zn-SOD), manganese-dependent superoxide dismutase (Mn-SOD), and glutathione peroxidase in basal ganglia of adult rat were investigated using in situ hybridization histochemistry and oligodeoxynucleotide (single-stranded complementary DNA) probes. The 6-hydroxydopamine (6-OHDA)-induced destruction of the nigrostriatal pathway resulted in contralateral rotation to apomorphine and a marked loss of specific [(3)H]mazindol binding in the striatum (93%; P<0.05) and of tyrosine hydroxylase mRNA in substantia nigra pars compacta (SC) (93%; P<0.05) compared with control rats. Levels of Cu,Zn-SOD mRNA were decreased in the striatum, globus pallidus, and SC on the lesioned side of 6-OHDA-lesioned rats compared with sham-lesioned rats (P<0.05). Levels of Mn-SOD mRNA were increased in the nucleus accumbens (P<0.05), but decreased in the SC (P<0.05) on the lesioned side of 6-OHDA-treated rats compared with sham-lesioned rats. Lesioning with 6-OHDA had no effect on glutathione peroxidase mRNA levels in any region of basal ganglia examined. The significant changes in Cu,Zn-SOD and Mn-SOD mRNA indicate that SOD is primarily expressed by dopaminergic neurons of the nigrostriatal pathway, and that the Mn-SOD gene appears to be inducible in rat basal ganglia in response to both physical and chemical damage 5 weeks after 6-OHDA-lesioning. These findings may clarify the status of antioxidant enzymes, particularly Mn-SOD, in patients with Parkinson's disease and their relevance to disease pathogenesis.

  11. PI3 kinase/Akt activation mediates estrogen and IGF-1 nigral DA neuronal neuroprotection against a unilateral rat model of Parkinson's disease.

    PubMed

    Quesada, Arnulfo; Lee, Becky Y; Micevych, Paul E

    2008-04-01

    Recently, using the medial forebrain bundle (MFB) 6-hydroxydopmaine (6-OHDA) lesion rat model of Parkinson's disease (PD), we have demonstrated that blockade of central IGF-1 receptors (IGF-1R) attenuated estrogen neuroprotection of substantia nigra pars compacta (SNpc) DA neurons, but exacerbated 6-OHDA lesions in IGF-1 only treated rats (Quesada and Micevych [2004]: J Neurosci Res 75:107-116). This suggested that the IGF-1 system is a central mechanism through which estrogen acts to protect the nigrostriatal DA system. Moreover, these results also suggest that IGF-1R-induced intracellular signaling pathways are involved in the estrogen mechanism that promotes neuronal survival. In vitro, two convergent intracellular signaling pathways used by estrogen and IGF-1, the mitogen-activated protein kinase (MAPK/ERK), and phosphatidyl-inositol-3-kinase/Akt (PI3K/Akt), have been demonstrated to be neuroprotective. Continuous central infusions of MAPK/ERK and PI3K/Akt inhibitors were used to test the hypothesis that one or both of these signal transduction pathways mediates estrogen and/or IGF-1 neuroprotection of SNpc DA neurons after a unilateral administration of 6-OHDA into the MFB of rats. Motor behavior tests and tyrosine hydroxylase immunoreactivity revealed that the inhibitor of the PI3K/Akt pathway (LY294002) blocked the survival effects of both estrogen and IGF-1, while an inhibitor of the MAPK/ERK signaling (PD98059) was ineffective. Western blot analyses showed that estrogen and IGF-1 treatments increased PI3K/Akt activation in the SN; however, MAPK/ERK activation was decreased in the SN. Indeed, continuous infusions of inhibitors blocked phosphorylation of PI3K/Akt and MAPK/ERK. These findings indicate that estrogen and IGF-1-mediated SNpc DA neuronal protection is dependent on PI3K/Akt signaling, but not on the MAPK/ERK pathway.

  12. Malignancy Risk Models for Oral Lesions

    PubMed Central

    Zarate, Ana M.; Brezzo, María M.; Secchi, Dante G.; Barra, José L.

    2013-01-01

    Objectives: The aim of this work was to assess risk habits, clinical and cellular phenotypes and TP53 DNA changes in oral mucosa samples from patients with Oral Potentially Malignant Disorders (OPMD), in order to create models that enable genotypic and phenotypic patterns to be obtained that determine the risk of lesions becoming malignant. Study Design: Clinical phenotypes, family history of cancer and risk habits were collected in clinical histories. TP53 gene mutation and morphometric-morphological features were studied, and multivariate models were applied. Three groups were estabished: a) oral cancer (OC) group (n=10), b) OPMD group (n=10), and c) control group (n=8). Results: An average of 50% of patients with malignancy were found to have smoking and drinking habits. A high percentage of TP53 mutations were observed in OC (30%) and OPMD (average 20%) lesions (p=0.000). The majority of these mutations were GC ? TA transversion mutations (60%). However, patients with OC presented mutations in all the exons and introns studied. Highest diagnostic accuracy (p=0.0001) was observed when incorporating alcohol and tobacco habits variables with TP53 mutations. Conclusions: Our results prove to be statistically reliable, with parameter estimates that are nearly unbiased even for small sample sizes. Models 2 and 3 were the most accurate for assessing the risk of an OPMD becoming cancerous. However, in a public health context, model 3 is the most recommended because the characteristics considered are easier and less costly to evaluate. Key words:TP53, oral potentially malignant disorders, risk factors, genotype, phenotype. PMID:23722122

  13. Intrastriatal injection of sonic hedgehog reduces behavioral impairment in a rat model of Parkinson's disease.

    PubMed

    Tsuboi, Kyoko; Shults, Clifford W

    2002-01-01

    Sonic hedgehog (Shh), a member of hedgehog (hh) family of signaling molecules, is necessary for normal axial patterning and cellular differentiation in the developing central nervous system. Shh also promotes the survival of fetal dopaminergic neurons and protects cultures of fetal midbrain dopaminergic neurons from the toxic effects of N-methyl-4-phenylpyridinium (MPP(+)), a neurotoxin that selectively injures nigral dopaminergic neurons. The mRNA expression of Shh and its putative receptor in the adult brain indicates an important role of Shh in the mature nervous system in addition to its roles during embryogenesis. In this study we examined the behavioral and anatomical effects of intrastriatal injection of singly myristoylated wild-type human Sonic hedgehog N-terminal fragment (Shh-M) in a rat model of Parkinson's disease (PD). Five groups of rats received a series of four intrastriatal injections of Shh-M (180 ng, 540 ng, or 4.275 microg per injection), glial cell line-derived neurotrophic factor (GDNF) (1 microg/injection), or vehicle on days 1, 3, 5, and 8. On day 4, the animals received an intrastriatal injection of 15 microg 6-hydroxydopamine (6-OHDA) free base. Intrastriatal administration of Shh (180 ng/injection) twice before and after a single intrastriatal injection of 6-OHDA reduced apomorphine- and amphetamine-induced rotation and forelimb akinesia and partially preserved dopaminergic axons in the striatum. This is the first demonstration in vivo that Shh reduces behavioral deficits induced by intrastriatal 6-OHDA lesion and suggests that Shh may be useful in the treatment of disorders that affect the nigrostriatal system, such as PD.

  14. Topographical Distribution of Morphological Changes in a Partial Model of Parkinson's Disease--Effects of Nanoencapsulated Neurotrophic Factors Administration.

    PubMed

    Requejo, C; Ruiz-Ortega, J A; Bengoetxea, H; Garcia-Blanco, A; Herrán, E; Aristieta, A; Igartua, M; Ugedo, L; Pedraz, J L; Hernández, R M; Lafuente, J V

    2015-10-01

    Administration of various neurotrophic factors is a promising strategy against Parkinson's disease (PD). An intrastriatal infusion of 6-hydroxidopamine (6-OHDA) in rats is a suitable model to study PD. This work aims to describe stereological parameters regarding rostro-caudal gradient, in order to characterize the model and verify its suitability for elucidating the benefits of therapeutic strategies. Administration of 6-OHDA induced a reduction in tyrosine hidroxylase (TH) reactivity in the dorsolateral part of the striatum, being higher in the caudal section than in the rostral one. Loss of TH-positive neurons and axodendritic network was highly significant in the external third of substantia nigra (e-SN) in the 6-OHDA group versus the saline one. After the administration of nanospheres loaded with neurotrophic factors (NTF: vascular endothelial growth factor (VEGF) + glial cell line-derived neurotrophic factor (GDNF)), parkinsonized rats showed more TH-positive fibers than those of control groups; this recovery taking place chiefly in the rostral sections. Neuronal density and axodendritic network in e-SN was more significant than in the entire SN; the topographical analysis showed that the highest difference between NTF versus control group was attained in the middle section. A high number of bromodeoxyuridine (BrdU)-positive cells were found in sub- and periventricular areas in the group receiving NTF, where most of them co-expressed doublecortin. Measurements on the e-SN achieved more specific and significant results than in the entire SN. This difference in rostro-caudal gradients underpins the usefulness of a topological approach to the assessment of the lesion and therapeutic strategies. Findings confirmed the neurorestorative, neurogenic, and synergistic effects of VEGF+GDNF administration.

  15. c-Fos expression after deep brain stimulation of the pedunculopontine tegmental nucleus in the rat 6-hydroxydopamine Parkinson model.

    PubMed

    Saryyeva, Assel; Nakamura, Makoto; Krauss, Joachim K; Schwabe, Kerstin

    2011-11-01

    Deep brain stimulation (DBS) is used to alleviate motor dysfunction in Parkinson's disease (PD). The pedunculopontine nucleus (PPN) may be a potential target for severe freezing and postural instability with 25 Hz stimulation being considered more effective than 130 Hz stimulation. Here we evaluated the expression of c-Fos after 25 Hz and 130 Hz DBS of the pedunculopontine tegmental nucleus (PPTg, i.e., the rodent equivalent to the human PPN) in the rat 6-hydroxydopamine (6-OHDA) PD model. Anaesthetized male Sprague Dawley rats with unilateral 6-OHDA-induced nigrostriatal lesions were stimulated with 25 Hz, 130 Hz, or 0 Hz sham-stimulation for 4h by electrodes implanted into the ipsilateral PPTg. Thereafter the distribution and number of neurons expressing the immediate early gene c-Fos, a marker for acute neuronal activity, was assessed. DBS of the PPTg induced strong ipsilateral c-Fos expression at the stimulation site, with 25 Hz having a more marked impact than 130 Hz. Additionally, c-Fos was strongly expressed in the central gray. In the dorsal part expression was stronger after 25 Hz stimulation, while in the medial and ventral part there was no difference between 25 Hz and 130 Hz stimulation. Expression in the basal ganglia was negligible. In the rat 6-OHDA PD model stimulation of the PPTg did not affect c-Fos expression in the basal ganglia, but had a strong impact on other functional circuitries. PPN stimulation in humans might therefore also have an impact on other systems than the motor system.

  16. Sexual behavior in male rats after radiofrequency or dopamine-depleting lesions in nucleus accumbens.

    PubMed

    Liu, Y C; Sachs, B D; Salamone, J D

    1998-06-01

    Considerable neurochemical evidence links dopamine (DA) in nucleus accumbens (NAcc) to male sexual behavior. The present experiments were conducted to extend this information to the male's sexual response to remote stimuli from estrous female (noncontact erection; NCE). Male rats were tested for copulation and NCE after either 6-hydroxydopamine (6-OHDA) or radiofrequency (RF) lesions in NAcc). Males with an average 78% depletion of DA in NAcc had a lower incidence of NCE, longer latency to display NCE, and fewer erections. DA-depleted males also had less locomotor activity after injections of d-amphetamine, and reductions in apomorphine-induced yawning, but a normal incidence of penile erection. Males with RF lesions of the NAcc had longer NCE latencies. All males copulated to ejaculation after either 6-OHDA or RF lesions with little or no deficit, although the 6-OHDA-treated males had longer intromission latencies. The NCE deficit supports the hypothesized role of NAcc DA in arousal processes in responding to remote cues from estrous females. The minimal effect of lesions on copulation suggests that the presence of additional proximal stimulation during copulation may overcome the deficits induced by DA depletions or lesions in NAcc.

  17. Cat retinal ganglion cell receptive-field alterations after 6-hydroxydopamine induced dopaminergic amacrine cell lesions

    SciTech Connect

    Maguire, G.W.; Smith, E.L. III

    1985-06-01

    Optic tract single-unit recordings were used to study ganglion cell response functions of the intact cat eye after 6-hydroxydopamine (6-OHDA) lesioning of the dopaminergic amacrine cell (AC) population of the inner retina. The impairment of the dopaminergic AC was verified by high pressure-liquid chromatography with electrochemical detection of endogenous dopamine content and by (/sup 3/H)dopamine high-affinity uptake; the dopaminergic ACs of the treated eyes demonstrated reduced endogenous dopamine content and reduced (/sup 3/H)dopamine uptake compared with that of their matched controls. Normal appearing (/sup 3/H)GABA and (/sup 3/H)-glycine uptake in the treated retinas suggests the absence of any nonspecific action of the 6-OHDA on the neural retina. The impairment of the dopaminergic AC population was found to alter a number of response properties in off-center ganglion cells, but this impairment had only a modest effect on the on-center cells. An abnormally high proportion of the off-center ganglion cells in the 6-OHDA treated eyes possessed nonlinear, Y-type receptive fields. These cells also possessed shift-responses of greater than normal amplitude, altered intensity-response functions, reduced maintained activities, and more transient center responses. Of the on-center type cells, only the Y-type on-center cells were affected by 6-OHDA, possessing higher than normal maintained activities and altered intensity-response functions. The on-center X-cells were unaffected by 6-OHDA treatment. The dopaminergic AC of the photopically adapted cat retina therefore modulates a number of ganglion cell response properties and within the limits of this study is most prominent in off-center ganglion cell circuitry.

  18. Laser Acupuncture at HT7 Acupoint Improves Cognitive Deficit, Neuronal Loss, Oxidative Stress, and Functions of Cholinergic and Dopaminergic Systems in Animal Model of Parkinson's Disease.

    PubMed

    Wattanathorn, Jintanaporn; Sutalangka, Chatchada

    2014-01-01

    To date, the therapeutic strategy against cognitive impairment in Parkinson's disease (PD) is still not in satisfaction level and requires novel effective intervention. Based the oxidative stress reduction and cognitive enhancement induced by laser acupuncture at HT7, the beneficial effect of laser acupuncture at HT7 against cognitive impairment in PD has been focused. In this study, we aimed to determine the effect of laser acupuncture at HT7 on memory impairment, oxidative stress status, and the functions of both cholinergic and dopaminergic systems in hippocampus of animal model of PD. Male Wistar rats, weighing 180-220 g, were induced unilateral lesion at right substantianigra by 6-OHDA and were treated with laser acupuncture continuously at a period of 14 days. The results showed that laser acupuncture at HT7 enhanced memory and neuron density in CA3 and dentate gyrus. The decreased AChE, MAO-B, and MDA together with increased GSH-Px in hippocampus of a 6-OHDA lesion rats were also observed. In conclusion, laser acupuncture at HT7 can improve neuron degeneration and memory impairment in animal model of PD partly via the decreased oxidative stress and the improved cholinergic and dopaminergic functions. More researches concerning effect of treatment duration are still required.

  19. Intracarotid Infusion of Mesenchymal Stem Cells in an Animal Model of Parkinson’s Disease, Focusing on Cell Distribution and Neuroprotective and Behavioral Effects

    PubMed Central

    Cerri, Silvia; Greco, Rosaria; Levandis, Giovanna; Ghezzi, Cristina; Mangione, Antonina Stefania; Fuzzati-Armentero, Marie-Therese; Bonizzi, Arianna; Avanzini, Maria Antonietta; Maccario, Rita

    2015-01-01

    Mesenchymal stem cells (MSCs) have been proposed as a potential therapeutic tool for Parkinson’s disease (PD) and systemic administration of these cells has been tested in preclinical and clinical studies. However, no information on survival and actual capacity of MSCs to reach the brain has been provided. In this study, we evaluated homing of intraarterially infused rat MSCs (rMSCs) in the brain of rats bearing a 6-hydroxydopamine (6-OHDA)-induced lesion of the nigrostriatal tract, to establish whether the toxin-induced damage is sufficient to grant MSC passage across the blood-brain barrier (BBB) or if a transient BBB disruption is necessary. The rMSC distribution in peripheral organs and the effects of cell infusion on neurodegenerative process and motor deficits were also investigated. rMSCs were infused 14 days after 6-OHDA injection. A hyperosmolar solution of mannitol was used to transiently permeabilize the BBB. Behavioral impairment was assessed by adjusting step test and response to apomorphine. Animals were sacrificed 7 and 28 days after cell infusion. Our work shows that appreciable delivery of rMSCs to the brain of 6-OHDA-lesioned animals can be obtained only after mannitol pretreatment. A notable percentage of infused cells accumulated in peripheral organs. Infusion of rMSCs did not modify the progression of 6-OHDA-induced damage or the motor impairment at the stepping test, but induced progressive normalization of the pathological response (contralateral turning) to apomorphine administration. These findings suggest that many aspects should be further investigated before considering any translation of MSC systemic administration into the clinical setting for PD treatment. Significance This study demonstrates that mesenchymal stem cells infused through the carotid artery do not efficiently cross the blood-brain barrier in rats with a Parkinson’s disease-like degeneration of nigrostriatal neurons, unless a permeabilizing agent (e.g., mannitol) is

  20. Visual discrimination modeling of lesion detectability

    NASA Astrophysics Data System (ADS)

    Johnson, Jeffrey P.; Lubin, Jeffrey; Nafziger, John S.; Chakraborty, Dev P.

    2002-04-01

    The Sarnoff JNDmetrix visual discrimination model (VDM) was applied to predict human psychophysical performance in the detection of simulated mammographic lesions. Contrast thresholds for the detection of synthetic Gaussian masses on mean backgrounds and simulated mammographic backgrounds were measured in two-alternative, forced-choice (2AFC) trials. Experimental thresholds for 2-D Gaussian signal detection decreased with increasing signal size on mean backgrounds and on 1/f3 filtered noise images presented with identical (paired) backgrounds. For 2AFC presentations of different (unpaired) filtered noise backgrounds, detection thresholds increased with increasing signal diameter, consistent with a decreasing signal-to-noise ratio. Thresholds for mean and paired filtered noise backgrounds were used to calibrate a new low-pass, spatial-frequency channel in the VDM. The calibrated VDM was able to predict accurate detection thresholds for Gaussian signals on mean and paired 1/f3 filtered noise backgrounds. To simulate noise-limited detection thresholds for unpaired backgrounds, an approach is outlined for the development of a VDM-based model observer based on statistical decision theory.

  1. Long-term treatment with L-DOPA or pramipexole affects adult neurogenesis and corresponding non-motor behavior in a mouse model of Parkinson's disease.

    PubMed

    Chiu, W-H; Depboylu, C; Hermanns, G; Maurer, L; Windolph, A; Oertel, W H; Ries, V; Höglinger, G U

    2015-08-01

    Non-motor symptoms such as hyposmia and depression are often observed in Parkinson's disease (PD) and can precede the onset of motor symptoms for years. The underlying pathological alterations in the brain are not fully understood so far. Dysregulation of adult neurogenesis in the dentate gyrus of the hippocampus and the olfactory bulb has been recently suggested to be implicated in non-motor symptoms of PD. However, there is so far no direct evidence to support the relationship of non-motor symptoms and the modulation of adult neurogenesis following dopamine depletion and/or dopamine replacement. In this study, we investigated the long-term effects of l-DOPA and pramipexole, a dopamine agonist, in a mouse model of bilateral intranigral 6-OHDA lesion, in order to assess the impact of adult neurogenesis on non-motor behavior. We found that l-DOPA and pramipexole can normalize decreased neurogenesis in the hippocampal dentate gyrus and the periglomerular layer of the olfactory bulb caused by a 6-OHDA lesion. Interestingly, pramipexole showed an antidepressant and anxiolytic effect in the forced swim test and social interaction test. However, there was no significant change in learning and memory function after dopamine depletion and dopamine replacement, respectively.

  2. Fixed-ratio discrimination training as replacement therapy in Parkinson's disease: studies in a 6-hydroxydopamine-treated rat model.

    PubMed

    Van Keuren, K R; Stodgell, C J; Schroeder, S R; Tessel, R E

    1998-01-05

    Severe 6-hydroxydopamine (6-OHDA)-induced neostriatal dopamine (DA) depletion is generally held to be irreversible. Adult rats administered 6-OHDA soon after weaning, or neonatally, respectively model Parkinson's disease (PD) and Lesch-Nyhan syndrome (LNS). Prior studies in our laboratory indicate that prolonged training on incrementally more difficult fixed-ratio (FR) discriminations can reverse 'irreversible' 6-OHDA-induced neostriatal DA depletion in adult LNS rats. The present study evaluated the effects of such training on neostriatal DA depletion and its functional consequences in adult PD and control (vehicle-injected) rats. After recovery from 6-OHDA-induced hypophagia, rats were sacrificed to assess neostriatal DA depletion magnitude, or were food-deprived and either subjected to food-maintained operant FR discrimination training or allowed to remain in their home cages. 6-OHDA treatment antagonized amphetamine (AMP)-induced increases in brief rearing behavior and locomotor activity in 3-month-old PD rats prior to training, and reduced operant response rates throughout training without affecting learning rates. One week after training, AMP-increased locomotor and brief-rearing frequencies were augmented in all groups except trained controls, and the prior inhibitory effect of 6-OHDA treatment on AMP-increased behavioral frequencies was essentially eliminated. Cumulative apomorphine (APO) dose-effect curve (0.1-3.2 mg/kg) construction 3 weeks post-training revealed that 6-OHDA treatment abolished APO-induced intense licking behavior. However, training eliminated the hyperresponsiveness of 6-OHDA-treated rats to the locomotor- and brief-rearing stimulant effects of APO but did not affect the depletion of neostriatal DA. Nevertheless, 6-OHDA-induced increases in neostriatal DOPAC/DA and HVA/DA ratios were normalized by age/food-deprivation while that of 3MT/DA was not. These findings suggest that training reduces the functional responsiveness of at least some

  3. Magnetic resonance imaging as a tool to image neuroinflammation in a rat model of Parkinson's disease--phagocyte influx to the brain is promoted by bilberry-enriched diet.

    PubMed

    Virel, Ana; Rehnmark, Anna; Orädd, Greger; Olmedo-Díaz, Sonia; Faergemann, Erik; Strömberg, Ingrid

    2015-11-01

    Neuroinflammation is a chronic event in neurodegenerative disorders. In the rat model of Parkinson's disease, including a striatal injection of the neurotoxin 6-hydroxydopamine (6-OHDA), antioxidant treatment affects the inflammatory process. Despite a heavy accumulation of microglia early after the injury, dopamine nerve fibre regeneration occurs. It remains unclear why this heavy accumulation of microglia is found early after the lesion in antioxidant-treated animals, or even more, what is the origin of these microglia. In this study magnetic resonance imaging (MRI) was used to elucidate whether the inflammatory response was generated from the blood or from activated brain microglia. Superparamagnetic iron oxide (SPIO) nanoparticles were injected intravenously prior to a striatal 6-OHDA injection to tag phagocytes in the blood. Rats were fed either with bilberry-enriched or control diet. T2*-weighted MRI scans were performed 1 week after the lesion, and hypointense areas were calculated from T2*-weighted images, to monitor the presence of SPIO particles. The results revealed that feeding the animals with bilberries significantly promoted accumulation of blood-derived immune cells. Gadolinium-enhanced MRI demonstrated no difference in leakage of the blood-brain barrier independent of diets. To conclude, bilberry-enriched diet promotes an influx of periphery-derived immune cells to the brain early after injury.

  4. Effects of age, gender, and gonadectomy on neurochemistry and behavior in animal models of Parkinson's disease.

    PubMed

    Tamás, Andrea; Lubics, Andrea; Lengvári, István; Reglodi, Dóra

    2006-04-01

    The effects of aging and gender on the neurochemistry of the dopaminergic system have been studied extensively; however, data on comparative behavioral consequences of lesions of the dopaminergic system in aging and in female animals are limited. This study presents experimental results on the behavioral and morphological outcome in young, aging, and gonadectomized male and female rats in the 6-OHDA model of Parkinson's disease. Both young and aging male animals were more susceptible to 6-OHDA than females: female rats had significantly less dopaminergic cell loss and showed a higher degree of behavioral recovery. Although the dopaminergic cell loss was only slightly more in the aging rats of the same sex, they showed more severe behavioral deficits in both gender groups. Ovariectomy did not significantly influence the dopaminergic cell loss, but behavioral recovery was worse when compared to non-ovariectomized females. In contrast, castrated males had significantly less dopaminergic cell loss than non-castrated males, but the behavioral recovery was not significantly better. The obtained results are discussed in light of the available literature on the age and gender differences in animals models of Parkinson's disease.

  5. In vivo bioluminescence imaging of neurogenesis - the role of the blood brain barrier in an experimental model of Parkinson's disease.

    PubMed

    Fricke, Inga B; Schelhaas, Sonja; Zinnhardt, Bastian; Viel, Thomas; Hermann, Sven; Couillard-Després, Sébastien; Jacobs, Andreas H

    2017-02-13

    Bioluminescence imaging in transgenic mice expressing firefly luciferase in Doublecortin(+) (Dcx) neuroblasts might serve as a powerful tool to study the role of neurogenesis in models of brain injury and neurodegeneration using non-invasive, longitudinal in vivo imaging. Therefore, we aimed to use BLI in B6(Cg)-Tyrc-2J/J Dcx-Luc (Doublecortin-Luciferase, Dcx-Luc) mice to investigate its suitability to assess neurogenesis in a unilateral injection model of Parkinson's disease. We further aimed to assess the blood brain barrier leakage associated with the intranigral 6-OHDA injection to evaluate its impact on substrate delivery and bioluminescence signal intensity. Two weeks after lesion, we observed an increase in bioluminescence signal in the ipsilateral hippocampal region in both, 6-OHDA and vehicle injected Dcx-Luc mice. At the same time, no corresponding increase in Dcx(+) neuroblast numbers could be observed in the dentate gyrus of C57Bl6 mice. Blood brain barrier leakage was observed in the hippocampal region and in the degenerating substantia nigra of C57Bl6 mice in vivo using T1 weighted Magnetic Resonance Imaging with Gadovist(®) and ex vivo using Evans Blue Fluorescence Reflectance Imaging and mouse Immunoglobulin G staining. Our data suggests a BLI signal dependency on blood brain barrier permeability, underlining a major pitfall of substrate/tracer dependent imaging in invasive disease models.

  6. Carnosic acid protects against 6-hydroxydopamine-induced neurotoxicity in in vivo and in vitro model of Parkinson's disease: involvement of antioxidative enzymes induction.

    PubMed

    Wu, Chi-Rei; Tsai, Chia-Wen; Chang, Shu-Wei; Lin, Chia-Yuan; Huang, Li-Chun; Tsai, Chia-Wen

    2015-01-05

    The neuroprotective effects of carnosic acid (CA), a phenolic diterpene isolated from rosemary (Rosmarinus officinalis), have been widely investigated in recent years, however, its protection in in vivo still unclear. In this study, we investigated the behavioral activity and neuroprotective effects of CA in a rat model of Parkinson's disease (PD) induced by 6-hydroxydopamine (6-OHDA). Rats were treated with 20mg/kg body weight of CA for 3 weeks before 6-OHDA exposure. Results indicated that CA improved the locomotor activity and reduced the apomorphine-caused rotation in 6-OHDA-stimulated rats. Significant protection against lipid peroxidation and GSH reduction was observed in the 6-OHDA rats pretreated with CA. Pretreatment with CA increased the protein expression of γ-glutamate-cysteine ligase catalytic subunit, γ-glutamate-cysteine ligase modifier subunit, superoxide dismutase, and glutathione reductase compared with 6-OHDA-stimulated rats and SH-SY5Y cells. Immunoblots showed that the reduction of the Bcl-2/Bax ratio, the induction of caspase 3 cleavage, and the induction of poly(ADP-ribose) polymerase (PARP) cleavage by 6-OHDA was reversed in the presence of SB203580 (a p38 inhibitor) or SP600125 (a JNK inhibitor) in SH-SY5Y cells. Rats treated with CA reversed the 6-OHDA-mediated the activation of c-Jun NH2-terminal kinase and p38, the down-regulation of the Bcl-2/Bax ratio, the up-regulation of cleaved caspase 3/caspase 3 and cleaved PARP/PARP ratio, and the down-regulation of tyrosine hydroxylase protein. However, BAM7, an activator of Bax, attenuated the effect of CA on apoptosis in SH-SY5Y cells. These results suggest that CA protected against 6-OHDA-induced neurotoxicity is attributable to its anti-apoptotic and anti-oxidative action. The present findings may help to clarify the possible mechanisms of rosemary in the neuroprotection of PD.

  7. Decreased forelimb ability in mice intracerebroventricularly injected with low dose 6-hydroxidopamine: A model on the dissociation of bradykinesia from hypokinesia.

    PubMed

    Ribeiro, Renata Pietsch; Santos, Danúbia Bonfanti; Colle, Dirleise; Naime, Aline Aita; Gonçalves, Cinara Ludvig; Ghizoni, Heloisa; Hort, Mariana Appel; Godoi, Marcelo; Dias, Paulo Fernando; Braga, Antonio Luiz; Farina, Marcelo

    2016-05-15

    Bradykinesia and hypokinesia represent well-known motor symptoms of Parkinson's disease (PD). While bradykinesia (slow execution of movements) is present in less affected PD patients and aggravates as the disease severity increases, hypokinesia (reduction of movement) seems to emerge prominently only in the more affected patients. Here we developed a model based on the central infusion of low dose (40μg) 6-hydroxydopamine (6-OHDA) in mice in an attempt to discriminate bradykinesia (accessed through forelimb inability) from hypokinesia (accessed through locomotor and exploratory activities). The potential beneficial effects of succinobucol against 6-OHDA-induced forelimb inability were also evaluated. One week after the beginning of treatment with succinobucol (i.p. injections, 10mg/kg/day), mice received a single i.c.v. infusion of 6-OHDA (40μg/site). One week after 6-OHDA infusion, general locomotor/exploratory activities (open field test), muscle strength (grid test), forelimb skill (single pellet task), as well as striatal biochemical parameters related to oxidative stress and cellular homeostasis (glutathione peroxidase, glutathione reductase and NADH dehydrogenases activities, lipid peroxidation and TH levels), were evaluated. 6-OHDA infusions did not change locomotor/exploratory activities and muscle strength, as well as the evaluated striatal biochemical parameters. However, 6-OHDA infusions caused significant reductions (50%) in the single pellet reaching task performance, which detects forelimb skill inability and can be used to experimentally identify bradykinesia. Succinobucol partially protected against 6-OHDA-induced forelimb inability. The decreased forelimb ability with no changes in locomotor/exploratory behavior indicates that our 6-OHDA-based protocol represents a useful tool to mechanistically study the dissociation of bradykinesia and hypokinesia in PD.

  8. Assessment of the Protection of Dopaminergic Neurons by an α7 Nicotinic Receptor Agonist, PHA 543613 Using [18F]LBT-999 in a Parkinson’s Disease Rat Model

    PubMed Central

    Sérrière, Sophie; Doméné, Aurélie; Vercouillie, Johnny; Mothes, Céline; Bodard, Sylvie; Rodrigues, Nuno; Guilloteau, Denis; Routier, Sylvain; Page, Guylène; Chalon, Sylvie

    2015-01-01

    The inverse association between nicotine intake and Parkinson’s disease (PD) is well established and suggests that this molecule could be neuroprotective through anti-inflammatory action mediated by nicotinic receptors, including the α7-subtype (α7R). The objective of this study was to evaluate the effects of an agonist of α7R, PHA 543613, on striatal dopaminergic neurodegeneration and neuroinflammation in a rat model of PD induced by 6-hydroxydopamine (6-OHDA) lesion. Adult male Wistar rats were lesioned in the right striatum and assigned to either the PHA group (n = 7) or the Sham group (n = 5). PHA 543613 hydrochloride at the concentration of 6 mg/kg (PHA group) or vehicle (Sham group) was intra-peritoneally injected 2 h before 6-OHDA lesioning and then at days 2, 4, and 6 post-lesion. Positron emission tomography (PET) imaging was performed at 7 days post-lesion using [18F]LBT-999 to quantify the striatal dopamine transporter (DAT). After PET imaging, neuroinflammation was evaluated in same animals in vitro through the measurement of the microglial activation marker 18 kDa translocator protein (TSPO) by quantitative autoradiography with [3H]PK-11195. The DAT density reflecting the integrity of dopaminergic neurons was significantly decreased while the intensity of neuroinflammation measured by TSPO density was significantly increased in the lesioned compared to intact striatum in both groups. However, these both modifications were partially reversed in the PHA group compared to Sham. In addition, a significant positive correlation between the degree of lesion and the intensity of neuroinflammation was evidenced. These findings indicate that PHA 543613 exerts neuroprotective effects on the striatal dopaminergic neurons associated with a reduction in microglial activation in this model of PD. This reinforces the hypothesis that an α7R agonist could provide beneficial effects for the treatment of PD. PMID:26389120

  9. Neuron-derived IgG protects dopaminergic neurons from insult by 6-OHDA and activates microglia through the FcγR I and TLR4 pathways.

    PubMed

    Zhang, Jie; Niu, Na; Wang, Mingyu; McNutt, Michael A; Zhang, Donghong; Zhang, Baogang; Lu, Shijun; Liu, Yuqing; Liu, Zhihui

    2013-08-01

    Oxidative and immune attacks from the environment or microglia have been implicated in the loss of dopaminergic neurons of Parkinson's disease. The role of IgG which is an important immunologic molecule in the process of Parkinson's disease has been unclear. Evidence suggests that IgG can be produced by neurons in addition to its traditionally recognized source B lymphocytes, but its function in neurons is poorly understood. In this study, extensive expression of neuron-derived IgG was demonstrated in dopaminergic neurons of human and rat mesencephalon. With an in vitro Parkinson's disease model, we found that neuron-derived IgG can improve the survival and reduce apoptosis of dopaminergic neurons induced by 6-hydroxydopamine toxicity, and also depress the release of NO from microglia triggered by 6-hydroxydopamine. Expression of TNF-α and IL-10 in microglia was elevated to protective levels by neuron-derived IgG at a physiologic level via the FcγR I and TLR4 pathways and microglial activation could be attenuated by IgG blocking. All these data suggested that neuron-derived IgG may exert a self-protective function by activating microglia properly, and IgG may be involved in maintaining immunity homeostasis in the central nervous system and serve as an active factor under pathological conditions such as Parkinson's disease.

  10. Preventive effects of soy meal (+/- isoflavone) on spatial cognitive deficiency and body weight in an ovariectomized animal model of Parkinson's disease.

    PubMed

    Sarkaki, A; Badavi, M; Aligholi, H; Moghaddam, A Zand

    2009-10-15

    The aim of the present study was to investigate the preventive effect of 4 weeks soy meal (+/- isoflavone) on post-menopausal cognitive deficiency and body weight alteration in ovariectomized (OVX)-6-hydroxy dopamine (6-OHDA)-induced animal model of Parkinson's Disease (PD) which mimics status in menopause women. Female Wistar rats (250-300 g, 5-6 months old) were divided into 2 main groups. (1) Control; (2) OVX; included 5 subgroups that were pre-treated with 10 or 20 g soy with isoflavone in 30 g daily diet (10 and 20 groups, respectively), 10 or 20 g soy without isoflavone in 30 g daily diet (-10 and -20 groups, respectively) and 0 g soy (sham treated group) during 4 weeks after OVX. To induce animal model ofPD in main second group (OVX rats) the substantia nigra pars compacta (SNpc) was lesioned by 6-hydroxydopamine (6-OHDA) (8 microg kg(-1) 4 microL(-1) normal saline contains 0.1% ascorbate). All animals were trained in Morris water maze for evaluating the spatial learning and memory. The results indicated that pre-treatment of Parkinsonian rats with different doses of dietary soy meal (+/- isoflavone) improved the spatial learning and memory and prevents increasing the body weight after menopause significantly. Our data show that, long-duration dietary soy meal may have the potential neuroprotective effect against post-menopausal cognitive deficiency induced by degeneration of nigrostriatal dopaminergic system and constant body weight during post-menopausal life cycle.

  11. Exposure to Early Life Stress Results in Epigenetic Changes in Neurotrophic Factor Gene Expression in a Parkinsonian Rat Model

    PubMed Central

    Mpofana, Thabisile; Daniels, Willie M. U.; Mabandla, Musa V.

    2016-01-01

    Early life adversity increases the risk of mental disorders later in life. Chronic early life stress may alter neurotrophic factor gene expression including those for brain derived neurotrophic factor (BDNF) and glial cell derived neurotrophic factor (GDNF) that are important in neuronal growth, survival, and maintenance. Maternal separation was used in this study to model early life stress. Following unilateral injection of a mild dose of 6-hydroxydopamine (6-OHDA), we measured corticosterone (CORT) in the blood and striatum of stressed and nonstressed rats; we also measured DNA methylation and BDNF and GDNF gene expression in the striatum using real time PCR. In the presence of stress, we found that there was increased corticosterone concentration in both blood and striatal tissue. Further to this, we found higher DNA methylation and decreased neurotrophic factor gene expression. 6-OHDA lesion increased neurotrophic factor gene expression in both stressed and nonstressed rats but this increase was higher in the nonstressed rats. Our results suggest that exposure to early postnatal stress increases corticosterone concentration which leads to increased DNA methylation. This effect results in decreased BDNF and GDNF gene expression in the striatum leading to decreased protection against subsequent insults later in life. PMID:26881180

  12. Acupuncture inhibits oxidative stress and rotational behavior in 6-hydroxydopamine lesioned rat.

    PubMed

    Yu, Yong-Peng; Ju, Wei-Ping; Li, Zhen-Guang; Wang, Dao-Zhen; Wang, Yuan-Chen; Xie, An-Mu

    2010-06-08

    Increasing evidence suggests the beneficial effects of acupuncture on Parkinson's disease (PD). Although clinical evidence for the acupuncture anti-Parkinson's disease effect has been demonstrated, the precise mechanism still remains elusive. It has been suggested a relationship between PD and reactive oxygen species (ROS) can result in neurodegeneration. The aim of this study was to evaluate the status of oxidative stress, as well as the antioxidant enzyme response, and the role of acupuncture stimulation at GB34 (Yanglingquan), LR3 (Taichong), ST36 (Zusanli) and SP10 (Xuehai) acupoints on regulating oxidative stress in the nigrostriatal system in the 6-hydroxydopamine (6-OHDA) lesioned rat. Two weeks after unilateral injection of 6-OHDA into the left medial forebrain bundle (MFB), an apomorphine induced rotational behavior test was performed. The levels of enzymatic, viz., superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and nonenzymatic, viz., reduced glutathione (GSH), and the levels of malondialdehyde (MDA) in the nigrostriatal system were measured to assess the oxidative stress status. Brain MDA levels significantly increased, while GSH levels were decreased in impaired groups with 6-OHDA injection only, accompanied by a marked reduction in the level of SOD and GSH-Px. The levels of oxidative stress related parameters except CAT, as well as the rotational asymmetry, were reversed by acupuncture stimulation. These results showed that acupuncture treatment displayed antioxidative and/or neuroprotective properties in the 6-OHDA lesioned rat and these protective properties might be mediated, at least in part, by involving regulation of the antioxidant defense system.

  13. MODELING OPERANT BEHAVIOR IN THE PARKINSONIAN RAT

    PubMed Central

    Avila, Irene; Reilly, Mark P.; Sanabria, Federico; Posadas-Sánchez, Diana; Chavez, Claudia L.; Banerjee, Nikhil; Killeen, Peter; Castañeda, Edward

    2009-01-01

    Mathematical principles of reinforcement (MPR; Killeen, 1994) is a quantitative model of operant behavior that contains 3 parameters representing motor capacity (δ), motivation (a), and short term memory (λ). The present study applied MPR to characterize the effects of bilateral infusions of 6-OHDA into the substantia nigra pars compacta in the rat, a model of Parkinson’s disease. Rats were trained to lever press under a 5-component fixed ratio (5, 15, 30, 60, and 100) schedule of food reinforcement. Rats were tested for 15 days prior to dopamine lesions and again for 15 days post-lesion. To characterize functional loss relative to lesion size, rats were grouped according to the extent and the degree of lateralization of their dopamine loss. Response rates decreased as a function of dopamine depletion, primarily at intermediate ratios. MPR accounted for 98% of variance in pre- and post-lesion response rates. Consistent with reported disruptions in motor behavior induced by dopaminergic lesions, estimates of δ increased when dopamine was severely depleted. There was no support for different estimates of a based on pre- and post-lesion performance of any lesion group, suggesting that dopamine loss has negligible effects on incentive motivation. The present study demonstrates the usefulness of combining operant techniques with a theoretical model to better understand the effects of a neurochemical manipulation. PMID:19073222

  14. Lesioning noradrenergic neurons of the locus coeruleus in C57Bl/6 mice with unilateral 6-hydroxydopamine injection, to assess molecular, electrophysiological and biochemical changes in noradrenergic signaling

    PubMed Central

    Szot, P.; Knight, L.; Franklin, A.; Sikkema, C.; Foster, S.; Wilkinson, C.W.; White, S.S.; Raskind, M.A.

    2012-01-01

    The locus coeruleus (LC) is the major loci of noradrenergic innervation to the forebrain. Due to the extensive central nervous system innervation of the LC noradrenergic system, a reduction in the number of LC neurons could result in significant changes in noradrenergic function in many forebrain regions. LC noradrenergic neurons were lesioned in adult male C57Bl/6 mice with the unilateral administration of 6-hydroxydopamine (6OHDA) (vehicle on the alternate side). Noradrenergic markers were measured 3 weeks later to determine the consequence of LC loss in the forebrain. Direct administration of 6OHDA into the LC results in the specific reduction of noradrenergic neurons in the LC (as measured by electrophysiology, immunoreactivity and in situ hybridization), the lateral tegmental neurons and dopaminergic neurons in the substantia nigra (SN) and ventral tegmental region were unaffected. The loss of LC noradrenergic neurons did not result in compensatory changes in the expression of mRNA for norepinephrine (NE) synthesizing enzymes. The loss of LC noradrenergic neurons is associated with reduced NE tissue concentration and NE transporter (NET) binding sites in the frontal cortex and hippocampus, as well as other forebrain regions such as the amygdala and SN. Adrenoreceptor (AR) binding sites (α1- and α2-AR) were not significantly affected on the 6OHDA-treated side compared to the vehicle-treated side, although there is a reduction of AR binding sites on both the vehicle- and 6OHDA-treated side in specific forebrain regions. These studies indicate that unilateral stereotaxic injection of 6OHDA into mice reduces noradrenergic LC neurons and reduces noradrenergic innervation to many forebrain regions, including the contralateral side. PMID:22542679

  15. Forelimb akinesia in the rat Parkinson model: differential effects of dopamine agonists and nigral transplants as assessed by a new stepping test.

    PubMed

    Olsson, M; Nikkhah, G; Bentlage, C; Björklund, A

    1995-05-01

    Methods for the assessment of akinesia in the unilateral rat Parkinson model have so far been lacking. The experiments reported here evaluate the usefulness of a new "stepping test" to monitor forelimb akinesia in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the mesencephalic dopamine (DA) system, and to assess the ability of DA-receptor agonists and fetal DA neuron transplants to reverse these deficits. The 6-OHDA lesion induced marked and long-lasting impairments in the initiation of stepping movements with the contralateral paw. Systemic injections of low doses (chosen to be subthreshold for induction of rotation) of the mixed D1 and D2 receptor agonist apomorphine, the D1-selective agonist SKF 38393, and to a lesser extent also the D2-selective agonist quinpirole were effective in reversing these deficits. Similar effects was seen after a subrotational dose of L-dopa, whereas amphetamine had no effect. Fetal nigral transplants, implanted as multiple deposits in the ipsilateral caudate-putamen and substantia nigra, restored initiation of stepping to a similar degree as the DA agonists. Nigral grafts placed in substantia nigra alone were also effective, although the improvement was less pronounced. Apomorphine, at a dose effective in the lesion-only animals, had no additive effect in the grafted rats, whereas amphetamine appeared to further improve stepping in the rats with intranigral transplants. Identical experiments were performed on skilled forelimb use in the so-called staircase test. Interestingly, neither the DA agonist drugs nor the nigral transplants had any effects on the lesion induced deficits in this more complex task. The results show that forelimb stepping is a highly useful test to monitor lesion-/and transplant-induced changes in forelimb akinesia, a behavioral parameter that may be analogous to limb akinesia and gait problems seen in patients with Parkinson's disease.

  16. Increasing extracellular potassium results in subthalamic neuron activity resembling that seen in a 6-hydroxydopamine lesion.

    PubMed

    Strauss, Ulf; Zhou, Fu-Wen; Henning, Jeannette; Battefeld, Arne; Wree, Andreas; Köhling, Rüdiger; Haas, Stefan Jean-Pierre; Benecke, Reiner; Rolfs, Arndt; Gimsa, Ulrike

    2008-06-01

    Abnormal neuronal activity in the subthalamic nucleus (STN) plays a crucial role in the pathophysiology of Parkinson's disease (PD). Although altered extracellular potassium concentration ([K+]o) and sensitivity to [K+]o modulates neuronal activity, little is known about the potassium balance in the healthy and diseased STN. In vivo measurements of [K+]o using ion-selective electrodes demonstrated a twofold increase in the decay time constant of lesion-induced [K+]o transients in the STN of adult Wistar rats with a unilateral 6-hydroxydopamine (6-OHDA) median forebrain bundle lesion, employed as a model of PD, compared with nonlesioned rats. Various [K+]o concentrations (1.5-12.5 mM) were applied to in vitro slice preparations of three experimental groups of STN slices from nonlesioned control rats, ipsilateral hemispheres, and contralateral hemispheres of lesioned rats. The majority of STN neurons of nonlesioned rats and in slices contralateral to the lesion fired spontaneously, predominantly in a regular pattern, whereas those in slices ipsilateral to the lesion fired more irregularly or even in bursts. Experimentally increased [K+]o led to an increase in the number of spontaneously firing neurons and action potential firing rates in all groups. This was accompanied by a decrease in the amplitude of post spike afterhyperpolarization (AHP) and the amplitude and duration of the posttrain AHP. Lesion effects in ipsilateral neurons at physiological [K+]o resembled the effects of elevated [K+]o in nonlesioned rats. Our data suggest that changed potassium sensitivity due to conductivity alterations and delayed clearance may be critical for shaping STN activity in parkinsonian states.

  17. Effect of different doses of estrogen on the nigrostriatal dopaminergic system in two 6-hydroxydopamine-induced lesion models of Parkinson's disease.

    PubMed

    Cordellini, Marcela Ferreira; Piazzetta, Giovana; Pinto, Karin Cristine; Delattre, Ana Márcia; Matheussi, Francesca; Carolino, Ruither O G; Szawka, Raphael Escorsim; Anselmo-Franci, Janete A; Ferraz, Anete Curte

    2011-06-01

    Parkinson's disease results from a degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc) and it is more prevalent in men than in women. Estrogen has neuroprotective action of the nigrostriatal dopaminergic (NSDA) neurons. It was investigated whether differences in plasma 17β-estradiol (E2) levels alter the degree of neuroprotection in NSDA neurons. Ovariectomized rats, implanted with subcutaneous capsules containing 400, 800 or 1,600 μg of E2 or corn oil, were injected with 1 μg of 6-OHDA in the SNpc or the medial forebrain bundle (MFB). Striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and plasma E2 levels were measured. Only at 400 μg, E2 protected striatal DA against lesion of the MFB. In the SNpc, E2 failed to prevent DA depletion, but increased DOPAC/DA ratio in the striatum. In an NSDA moderate lesion, E2 has a neuroprotective action. In a severe lesion, E2 could stimulate DA activity in remaining neurons.

  18. Amantadine increases L-DOPA-derived extracellular dopamine in the striatum of 6-hydroxydopamine-lesioned rats.

    PubMed

    Arai, Akira; Kannari, Kazuya; Shen, Huo; Maeda, Tetsuya; Suda, Toshihiro; Matsunaga, Muneo

    2003-05-16

    We investigated the effect of amantadine on L-DOPA-derived extracellular dopamine (DA) levels and aromatic L-amino acid decarboxylase (AADC) activity in the striatum of rats with nigrostriatal dopaminergic denervation by 6-hydroxydopamine (6-OHDA). Pretreatment with 30 mg/kg amantadine increased the cumulative amount of extracellular DA in the striatum of 6-OHDA-lesioned rats treated with 10 mg/kg benserazide and 50 mg/kg L-DOPA to 250% of that without amantadine (P<0.01). Under pretreatment with 10 mg/kg benserazide, AADC activity after 30 mg/kg amantadine administration was reduced to 43% of controls (P<0.01). Amantadine-induced increase in L-DOPA-derived extracellular DA provides the basis for the clinical usefulness of amantadine in combination with L-DOPA. However, the effect of amantadine on L-DOPA-derived extracellular DA may not be caused by changes in AADC activity.

  19. Comparative assessment of 6-[(18) F]fluoro-L-m-tyrosine and 6-[(18) F]fluoro-L-dopa to evaluate dopaminergic presynaptic integrity in a Parkinson's disease rat model.

    PubMed

    Becker, Guillaume; Bahri, Mohamed Ali; Michel, Anne; Hustadt, Fabian; Garraux, Gaëtan; Luxen, André; Lemaire, Christian; Plenevaux, Alain

    2017-03-10

    Because of the progressive loss of nigro-striatal dopaminergic terminals in Parkinson's disease (PD), in vivo quantitative imaging of dopamine (DA) containing neurons in animal models of PD is of critical importance in the preclinical evaluation of highly awaited disease-modifying therapies. Among existing methods, the high sensitivity of positron emission tomography (PET) is attractive to achieve that goal. The aim of this study was to perform a quantitative comparison of brain images obtained in 6-hydroxydopamine (6-OHDA) lesioned rats using two dopaminergic PET radiotracers, namely [(18) F]fluoro-3,4-dihydroxyphenyl-L-alanine ([(18) F]FDOPA) and 6-[(18) F]fluoro-L-m-tyrosine ([(18) F]FMT). Because the imaging signal is theoretically less contaminated by metabolites, we hypothesized that the latter would show stronger relationship with behavioural and post-mortem measures of striatal dopaminergic deficiency. We used a within-subject design to measure striatal [(18) F]FMT and [(18) F]FDOPA uptake in eight partially lesioned, eight fully lesioned and ten sham-treated rats. Animals were pretreated with an L-aromatic amino acid decarboxylase inhibitor. A catechol-O-methyl transferase inhibitor was also given before [(18) F]FDOPA PET. Quantitative estimates of striatal uptake were computed using conventional graphical Patlak method. Striatal dopaminergic deficiencies were measured with apomorphine-induced rotations and post-mortem striatal DA content. We observed a strong relationship between [(18) F]FMT and [(18) F]FDOPA estimates of decreased uptake in the denervated striatum using the tissue-derived uptake rate constant Kc . However, only [(18) F]FMT Kc succeeded to discriminate between the partial and the full 6-OHDA lesion and correlated well with the post-mortem striatal DA content. This study indicates that the [(18) F]FMT could be more sensitive, with respect of [(18) F]FDOPA, to investigate DA terminals loss in 6-OHDA rats, and open the way to in vivo L

  20. Acupuncture prevents 6-hydroxydopamine-induced neuronal death in the nigrostriatal dopaminergic system in the rat Parkinson's disease model.

    PubMed

    Park, Hi-Joon; Lim, Sabina; Joo, Wan-Seok; Yin, Chang-Shik; Lee, Hyang-Sook; Lee, Hye-Jung; Seo, Jung Chul; Leem, Kanghyun; Son, Yang-Sun; Kim, Youn-Jung; Kim, Chang-Ju; Kim, Yong-Sik; Chung, Joo-Ho

    2003-03-01

    Parkinson's disease (PD) is a chronic neurodegenerative disorder, and it has been suggested that treatments promoting survival and functional recovery of affected dopaminergic neurons could have a significant and long-term therapeutic value. In the present study, we investigated the neuroprotective effects of acupuncture on the nigrostriatal system in rat unilaterally lesioned with 6-hydroxydopamine (6-OHDA, 4 microg/microl, intrastriatal injection) using tyrosine hydroxylase (TH) and receptor for brain-derived neurotrophic factor, trkB, immunohistochemistries. Two weeks after the lesions were made, rats presented with asymmetry in rotational behavior (118.3 +/- 17.5 turns/h) following injection with apomorphine, a dopamine receptor agonist (0.5 mg/kg, sc). In contrast, acupunctural treatment at acupoints GB34 and LI3 was shown to significantly reduce this motor deficit (14.6 +/- 13.4 turns/h). Analysis via TH immunohistochemistry revealed a substantial loss of cell bodies in the substantia nigra (SN) (45.7% loss) and their terminals in the dorsolateral striatum ipsilateral to the 6-OHDA-induced lesion. However, acupunctural treatment resulted in the enhanced survival of dopaminergic neurons in the SN (21.4% loss) and their terminals in the dorsolateral striatum. Acupuncture also increased the expression of trkB significantly (35.6% increase) in the ipsilateral SN. In conclusion, we observed that only acupuncturing without the use of any drug has the neuroprotective effects against neuronal death in the rat PD model and these protective properties of acupuncture could be mediated by trkB.

  1. Exercise-induced rescue of tongue function without striatal dopamine sparing in a rat neurotoxin model of Parkinson disease.

    PubMed

    Ciucci, Michelle R; Schaser, Allison J; Russell, John A

    2013-09-01

    Unilateral lesions to the medial forebrain bundle with 6-hydroxydopamine (6-OHDA) lead to force and timing deficits during a complex licking task. We hypothesized that training targeting tongue force generation during licking would improve timing and force measures and also lead to striatal dopamine sparing. Nine month-old male Fisher344/Brown Norway rats were used in this experiment. Sixteen rats were in the control condition and received tongue exercise (n=8) or no exercise (n=8). Fourteen rats were in the 6-OHDA lesion condition and underwent tongue exercise (n=7) and or no exercise (n=7). Following 4 weeks of training and post-training measures, all animals underwent bilateral stimulation of the hypoglossal nerves to measure muscle contractile properties and were then transcardially perfused and brain tissues collected for immunohistochemistry to examine striatal dopamine content. Results demonstrated that exercise animals performed better for maximal force, average force, and press rate than their no-exercise counterparts, and the 6-OHDA animals that underwent exercise performed as well as the Control No Exercise group. Interestingly, there were no group differences for tetanic muscle force, despite behavioral recovery of forces. Additionally, behavioral and neurochemical analyses indicate that there were no differences in striatal dopamine. Thus, targeted exercise can improve tongue force and timing deficits related to 6-OHDA lesions and this exercise likely has a central, versus peripheral (muscle strength) mechanism. However, this mechanism is not related to sparing of striatal dopamine content.

  2. Locomotor effects of imidazoline I2-site-specific ligands and monoamine oxidase inhibitors in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway

    PubMed Central

    MacInnes, Nicholas; Duty, Susan

    2004-01-01

    The present study examined the ability of the selective imidazoline I2-site ligands 2-(-2-benzofuranyl)-2-imidazoline (2-BFI) and 2-[4,5-dihydroimidaz-2-yl]-quinoline (BU224) and selected monoamine oxidase (MAO) inhibitors to evoke locomotor activity in rats bearing a lesion of the nigrostriatal pathway. Male Sprague–Dawley rats were injected with 12.5 μg 6-hydroxydopamine (6-OHDA) into the right median forebrain bundle to induce a unilateral lesion of the nigrostriatal tract. After 6 weeks, test drugs were administered either alone or in combination with L-DOPA (L-3,4-dihydroxyphenylamine) and the circling behaviour of animals was monitored as an index of anti-Parkinsonian activity. Intraperitoneal (i.p.) administration of the irreversible MAO-B inhibitor deprenyl (20 mg kg−1) or the imidazoline I2-site ligands BU224 (14 mg kg−1) and 2-BFI (7 and 14 mg kg−1) produced significant increases in ipsiversive rotations compared to vehicle controls totaling, at the highest respective doses tested, 521±120, 131±37 and 92.5±16.3 net contraversive rotations in 30 (deprenyl) or 60 (BU224 and 2-BFI) min. In contrast, the reversible MAO-A inhibitor moclobemide (2.5–10 mg kg−1) and the reversible MAO-B inhibitor lazabemide (2.5–10 mg kg−1) failed to instigate significant rotational behaviour compared to vehicle. Coadministration of lazabemide (10 mg kg−1), moclobemide (10 mg kg−1) or 2-BFI (14 mg kg−1) with L-DOPA (20 mg kg−1) significantly increased either the duration or total number of contraversive rotations emitted over the testing period in comparison to L-DOPA alone. These data suggest that I2-specific ligands have dual effects in the 6-OHDA-lesioned rat model of Parkinson's disease; a first effect associated with an increase in activity in the intact hemisphere, probably via an increase in striatal dopamine content, and a secondary action which, through the previously documented inhibition of MAO-A and/or MAO-B, increases the availability of

  3. Comparative study of the neurotrophic effects elicited by VEGF-B and GDNF in preclinical in vivo models of Parkinson's disease.

    PubMed

    Yue, X; Hariri, D J; Caballero, B; Zhang, S; Bartlett, M J; Kaut, O; Mount, D W; Wüllner, U; Sherman, S J; Falk, T

    2014-01-31

    Vascular endothelial growth factor B (VEGF-B) has recently been shown to be a promising novel neuroprotective agent for several neurodegenerative conditions. In the current study we extended previous work on neuroprotective potential for Parkinson's disease (PD) by testing an expanded dose range of VEGF-B (1 and 10 μg) and directly comparing both neuroprotective and neurorestorative effects of VEGF-B in progressive unilateral 6-hydroxydopamine (6-OHDA) PD models to a single dose of glial cell line-derived neurotrophic factor (GDNF, 10 μg), that has been established by several groups as a standard in both preclinical PD models. In the amphetamine-induced rotational tests the treatment with 1 and 10 μg VEGF-B resulted in significantly improved motor function of 6-OHDA-lesioned rats compared to vehicle-treated 6-OHDA-lesioned rats in the neuroprotection paradigm. Both doses of VEGF-B caused an increase in tyrosine hydroxylase (TH)-positive cell and fiber count in the substantia nigra (SN) and striatum in the neuroprotective experiment. The effect size was comparable to the effects seen with GDNF. In the neurorestoration paradigm, VEGF-B injection had no significant effect in either the behavioral or the immunohistochemical analyses, whereas GDNF injection significantly improved the amphetamine-induced rotational behavior and reduced TH-positive neuronal cell loss in the SN. We also present a strong positive correlation (p=1.9e-50) of the expression of VEGF-B with nuclear-encoded mitochondrial genes involved in fatty acid metabolism in rat midbrain, pointing to the mitochondria as a site of action of VEGF-B. GDNF showed a positive correlation with nuclear-encoded mitochondrial genes that was not nearly as strong (p=0.018). VEGF-B counteracted rotenone-induced reduction of (a) fatty acid transport protein 1 and 4 levels and (b) both Akt protein and phosphorylation levels in SH-SY5Y cells. We further verified VEGF-B expression in the human SN pars compacta of healthy

  4. Impaired hepatic function and central dopaminergic denervation in a rodent model of Parkinson's disease: a self-perpetuating crosstalk?

    PubMed

    Vairetti, Mariapia; Ferrigno, Andrea; Rizzo, Vittoria; Ambrosi, Giulia; Bianchi, Alberto; Richelmi, Plinio; Blandini, Fabio; Armentero, Marie-Therese

    2012-02-01

    In Parkinson's disease (PD), aside from the central lesion, involvement of visceral organs has been proposed as part of the complex clinical picture of the disease. The issue is still poorly understood and relatively unexplored. In this study we used a classic rodent model of nigrostriatal degeneration, induced by the intrastriatal injection of 6-hydroxydopamine (6-OHDA), to investigate whether and how a PD-like central dopaminergic denervation may influence hepatic functions. Rats received an intrastriatal injection of 6-OHDA or saline (sham), and blood, cerebrospinal fluid, liver and brain samples were obtained for up to 8 weeks after surgery. Specimens were analyzed for changes in cytokine and thyroid hormone levels, as well as liver mitochondrial alterations. Hepatic mitochondria isolated from animals bearing extended nigrostriatal lesion displayed increased ROS production, while membrane potential (ΔΨ) and ATP production were significantly decreased. Reduced ATP production correlated with nigral neuronal loss. Thyroid hormone levels were significantly increased in serum of PD rats compared to sham animals while steady expression of selected cytokines was detected in all groups. Hepatic enzyme functions were comparable in all animals. Our study indicates for the first time that in a rodent model of PD, hepatic mitochondria dysfunctions arise as a consequence of nigrostriatal degeneration, and that thyroid hormone represents a key interface in this CNS-liver interaction. Liver plays a fundamental detoxifying function and a better understanding of PD-related hepatic mitochondrial alterations, which might further promote neurodegeneration, may represent an important step for the development of novel therapeutic strategies.

  5. Comparison of the SERT-selective [18F]FPBM and VMAT2-selective [18F]AV-133 radiotracers in a rat model of Parkinson’s Disease

    PubMed Central

    Wang, Julie L.; Oya, Shunichi; Parhi, Ajit K.; Lieberman, Brian P.; Ploessl, Karl; Hou, Catherine; Kung, Hank F.

    2010-01-01

    Introduction The utility of [18F]FPBM (2-(2′-((dimethylamino)methyl)-4′-(3-[18F]-fluoropropoxy)phenylthio)benzenamine), a selective serotonin transporter (SERT) tracer, and [18F]AV-133 ((+)-2-Hydroxy-3-isobutyl-9-(3-fluoropropoxy)-10-methoxy-1,2,3,4,6,7-hexahydro-11bH-benzo[a]quinolizine), a selective vesicular monoamine transporter 2 (VMAT2) tracer, were tested in the 6-hydroxydopamine (6-OHDA) unilateral lesioned rat model. Methods PET imaging of three 6-OHDA unilateral lesioned male Sprague Dawley rats (rats #1-3) were performed with [18F]FPBM and [18F]AV-133 to examine whether changes in SERT and VMAT2 binding, respectively, could be detected in the brain. The brains of the three rats were then removed and examined by in vitro autoradiography with [18F]FPBM and the dopamine transporter ligand, [125I]IPT, for confirmation. Results PET image analysis showed varying levels of SERT binding reduction (rat #1 = −11%, rat #2 = −4%, rat #3 = −43%; n = 2) and a clear and definitive loss of VMAT2 binding (rat #1 = −87%, rat #2 = −72%, and rat #3 = −91%; n = 1) in the left striatum when compared to the right (non-lesioned side) striatum. The results from PET imaging were corroborated with quantitative in vitro autoradiography. Rats treated with a selective serotonin toxin (PCA, p-chloroamphetamine) showed a significant reduction of uptake in the cortex and hypothalamus regions of the brain. Conclusion The preliminary data suggest that [18F]FPBM and [18F]AV-133 may be useful for the examination of serotonergic and dopaminergic neuron integrity, respectively, in the living brain. PMID:20447560

  6. Symptomatic and neuroprotective effects following activation of nigral group III metabotropic glutamate receptors in rodent models of Parkinson's disease

    PubMed Central

    Austin, PJ; Betts, MJ; Broadstock, M; O'Neill, MJ; Mitchell, SN; Duty, S

    2010-01-01

    Background and purpose: Increased glutamatergic innervation of the substantia nigra pars reticulata (SNpr) and pars compacta (SNpc) may contribute to the motor deficits and neurodegeneration, respectively, in Parkinson's disease (PD). This study aimed to establish whether activation of pre-synaptic group III metabotropic glutamate (mGlu) receptors reduced glutamate release in the SN, and provided symptomatic or neuroprotective relief in animal models of PD. Experimental approach: Broad-spectrum group III mGlu receptor agonists, O-phospho-l-serine (l-SOP) and l-2-amino-4-phosphonobutyrate (l-AP4), were assessed for their ability to inhibit KCl-evoked [3H]-d-aspartate release in rat nigral prisms or inhibit KCl-evoked endogenous glutamate release in the SNpr in vivo using microdialysis. Reversal of akinesia in reserpine-treated rats was assessed following intranigral injection of l-SOP and l-AP4. Finally, the neuroprotective effect of 7 days' supra-nigral treatment with l-AP4 was examined in 6-hydroxydopamine (6-OHDA)-lesioned rats. Key results: l-SOP and l-AP4 inhibited [3H]-d-aspartate release by 33 and 44% respectively. These effects were blocked by the selective group III mGlu antagonist (RS)-α-cyclopropyl-4-phosphonophenylglycine (CPPG). l-SOP also reduced glutamate release in the SNpr in vivo by 48%. Injection of l-SOP and l-AP4 into the SNpr reversed reserpine-induced akinesia. Following administration above the SNpc, l-AP4 provided neurochemical, histological and functional protection against 6-OHDA lesion of the nigrostriatal tract. Pretreatment with CPPG inhibited these effects. Conclusions and implications: These findings highlight group III mGlu receptors in the SN as potential targets for providing both symptomatic and neuroprotective relief in PD, and indicate that inhibition of glutamate release in the SN may underlie these effects. PMID:20649576

  7. Continuous and intermittent nicotine treatment reduces L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias in a rat model of Parkinson's disease.

    PubMed

    Bordia, Tanuja; Campos, Carla; Huang, Luping; Quik, Maryka

    2008-10-01

    The development of abnormal involuntary movements (AIMs) or dyskinesias is a serious complication of L-DOPA [L-3,4-dihydroxyphenylalanine] therapy for Parkinson's disease. Our previous work had shown that intermittent nicotine dosing reduced L-DOPA-induced dyskinetic-like movements in nonhuman primates. A readily available nicotine formulation is the nicotine patch, which provides a constant source of nicotine. However, constant nicotine administration more readily desensitizes nicotinic receptors, to possibly yield alternate behavioral outcomes. Therefore, we investigated whether constant nicotine administration reduced L-DOPA-induced AIMs in a rat parkinsonian model, with results compared with those with intermittent nicotine dosing. Rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion were exposed to either intermittent (drinking water) or constant (minipump) nicotine for > or = 2 weeks at doses that yielded plasma levels of the nicotine metabolite cotinine similar to those in smokers. The rats were next treated with L-DOPA/benserazide (8 or 12 mg/kg/15 mg/kg) for > or = 3 weeks to allow for the development of AIMs, with nicotine treatment continued. Both modes of nicotine administration resulted in > or = 50% decline in L-DOPA-induced AIMs. Nicotine treatment also significantly reduced AIMs in L-DOPA-primed rats using either dosing regimen, whereas nicotine removal led to an increase in AIMs. There was no effect of nicotine on various measures of motor performance in 6-OHDA-lesioned rats. In summary, nicotine provided either via the drinking water or minipump reduced L-DOPA-induced AIMs in a rat model of Parkinson's disease. These results suggest that either intermittent or constant nicotine treatment may be useful in the treatment of L-DOPA-induced dyskinesias in patients with Parkinson's disease.

  8. Microglial Cells Are Involved in the Susceptibility of NADPH Oxidase Knockout Mice to 6-Hydroxy-Dopamine-Induced Neurodegeneration

    PubMed Central

    Hernandes, Marina S.; Santos, Graziella D. R.; Café-Mendes, Cecília C.; Lima, Larissa S.; Scavone, Cristoforo; Munhoz, Carolina D.; Britto, Luiz R. G.

    2013-01-01

    We explored the impact of Nox-2 in modulating inflammatory-mediated microglial responses in the 6-hydroxydopamine (6-OHDA)-induced Parkinson’s disease (PD) model. Nox1 and Nox2 gene expression were found to increase in striatum, whereas a marked increase of Nox2 expression was observed in substantia nigra (SN) of wild-type (wt) mice after PD induction. Gp91phox-/- 6-OHDA-lesioned mice exhibited a significant reduction in the apomorphine-induced rotational behavior, when compared to wt mice. Immunolabeling assays indicated that striatal 6-OHDA injections reduced the number of dopaminergic (DA) neurons in the SN of wt mice. In gp91phox-/- 6-OHDA-lesioned mice the DA degeneration was negligible, suggesting an involvement of Nox in 6-OHDA-mediated SN degeneration. Gp91phox-/- 6-OHDA-lesioned mice treated with minocycline, a tetracycline derivative that exerts multiple anti-inflammatory effects, including microglial inhibition, exhibited increased apomorphine-induced rotational behavior and degeneration of DA neurons after 6-OHDA injections. The same treatment also increased TNF-α release and potentiated NF-κB activation in the SN of gp91phox-/--lesioned mice. Our results demonstrate for the first time that inhibition of microglial cells increases the susceptibility of gp91phox-/- 6-OHDA lesioned mice to develop PD. Blockade of microglia leads to NF-κB activation and TNF-α release into the SN of gp91phox-/- 6-OHDA lesioned mice, a likely mechanism whereby gp91phox-/- 6-OHDA lesioned mice may be more susceptible to develop PD after microglial cell inhibition. Nox2 adds an essential level of regulation to signaling pathways underlying the inflammatory response after PD induction. PMID:24086556

  9. Partial lesion of dopamine neurons of rat substantia nigra impairs conditioned place aversion but spares conditioned place preference.

    PubMed

    Lima, Bernardo F C; Ramos, Daniele C; Barbiero, Janaína K; Pulido, Laura; Redgrave, Peter; Robinson, Donita L; Gómez-A, Alexander; Da Cunha, Claudio

    2017-05-04

    Midbrain dopamine neurons play critical roles in reward- and aversion-driven associative learning. However, it is not clear whether they do this by a common mechanism or by separate mechanisms that can be dissociated. In the present study we addressed this question by testing whether a partial lesion of the dopamine neurons of the rat SNc has comparable effects on conditioned place preference (CPP) learning and conditioned place aversion (CPA) learning. Partial lesions of dopamine neurons in the rat substantia nigra pars compacta (SNc) induced by bilateral intranigral infusion of 6-hydroxydopamine (6-OHDA, 3μg/side) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 200μg/side) impaired learning of conditioned place aversion (CPA) without affecting conditioned place preference (CPP) learning. Control experiments demonstrated that these lesions did not impair motor performance and did not alter the hedonic value of the sucrose and quinine. The number of dopamine neurons in the caudal part of the SNc positively correlated with the CPP scores of the 6-OHDA rats and negatively correlated with CPA scores of the SHAM rats. In addition, the CPA scores of the 6-OHDA rats positively correlated with the tissue content of striatal dopamine. Insomuch as reward-driven learning depends on an increase in dopamine release by nigral neurons, these findings show that this mechanism is functional even in rats with a partial lesion of the SNc. On the other hand, if aversion-driven learning depends on a reduction of extracellular dopamine in the striatum, the present study suggests that this mechanism is no longer functional after the partial SNc lesion.

  10. The metabotropic glutamate receptor 4-positive allosteric modulator VU0364770 produces efficacy alone and in combination with L-DOPA or an adenosine 2A antagonist in preclinical rodent models of Parkinson's disease.

    PubMed

    Jones, Carrie K; Bubser, Michael; Thompson, Analisa D; Dickerson, Jonathan W; Turle-Lorenzo, Nathalie; Amalric, Marianne; Blobaum, Anna L; Bridges, Thomas M; Morrison, Ryan D; Jadhav, Satyawan; Engers, Darren W; Italiano, Kimberly; Bode, Jacob; Daniels, J Scott; Lindsley, Craig W; Hopkins, Corey R; Conn, P Jeffrey; Niswender, Colleen M

    2012-02-01

    Parkinson's disease (PD) is a debilitating neurodegenerative disorder associated with severe motor impairments caused by the loss of dopaminergic innervation of the striatum. Previous studies have demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGlu₄), including N-phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxamide, can produce antiparkinsonian-like effects in preclinical models of PD. However, these early mGlu₄ PAMsexhibited unsuitable physiochemical properties for systemic dosing, requiring intracerebroventricular administration and limiting their broader utility as in vivo tools to further understand the role of mGlu₄ in the modulation of basal ganglia function relevant to PD. In the present study, we describe the pharmacologic characterization of a systemically active mGlu₄ PAM, N-(3-chlorophenyl)picolinamide (VU0364770), in several rodent PD models. VU0364770 showed efficacy alone or when administered in combination with L-DOPA or an adenosine 2A (A2A) receptor antagonist currently in clinical development (preladenant). When administered alone, VU0364770 exhibited efficacy in reversing haloperidol-induced catalepsy, forelimb asymmetry-induced by unilateral 6-hydroxydopamine (6-OHDA) lesions of the median forebrain bundle, and attentional deficits induced by bilateral 6-OHDA nigrostriatal lesions in rats. In addition, VU0364770 enhanced the efficacy of preladenant to reverse haloperidol-induced catalepsy when given in combination. The effects of VU0364770 to reverse forelimb asymmetry were also potentiated when the compound was coadministered with an inactive dose of L-DOPA, suggesting that mGlu₄ PAMs may provide L-DOPA-sparing activity. The present findings provide exciting support for the potential role of selective mGlu₄ PAMs as a novel approach for the symptomatic treatment of PD and a possible augmentation strategy with either L-DOPA or A2A antagonists.

  11. The Metabotropic Glutamate Receptor 4-Positive Allosteric Modulator VU0364770 Produces Efficacy Alone and in Combination with l-DOPA or an Adenosine 2A Antagonist in Preclinical Rodent Models of Parkinson's Disease

    PubMed Central

    Jones, Carrie K.; Bubser, Michael; Thompson, Analisa D.; Dickerson, Jonathan W.; Turle-Lorenzo, Nathalie; Amalric, Marianne; Blobaum, Anna L.; Bridges, Thomas M.; Morrison, Ryan D.; Jadhav, Satyawan; Engers, Darren W.; Italiano, Kimberly; Bode, Jacob; Daniels, J. Scott; Lindsley, Craig W.; Hopkins, Corey R.; Conn, P. Jeffrey

    2012-01-01

    Parkinson's disease (PD) is a debilitating neurodegenerative disorder associated with severe motor impairments caused by the loss of dopaminergic innervation of the striatum. Previous studies have demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGlu4), including N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide, can produce antiparkinsonian-like effects in preclinical models of PD. However, these early mGlu4 PAMs exhibited unsuitable physiochemical properties for systemic dosing, requiring intracerebroventricular administration and limiting their broader utility as in vivo tools to further understand the role of mGlu4 in the modulation of basal ganglia function relevant to PD. In the present study, we describe the pharmacologic characterization of a systemically active mGlu4 PAM, N-(3-chlorophenyl)picolinamide (VU0364770), in several rodent PD models. VU0364770 showed efficacy alone or when administered in combination with l-DOPA or an adenosine 2A (A2A) receptor antagonist currently in clinical development (preladenant). When administered alone, VU0364770 exhibited efficacy in reversing haloperidol-induced catalepsy, forelimb asymmetry-induced by unilateral 6-hydroxydopamine (6-OHDA) lesions of the median forebrain bundle, and attentional deficits induced by bilateral 6-OHDA nigrostriatal lesions in rats. In addition, VU0364770 enhanced the efficacy of preladenant to reverse haloperidol-induced catalepsy when given in combination. The effects of VU0364770 to reverse forelimb asymmetry were also potentiated when the compound was coadministered with an inactive dose of l-DOPA, suggesting that mGlu4 PAMs may provide l-DOPA-sparing activity. The present findings provide exciting support for the potential role of selective mGlu4 PAMs as a novel approach for the symptomatic treatment of PD and a possible augmentation strategy with either l-DOPA or A2A antagonists. PMID:22088953

  12. Effects of Postnatal Enriched Environment in a Model of Parkinson's Disease in Adult Rats.

    PubMed

    Jungling, Adel; Reglodi, Dora; Karadi, Zsofia Nozomi; Horvath, Gabor; Farkas, Jozsef; Gaszner, Balazs; Tamas, Andrea

    2017-02-14

    Environmental enrichment is a widespread neuroprotective strategy during development and also in the mature nervous system. Several research groups have described that enriched environment in adult rats has an impact on the progression of Parkinson's disease (PD). The aim of our present study was to examine the effects of early, postnatal environmental enrichment after 6-hydroxydopamine-induced (6-OHDA) lesion of the substantia nigra in adulthood. Newborn Wistar rats were divided into control and enriched groups according to their environmental conditions. For environmental enrichment, during the first five postnatal weeks animals were placed in larger cages and exposed to intensive complex stimuli. Dopaminergic cell loss, and hypokinetic and asymmetrical signs were evaluated after inducing PD with unilateral injections of 6-OHDA in three-month-old animals. Treatment with 6-OHDA led to a significant cell loss in the substantia nigra of control animals, however, postnatal enriched circumstances could rescue the dopaminergic cells. Although there was no significant difference in the percentage of surviving cells between 6-OHDA-treated control and enriched groups, the slightly less dopaminergic cell loss in the enriched group compared to control animals resulted in less severe hypokinesia. Our investigation is the first to provide evidence for the neuroprotective effect of postnatal enriched environment in PD later in life.

  13. Effects of Postnatal Enriched Environment in a Model of Parkinson’s Disease in Adult Rats

    PubMed Central

    Jungling, Adel; Reglodi, Dora; Karadi, Zsofia Nozomi; Horvath, Gabor; Farkas, Jozsef; Gaszner, Balazs; Tamas, Andrea

    2017-01-01

    Environmental enrichment is a widespread neuroprotective strategy during development and also in the mature nervous system. Several research groups have described that enriched environment in adult rats has an impact on the progression of Parkinson’s disease (PD). The aim of our present study was to examine the effects of early, postnatal environmental enrichment after 6-hydroxydopamine-induced (6-OHDA) lesion of the substantia nigra in adulthood. Newborn Wistar rats were divided into control and enriched groups according to their environmental conditions. For environmental enrichment, during the first five postnatal weeks animals were placed in larger cages and exposed to intensive complex stimuli. Dopaminergic cell loss, and hypokinetic and asymmetrical signs were evaluated after inducing PD with unilateral injections of 6-OHDA in three-month-old animals. Treatment with 6-OHDA led to a significant cell loss in the substantia nigra of control animals, however, postnatal enriched circumstances could rescue the dopaminergic cells. Although there was no significant difference in the percentage of surviving cells between 6-OHDA-treated control and enriched groups, the slightly less dopaminergic cell loss in the enriched group compared to control animals resulted in less severe hypokinesia. Our investigation is the first to provide evidence for the neuroprotective effect of postnatal enriched environment in PD later in life. PMID:28216584

  14. Image-based numerical modeling of HIFU-induced lesions

    NASA Astrophysics Data System (ADS)

    Almekkaway, Mohamed K.; Shehata, Islam A.; Haritonova, Alyona; Ballard, John; Casper, Andrew; Ebbini, Emad

    2017-03-01

    Atherosclerosis is a chronic vascular disease affecting large and medium sized arteries. Several treatment options are already available for treatment of this disease. Targeting atherosclerotic plaques by high intensity focused ultrasound (HIFU) using dual mode ultrasound arrays (DMUA) was recently introduced in literature. We present a finite difference time domain (FDTD) simulation modeling of the wave propagation in heterogeneous medium from the surface of a 3.5 MHz array prototype with 32-elements. After segmentation of the ultrasound image obtained for the treatment region in-vivo, we integrated this anatomical information into our simulation to account for different parameters that may be caused by these multi-region anatomical complexities. The simulation program showed that HIFU was able to induce damage in the prefocal region instead of the target area. The HIFU lesions, as predicted by our simulation, were well correlated with the actual damage detected in histology.

  15. CD24 expression does not affect dopamine neuronal survival in a mouse model of Parkinson's disease

    PubMed Central

    Hayat, Shaista; Carnwath, Tom; Garas, Shaady; Sleeman, Jonathan P.; Barker, Roger A.

    2017-01-01

    Parkinson’s disease (PD) is a progressive neurodegenerative condition that is characterised by the loss of specific populations of neurons in the brain. The mechanisms underlying this selective cell death are unknown but by using laser capture microdissection, the glycoprotein, CD24 has been identified as a potential marker of the populations of cells that are affected in PD. Using in situ hybridization and immunohistochemistry on sections of mouse brain, we confirmed that CD24 is robustly expressed by many of these subsets of cells. To determine if CD24 may have a functional role in PD, we modelled the dopamine cell loss of PD in Cd24 mutant mice using striatal delivery of the neurotoxin 6-OHDA. We found that Cd24 mutant mice have an anatomically normal dopamine system and that this glycoprotein does not modulate the lesion effects of 6-OHDA delivered into the striatum. We then undertook in situ hybridization studies on sections of human brain and found—as in the mouse brain—that CD24 is expressed by many of the subsets of the cells that are vulnerable in PD, but not those of the midbrain dopamine system. Finally, we sought to determine if CD24 is required for the neuroprotective effect of Glial cell-derived neurotrophic factor (GDNF) on the dopaminergic nigrostriatal pathway. Our results indicate that in the absence of CD24, there is a reduction in the protective effects of GDNF on the dopaminergic fibres in the striatum, but no difference in the survival of the cell bodies in the midbrain. While we found no obvious role for CD24 in the normal development and maintenance of the dopaminergic nigrostriatal system in mice, it may have a role in mediating the neuroprotective aspects of GDNF in this system. PMID:28182766

  16. L-DOPA-induced dyskinesia in the intrastriatal 6-hydroxydopamine model of parkinson's disease: relation to motor and cellular parameters of nigrostriatal function.

    PubMed

    Winkler, Christian; Kirik, Deniz; Björklund, Anders; Cenci, M Angela

    2002-07-01

    In order to assess the role of striatal dopamine (DA) afferents in L-DOPA-induced dyskinesia, we have studied a large series of rats sustaining 2, 3, or 4 unilateral injections of 6-hydroxydopamine (6-OHDA) in the lateral striatum. This type of lesion produced a dose-dependent depletion of DA fibers in the caudate-putamen, which was most pronounced in the lateral aspects of this structure. An additional group of rats was injected with 6-OHDA in the medial forebrain bundle to obtain complete DA denervation on one side of the brain. During a course of chronic L-DOPA treatment, rats with intrastriatal 6-OHDA lesions developed abnormal involuntary movements (AIMs), which mapped onto striatal domains exhibiting at least approximately 90% denervation, as judged by DA transporter autoradiography. The denervated areas showed local upregulation of preproenkephalin and prodynorphin mRNA, and FosB-like immunoreactivity, which were highly correlated with the rats' AIM scores. When compared to completely DA-denervated animals, the rats with intrastriatal 6-OHDA lesions showed an overall lower incidence, lower severity and different topographic distribution of AIMs. The involvement of proximal limb and axial muscles in the abnormal movements was proportional to the spreading of the lesion from lateral towards medial aspects of the caudate-putamen. Locomotive AIMs were only seen in rats with complete lesions, but not in any of the animals with intrastriatal 6-OHDA (which showed > 5% DA fiber sparing in the medial striatum). Intrastriatally 6-OHDA-lesioned rats had a larger therapeutic window for L-DOPA than did rats with complete bundle lesions, since they exhibited an overall lower predisposition to dyskinesia but a similar degree of drug-induced motor improvement in a test of forelimb stepping. Our results are the first to demonstrate that selective and partial DA denervation in the sensorimotor part of the striatum can confer cellular and behavioral supersensitivity to L

  17. On the role of P2X(7) receptors in dopamine nerve cell degeneration in a rat model of Parkinson's disease: studies with the P2X(7) receptor antagonist A-438079.

    PubMed

    Marcellino, Daniel; Suárez-Boomgaard, Diana; Sánchez-Reina, María Dolores; Aguirre, José A; Yoshitake, Takashi; Yoshitake, Shimako; Hagman, Beth; Kehr, Jan; Agnati, Luigi F; Fuxe, Kjell; Rivera, Alicia

    2010-06-01

    The role of the ATP-gated receptor, P2X(7), has been evaluated in the unilateral 6-OHDA rat model of Parkinson's disease using the P2X(7) competitive antagonist A-438079. Nigral P2X(7) immunoreactivity was mainly located in microglia but also in astroglia. A-438079 partially but significantly prevented the 6-OHDA-induced depletion of striatal DA stores. However, this was not associated with a reduction of DA cell loss. Blockade of P2X(7) receptors may represent a novel protective strategy for striatal DA terminals in Parkinson's disease and warrants further future investigation.

  18. Targeting the D1-N-methyl-D-aspartate receptor complex reduces L-dopa-induced dyskinesia in 6-hydroxydopamine-lesioned Parkinson's rats.

    PubMed

    Song, Lu; Zhang, Zhanzhao; Hu, Rongguo; Cheng, Jie; Li, Lin; Fan, Qinyi; Wu, Na; Gan, Jing; Zhou, Mingzhu; Liu, Zhenguo

    2016-01-01

    L-3,4-dihydroxyphenylalanine (L-dopa) remains the most effective therapy for Parkinson's disease (PD), but its long-term administration is associated with the development of debilitating motor complications known as L-dopa-induced dyskinesia (LID). Enhanced function of dopamine D1 receptor (D1R) and N-methyl-D-aspartate receptor (NMDAR) is believed to participate in the pathogenesis of LID. Given the existence of physical and functional interactions between D1R and NMDAR, we explored the effects of uncoupling D1R and NMDA GluN1 (GluN1) interaction on LID by using the Tat-conjugated interfering peptide (Tat-D1-t2). In this study, we demonstrated in 6-hydroxydopamine (6-OHDA)-lesioned PD rat model that intrastriatal injection of Tat-D1-t2 alleviated dyskinetic behaviors and downregulated the phosphorylation of DARPP-32 at Thr34 induced by levodopa. Moreover, we also showed intrastriatal administration of Tat-D1-t2 elicited alterations in membranous GluN1 and D1R expression. These findings indicate that D1R/GluN1 complexes may be a molecular target with therapeutic potential for the treatment of dyskinesia in Parkinson's patients.

  19. Spontaneous feline mammary intraepithelial lesions as a model for human estrogen receptor- and progesterone receptor-negative breast lesions

    PubMed Central

    2010-01-01

    Background Breast cancer is the most frequently diagnosed cancer in women. Intraepithelial lesions (IELs), such as usual ductal hyperplasia (UH), atypical ductal hyperplasia (ADH), and ductal carcinoma in situ (DCIS) are risk factors that predict a woman's chance of developing invasive breast cancer. Therefore, a comparative study that establishes an animal model of pre-invasive lesions is needed for the development of preventative measures and effective treatment for both mammary IELs and tumors. The purpose of this study was to characterize the histologic and molecular features of feline mammary IELs and compare them with those in women. Methods Formalin-fixed, paraffin-embedded specimens (n = 205) from 203 female cats with clinical mammary disease were retrieved from the archives of the Purdue University Animal Disease Diagnostic Laboratory and Veterinary Teaching Hospital (West Lafayette, IN), and the Department of Pathology and Veterinary Clinic, School of Veterinary Medicine (Sassari, Italy). Histologic sections, stained with hematoxylin and eosin (HE), were evaluated for the presence of IELs in tissue adjacent to excised mammary tumors. Lesions were compared to those of humans. Immunohistochemistry for estrogen receptor (ER-alpha), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2/neu) and Ki-67 was performed in IELs and adjacent tumor tissues. Results Intraepithelial lesions were found in 57 of 203 (28%) feline mammary specimens and were categorized as UH (27%), ADH (29%), and DCIS (44%). Most IELs with atypia (ADH and DCIS) were associated with mammary cancer (91%), whereas UH was associated with benign lesions in 53% of cases. Feline IELs were remarkably similar to human IELs. No ER or PR immunoreactivity was detected in intermediate-grade or high-grade DCIS or their associated malignant tumors. HER-2 protein overexpression was found in 27% of IELs. Conclusion The remarkable similarity of feline mammary IELs to those of humans

  20. Isolated development of inner (wall) caries like lesions in a bacterial-based in vitro model.

    PubMed

    Diercke, K; Lussi, A; Kersten, T; Seemann, R

    2009-12-01

    The study conducted in a bacterial-based in vitro caries model aimed to determine whether typical inner secondary caries lesions can be detected at cavity walls of restorations with selected gap widths when the development of outer lesions is inhibited. Sixty bovine tooth specimens were randomly assigned to the following groups: test group 50 (TG50; gap, 50 microm), test group 100 (TG100; gap, 100 microm), test group 250 (TG250; gap, 250 microm) and a control group (CG; gap, 250 microm). The outer tooth surface of the test group specimens was covered with an acid-resistant varnish to inhibit the development of an outer caries lesion. After incubation in the caries model, the area of demineralization at the cavity wall was determined by confocal laser scanning microscopy. All test group specimens demonstrated only wall lesions. The CG specimens developed outer and wall lesions. The TG250 specimens showed significantly less wall lesion area compared to the CG (p < 0.05). In the test groups, a statistically significant increase (p < 0.05) in lesion area could be detected in enamel between TG50 and TG250 and in dentine between TG50 and TG100. In conclusion, the inner wall lesions of secondary caries can develop without the presence of outer lesions and therefore can be regarded as an entity on their own. The extent of independently developed wall lesions increased with gap width in the present setting.

  1. Alterations of BDNF and trkB mRNA Expression in the 6-Hydroxydopamine-Induced Model of Preclinical Stages of Parkinson’s Disease: An Influence of Chronic Pramipexole in Rats

    PubMed Central

    Berghauzen-Maciejewska, Klemencja; Wardas, Jadwiga; Kosmowska, Barbara; Głowacka, Urszula; Kuter, Katarzyna; Ossowska, Krystyna

    2015-01-01

    Our recent study has indicated that a moderate lesion of the mesostriatal and mesolimbic pathways in rats, modelling preclinical stages of Parkinson’s disease, induces a depressive-like behaviour which is reversed by chronic treatment with pramipexole. The purpose of the present study was to examine the role of brain derived neurotrophic factor (BDNF) signalling in the aforementioned model of depression. Therefore, we investigated the influence of 6-hydoxydopamine (6-OHDA) administration into the ventral region of the caudate-putamen on mRNA levels of BDNF and tropomyosin-related kinase B (trkB) receptor. The BDNF and trkB mRNA levels were determined in the nigrostriatal and limbic structures by in situ hybridization 2 weeks after the operation. Pramipexole (1 mg/kg sc twice a day) and imipramine (10 mg/kg ip once a day) were injected for 2 weeks. The lesion lowered the BDNF and trkB mRNA levels in the hippocampus [CA1, CA3 and dentate gyrus (DG)] and amygdala (basolateral/lateral) as well as the BDNF mRNA content in the habenula (medial/lateral). The lesion did not influence BDNF and trkB expression in the caudate-putamen, substantia nigra, nucleus accumbens (shell and core) and ventral tegmental area (VTA). Chronic imipramine reversed the lesion-induced decreases in BDNF mRNA in the DG. Chronic pramipexole increased BDNF mRNA, but decreased trkB mRNA in the VTA in lesioned rats. Furthermore, it reduced BDNF and trkB mRNA expression in the shell and core of the nucleus accumbens, BDNF mRNA in the amygdala and trkB mRNA in the caudate-putamen in these animals. The present study indicates that both the 6-OHDA-induced dopaminergic lesion and chronic pramipexole influence BDNF signalling in limbic structures, which may be related to their pro-depressive and antidepressant activity in rats, respectively. PMID:25739024

  2. Alterations of BDNF and trkB mRNA expression in the 6-hydroxydopamine-induced model of preclinical stages of Parkinson's disease: an influence of chronic pramipexole in rats.

    PubMed

    Berghauzen-Maciejewska, Klemencja; Wardas, Jadwiga; Kosmowska, Barbara; Głowacka, Urszula; Kuter, Katarzyna; Ossowska, Krystyna

    2015-01-01

    Our recent study has indicated that a moderate lesion of the mesostriatal and mesolimbic pathways in rats, modelling preclinical stages of Parkinson's disease, induces a depressive-like behaviour which is reversed by chronic treatment with pramipexole. The purpose of the present study was to examine the role of brain derived neurotrophic factor (BDNF) signalling in the aforementioned model of depression. Therefore, we investigated the influence of 6-hydoxydopamine (6-OHDA) administration into the ventral region of the caudate-putamen on mRNA levels of BDNF and tropomyosin-related kinase B (trkB) receptor. The BDNF and trkB mRNA levels were determined in the nigrostriatal and limbic structures by in situ hybridization 2 weeks after the operation. Pramipexole (1 mg/kg sc twice a day) and imipramine (10 mg/kg ip once a day) were injected for 2 weeks. The lesion lowered the BDNF and trkB mRNA levels in the hippocampus [CA1, CA3 and dentate gyrus (DG)] and amygdala (basolateral/lateral) as well as the BDNF mRNA content in the habenula (medial/lateral). The lesion did not influence BDNF and trkB expression in the caudate-putamen, substantia nigra, nucleus accumbens (shell and core) and ventral tegmental area (VTA). Chronic imipramine reversed the lesion-induced decreases in BDNF mRNA in the DG. Chronic pramipexole increased BDNF mRNA, but decreased trkB mRNA in the VTA in lesioned rats. Furthermore, it reduced BDNF and trkB mRNA expression in the shell and core of the nucleus accumbens, BDNF mRNA in the amygdala and trkB mRNA in the caudate-putamen in these animals. The present study indicates that both the 6-OHDA-induced dopaminergic lesion and chronic pramipexole influence BDNF signalling in limbic structures, which may be related to their pro-depressive and antidepressant activity in rats, respectively.

  3. Image-based Modeling and Characterization of RF Ablation Lesions in Cardiac Arrhythmia Therapy.

    PubMed

    Linte, Cristian A; Camp, Jon J; Rettmann, Maryam E; Holmes, David R; Robb, Richard A

    2013-02-09

    In spite of significant efforts to enhance guidance for catheter navigation, limited research has been conducted to consider the changes that occur in the tissue during ablation as means to provide useful feedback on the progression of therapy delivery. We propose a technique to visualize lesion progression and monitor the effects of the RF energy delivery using a surrogate thermal ablation model. The model incorporates both physical and physiological tissue parameters, and uses heat transfer principles to estimate temperature distribution in the tissue and geometry of the generated lesion in near real time. The ablation model has been calibrated and evaluated using ex vivo beef muscle tissue in a clinically relevant ablation protocol. To validate the model, the predicted temperature distribution was assessed against that measured directly using fiberoptic temperature probes inserted in the tissue. Moreover, the model-predicted lesions were compared to the lesions observed in the post-ablation digital images. Results showed an agreement within 5°C between the model-predicted and experimentally measured tissue temperatures, as well as comparable predicted and observed lesion characteristics and geometry. These results suggest that the proposed technique is capable of providing reasonably accurate and sufficiently fast representations of the created RF ablation lesions, to generate lesion maps in near real time. These maps can be used to guide the placement of successive lesions to ensure continuous and enduring suppression of the arrhythmic pathway.

  4. Image-based modeling and characterization of RF ablation lesions in cardiac arrhythmia therapy

    NASA Astrophysics Data System (ADS)

    Linte, Cristian A.; Camp, Jon J.; Rettmann, Maryam E.; Holmes, David R.; Robb, Richard A.

    2013-03-01

    In spite of significant efforts to enhance guidance for catheter navigation, limited research has been conducted to consider the changes that occur in the tissue during ablation as means to provide useful feedback on the progression of therapy delivery. We propose a technique to visualize lesion progression and monitor the effects of the RF energy delivery using a surrogate thermal ablation model. The model incorporates both physical and physiological tissue parameters, and uses heat transfer principles to estimate temperature distribution in the tissue and geometry of the generated lesion in near real time. The ablation model has been calibrated and evaluated using ex vivo beef muscle tissue in a clinically relevant ablation protocol. To validate the model, the predicted temperature distribution was assessed against that measured directly using fiberoptic temperature probes inserted in the tissue. Moreover, the model-predicted lesions were compared to the lesions observed in the post-ablation digital images. Results showed an agreement within 5°C between the model-predicted and experimentally measured tissue temperatures, as well as comparable predicted and observed lesion characteristics and geometry. These results suggest that the proposed technique is capable of providing reasonably accurate and sufficiently fast representations of the created RF ablation lesions, to generate lesion maps in near real time. These maps can be used to guide the placement of successive lesions to ensure continuous and enduring suppression of the arrhythmic pathway.

  5. Repeated administration of the monoamine reuptake inhibitor BTS 74 398 induces ipsilateral circling in the 6-hydroxydopamine lesioned rat without sensitizing motor behaviours.

    PubMed

    Lane, E L; Cheetham, S C; Jenner, P

    2005-01-01

    BTS 74 398 (1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-(3-diaminethylaminopropylthio)ethanone monocitrate) is a monoamine reuptake inhibitor that reverses motor deficits in MPTP-treated (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) common marmosets without provoking established dyskinesia. However, it is not known whether BTS 74 398 primes the basal ganglia for dyskinesia induction. In this study, the ability of BTS 74 398 to sensitize 6-hydroxydopamine (6-OHDA)-lesioned rats for the production of abnormal motor behaviours and the induction of striatal DeltaFosB were determined in comparison with l-3,4-dihydroxyphenylalanine methyl ester (L-dopa). Acute administration of BTS 74 398 induced a dose-dependent ipsilateral circling response in unilaterally 6-OHDA-lesioned rats whereas L-dopa produced dose-dependent contraversive rotation. The ipsilateral circling response to BTS 74 398 did not alter during 21 days of administration. In contrast, L-dopa treatment for 21 days caused a marked increase in rotational response. Repeated administration of both L-dopa and BTS 74 398 increased general motor activity and stereotypic behaviour. In L-dopa-treated rats, orolingual, locomotive, forelimb and axial abnormal movements developed whereas BTS 74 398 produced only locomotion with a side bias but no other abnormal movements. Sensitization of circling responses and the development of abnormal movements in 6-OHDA-lesioned rats have been associated with the potential of dopaminergic drugs to induce dyskinesia. Furthermore, striatal DeltaFosB immunoreactivity, shown to correlate with dyskinesia induction, was increased by L-dopa but was unaffected by repeated BTS 74 398 administration. The lack of such changes following repeated BTS 74 398 treatment suggests that it may be an effective antiparkinsonian therapy that is unlikely to produce involuntary movements.

  6. Neuroprotective Effect of the Marine-Derived Compound 11-Dehydrosinulariolide through DJ-1-Related Pathway in In Vitro and In Vivo Models of Parkinson’s Disease

    PubMed Central

    Feng, Chien-Wei; Hung, Han-Chun; Huang, Shi-Ying; Chen, Chun-Hong; Chen, Yun-Ru; Chen, Chun-Yu; Yang, San-Nan; Wang, Hui-Min David; Sung, Ping-Jyun; Sheu, Jyh-Horng; Tsui, Kuan-Hao; Chen, Wu-Fu; Wen, Zhi-Hong

    2016-01-01

    Parkinson’s disease (PD) is a neurodegenerative disorder characterized by tremor, rigidity, bradykinesia, and gait impairment. In a previous study, we found that the marine-derived compound 11-dehydrosinulariolide (11-de) upregulates the Akt/PI3K pathway to protect cells against 6-hydroxydopamine (6-OHDA)-mediated damage. In the present study, SH-SY5Y, zebrafish and rats were used to examine the therapeutic effect of 11-de. The results revealed the mechanism by which 11-de exerts its therapeutic effect: the compound increases cytosolic or mitochondrial DJ-1 expression, and then activates the downstream Akt/PI3K, p-CREB, and Nrf2/HO-1 pathways. Additionally, we found that 11-de could reverse the 6-OHDA-induced downregulation of total swimming distance in a zebrafish model of PD. Using a rat model of PD, we showed that a 6-OHDA-induced increase in the number of turns, and increased time spent by rats on the beam, could be reversed by 11-de treatment. Lastly, we showed that 6-OHDA-induced attenuation in tyrosine hydroxylase (TH), a dopaminergic neuronal marker, in zebrafish and rat models of PD could also be reversed by treatment with 11-de. Moreover, the patterns of DJ-1 expression observed in this study in the zebrafish and rat models of PD corroborated the trend noted in previous in vitro studies. PMID:27763504

  7. Pituitary adenylate cyclase-activating polypeptide (PACAP) has a neuroprotective function in dopamine-based neurodegeneration in rat and snail parkinsonian models

    PubMed Central

    Kiss, Tibor; Jungling, Adel

    2017-01-01

    ABSTRACT Pituitary adenylate cyclase-activating polypeptide (PACAP) rescues dopaminergic neurons from neurodegeneration and improves motor changes induced by 6-hydroxy-dopamine (6-OHDA) in rat parkinsonian models. Recently, we investigated the molecular background of the neuroprotective effect of PACAP in dopamine (DA)-based neurodegeneration using rotenone-induced snail and 6-OHDA-induced rat models of Parkinson's disease. Behavioural activity, monoamine (DA and serotonin), metabolic enzyme (S-COMT, MB-COMT and MAO-B) and PARK7 protein concentrations were measured before and after PACAP treatment in both models. Locomotion and feeding activity were decreased in rotenone-treated snails, which corresponded well to findings obtained in 6-OHDA-induced rat experiments. PACAP was able to prevent the behavioural malfunctions caused by the toxins. Monoamine levels decreased in both models and the decreased DA level induced by toxins was attenuated by ∼50% in the PACAP-treated animals. In contrast, PACAP had no effect on the decreased serotonin (5HT) levels. S-COMT metabolic enzyme was also reduced but a protective effect of PACAP was not observed in either of the models. Following toxin treatment, a significant increase in MB-COMT was observed in both models and was restored to normal levels by PACAP. A decrease in PARK7 was also observed in both toxin-induced models; however, PACAP had a beneficial effect only on 6-OHDA-treated animals. The neuroprotective effect of PACAP in different animal models of Parkinson's disease is thus well correlated with neurotransmitter, enzyme and protein levels. The models successfully mimic several, but not all etiological properties of the disease, allowing us to study the mechanisms of neurodegeneration as well as testing new drugs. The rotenone and 6-OHDA rat and snail in vivo parkinsonian models offer an alternative method for investigation of the molecular mechanisms of neuroprotective agents, including PACAP. PMID:28067625

  8. Pituitary adenylate cyclase-activating polypeptide (PACAP) has a neuroprotective function in dopamine-based neurodegeneration in rat and snail parkinsonian models.

    PubMed

    Maasz, Gabor; Zrinyi, Zita; Reglodi, Dora; Petrovics, Dora; Rivnyak, Adam; Kiss, Tibor; Jungling, Adel; Tamas, Andrea; Pirger, Zsolt

    2017-02-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) rescues dopaminergic neurons from neurodegeneration and improves motor changes induced by 6-hydroxy-dopamine (6-OHDA) in rat parkinsonian models. Recently, we investigated the molecular background of the neuroprotective effect of PACAP in dopamine (DA)-based neurodegeneration using rotenone-induced snail and 6-OHDA-induced rat models of Parkinson's disease. Behavioural activity, monoamine (DA and serotonin), metabolic enzyme (S-COMT, MB-COMT and MAO-B) and PARK7 protein concentrations were measured before and after PACAP treatment in both models. Locomotion and feeding activity were decreased in rotenone-treated snails, which corresponded well to findings obtained in 6-OHDA-induced rat experiments. PACAP was able to prevent the behavioural malfunctions caused by the toxins. Monoamine levels decreased in both models and the decreased DA level induced by toxins was attenuated by ∼50% in the PACAP-treated animals. In contrast, PACAP had no effect on the decreased serotonin (5HT) levels. S-COMT metabolic enzyme was also reduced but a protective effect of PACAP was not observed in either of the models. Following toxin treatment, a significant increase in MB-COMT was observed in both models and was restored to normal levels by PACAP. A decrease in PARK7 was also observed in both toxin-induced models; however, PACAP had a beneficial effect only on 6-OHDA-treated animals. The neuroprotective effect of PACAP in different animal models of Parkinson's disease is thus well correlated with neurotransmitter, enzyme and protein levels. The models successfully mimic several, but not all etiological properties of the disease, allowing us to study the mechanisms of neurodegeneration as well as testing new drugs. The rotenone and 6-OHDA rat and snail in vivo parkinsonian models offer an alternative method for investigation of the molecular mechanisms of neuroprotective agents, including PACAP.

  9. Correlation between model observer and human observer performance in CT imaging when lesion location is uncertain

    SciTech Connect

    Leng, Shuai; Yu, Lifeng; Zhang, Yi; McCollough, Cynthia H.; Carter, Rickey; Toledano, Alicia Y.

    2013-08-15

    Purpose: The purpose of this study was to investigate the correlation between model observer and human observer performance in CT imaging for the task of lesion detection and localization when the lesion location is uncertain.Methods: Two cylindrical rods (3-mm and 5-mm diameters) were placed in a 35 × 26 cm torso-shaped water phantom to simulate lesions with −15 HU contrast at 120 kV. The phantom was scanned 100 times on a 128-slice CT scanner at each of four dose levels (CTDIvol = 5.7, 11.4, 17.1, and 22.8 mGy). Regions of interest (ROIs) around each lesion were extracted to generate images with signal-present, with each ROI containing 128 × 128 pixels. Corresponding ROIs of signal-absent images were generated from images without lesion mimicking rods. The location of the lesion (rod) in each ROI was randomly distributed by moving the ROIs around each lesion. Human observer studies were performed by having three trained observers identify the presence or absence of lesions, indicating the lesion location in each image and scoring confidence for the detection task on a 6-point scale. The same image data were analyzed using a channelized Hotelling model observer (CHO) with Gabor channels. Internal noise was added to the decision variables for the model observer study. Area under the curve (AUC) of ROC and localization ROC (LROC) curves were calculated using a nonparametric approach. The Spearman's rank order correlation between the average performance of the human observers and the model observer performance was calculated for the AUC of both ROC and LROC curves for both the 3- and 5-mm diameter lesions.Results: In both ROC and LROC analyses, AUC values for the model observer agreed well with the average values across the three human observers. The Spearman's rank order correlation values for both ROC and LROC analyses for both the 3- and 5-mm diameter lesions were all 1.0, indicating perfect rank ordering agreement of the figures of merit (AUC) between the

  10. Decreased response of interneurons in the medial prefrontal cortex to 5-HT₁A receptor activation in the rat 6-hydroxydopamine Parkinson model.

    PubMed

    Zhang, Qiaojun; Wang, Shuang; Zhang, Lina; Zhang, Huan; Qiao, Hongfei; Niu, Xiaolin; Liu, Jian

    2014-08-01

    This study examined the response of interneurons in the medial prefrontal cortex (mPFC) to 5-HT1A receptor agonist 8-OH-DPAT and change in expression of 5-HT1A receptor on glutamate decarboxylase 67 (GAD67)-positive neurons in rats with 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc). Systemic administration of 5-HT1A receptor agonist 8-OH-DPAT dose-dependently inhibited the firing rate of the interneurons at all doses tested in sham-operated rats. In 6-OHDA-lesioned rats, 8-OH-DPAT, at the same doses, also inhibited the firing rate of the interneurons, whereas the inhibition was significant only at a high cumulative dose. Furthermore, injection of 8-OH-DPAT into the mPFC inhibited the interneurons in sham-operated rats, while having no effect on firing rate of the interneurons in 6-OHDA-lesioned rats. In contrast to sham-operated rats, SNc lesion reduced the expression of 5-HT1A receptor on GAD67-positive neurons in the prelimbic cortex, a sub-region of the mPFC. Our results indicate that degeneration of the nigrostriatal pathway leads to decreased response of mPFC interneurons to 5-HT1A receptor activation, which attributes to the down-regulation of 5-HT1A receptor expression in these interneurons.

  11. Spatial Modeling of Colonic Lesions With Geographic Information Systems

    PubMed Central

    Imanieh, Mohammad Hadi; Goli, Ali; Imanieh, Mohammad Hossein; Geramizadeh, Bita

    2014-01-01

    Background: Geographic information system (GIS) software has been used in health care systems to display and analyze spatial pattern of diseases and health services. Objectives: This study was performed to assess spatial patterns of colon’s pathologic lesions based on the pathologic reports and assess whether it is possible to use GIS software in health services. Patients and Methods: Archives of pathology of Namazi and Faghihi hospitals, two main referral centers of south-west of Iran, were obtained and reviewed between January 2009 and September 2011 for biopsy reports of patients who underwent colonoscopy. Abnormal biopsies were categorized into five different subgroups according to the type of pathologic specimens. By GIS, spatial patterns of colon biopsies were plotted in different maps and spatial auto-correlation of colon biopsies was calculated using the Moran’s Index. Results: A total of 4815 biopsies from 2663 different patients were reviewed, 53.8% of which were men. Abnormal biopsies were 2781 of all specimens (57.8%). Neoplastic lesions, inflammatory bowel diseases and polyps were 9.3%, 19.3% and 29.2% of total biopsies, respectively. Pathologic biopsies were more common in the distal colon. Maps of all biopsies and maps of specific pathologies were manifested in GIS. Conclusions: Our study showed that left-sided lesions are still more common in the Iranian population. On the other hand, surveying the right side of colon is as important as the distal part, which necessitates total colonoscopy. PMID:25763265

  12. Can physical exercise have a protective effect in an animal model of sleep-related movement disorder?

    PubMed

    Esteves, Andrea M; Lopes, Cleide; Frank, Miriam K; Arida, Ricardo M; Frussa-Filho, Roberto; Tufik, Sergio; de Mello, Marco Túlio

    2016-05-15

    The purpose of the present study was to determine whether physical exercise (PE) has a protective effect in an experimental animal model of sleep-related movement disorder (A11 dopaminergic nuclei lesions with 6-OHDA). Rats were divided into four groups (Control PE-CTRL/PE, SHAM/PE, A11 lesion/NPE, A11 lesion/PE). Two experiments were performed: (1) the rats underwent PE before (2 weeks) and after (4 weeks) the A11 lesion; and (2) the rats underwent PE only after (4 weeks) the A11 lesion. Electrode insertion surgery was performed and sleep analyses were conducted over a period of 24h (baseline and after PE) and analyzed in 6 blocks of 4h. The results demonstrated that the A11 lesion produced an increased percentage of wakefulness in the final block of the dark period (3-7am) and a significant enhancement of the number of limb movements (LM) throughout the day. Four weeks of PE was important for reducing the number of LMs in the A11 lesion group in the rats that performed PE before and after the A11 lesion. However, in the analysis of the protective effect of PE on LM, the results showed that the number of LMs was lower at baseline in the group that had performed 2 weeks of PE prior to the A11 lesion than in the group that had not previously performed PE. In conclusion, these findings consistently demonstrate that non-pharmacological manipulations had a beneficial effect on the symptoms of sleep-related movement disorder.

  13. EPO-dependent activation of PI3K/Akt/FoxO3a signalling mediates neuroprotection in in vitro and in vivo models of Parkinson's disease.

    PubMed

    Jia, Yu; Mo, Shi-Jing; Feng, Qi-Qi; Zhan, Ma-Li; OuYang, Li-Si; Chen, Jia-Chang; Ma, Yu-Xin; Wu, Jia-Jia; Lei, Wan-Long

    2014-05-01

    Erythropoietin (EPO) may become a potential therapeutic candidate for the treatment of the neurodegenerative disorder -- Parkinson's disease (PD), since EPO has been found to prevent neuron apoptosis through the activation of cell survival signalling. However, the underlying mechanisms of how EPO exerts its neuroprotective effect are not fully elucidated. Here we investigated the mechanism by which EPO suppressed 6-hydroxydopamine (6-OHDA)-induced neuron death in in vitro and in vivo models of PD. EPO knockdown conferred 6-OHDA-induced cytotoxicity. This effect was reversed by EPO administration. Treatment of PC12 cells with EPO greatly diminished the toxicity induced by 6-OHDA in a dose- and time-dependent manner. EPO effectively reduced apoptosis of striatal neurons and induced a significant improvement on the neurological function score in the rat models of PD. Furthermore, EPO increased the expression of phosphorylated Akt and phosphorylated FoxO3a, and abrogated the 6-OHDA-induced dysregulation of Bcl-2, Bax and Caspase-3 in PC12 cells and in striatal neurons. Meanwhile, the EPO-dependent neuroprotection was notably reversed by pretreatment with LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K). Our data suggest that PI3K/Akt/FoxO3a signalling pathway may be a possible mechanism involved in the neuroprotective effect of EPO in PD.

  14. Neuroprotective Effects of Sulphated Agaran from Marine Alga Gracilaria cornea in Rat 6-Hydroxydopamine Parkinson's Disease Model: Behavioural, Neurochemical and Transcriptional Alterations.

    PubMed

    Souza, Ricardo Basto; Frota, Annyta Fernandes; Sousa, Rayane Siqueira; Cezario, Nayara Araújo; Santos, Tarcizio Brito; Souza, Luziana Mara Frota; Coura, Chistiane Oliveira; Monteiro, Valdécio Silvano; Cristino Filho, Gerardo; Vasconcelos, Silvânia Maria Mendes; da Cunha, Rodrigo Maranguape Silva; Aguiar, Lissiana Magna Vasconcelos; Benevides, Norma Maria Barros

    2017-02-01

    Parkinson's disease (PD) is a multifactorial disease associated with the degeneration of dopaminergic neurons and behavioural alterations. Natural bioactive compounds may provide new therapeutic alternatives for neurodegenerative disorders, such as PD. The sulphated polysaccharides isolated from marine algae are heterogenic molecules that show different biological activities. The red marine alga Gracilaria cornea has a sulphated polysaccharide (SA-Gc) with structure and anti-inflammatory and antinociceptive activities reported in the literature. Therefore, this study aimed to evaluate the neuroprotective effects of SA-Gc in rat model PD induced by 6-hydroxydopamine (6-OHDA). Firstly, we established the PD model in rats, induced by an intrastriatal injection (int.) of 6-OHDA, followed by a single administration of SA-Gc (15, 30 or 60 μg; int.). On the 14th day, behavioural tests were performed. After killing, brain areas were dissected and used for neurochemical and/or transcriptional analyses. The results showed that SA-Gc (60 μg, int.) promoted neuroprotective effects in vivo through reducing the oxidative/nitroactive stress and through alterations in the monoamine contents induced by 6-OHDA. Furthermore, SA-Gc modulated the transcription of neuroprotective and inflammatory genes, as well as returning behavioural activities and weight gain to normal conditions. Thus, this study reports the neuroprotective effects of SA-Gc against 6-OHDA in rats.

  15. Neuroprotective Activity of Peripherally Administered Liver Growth Factor in a Rat Model of Parkinson’s Disease

    PubMed Central

    Gonzalo-Gobernado, Rafael; Calatrava-Ferreras, Lucía; Reimers, Diana; Herranz, Antonio Sánchez; Rodríguez-Serrano, Macarena; Miranda, Cristina; Jiménez-Escrig, Adriano; Díaz-Gil, Juan José; Bazán, Eulalia

    2013-01-01

    Liver growth factor (LGF) is a hepatic mitogen purified some years ago that promotes proliferation of different cell types and the regeneration of damaged tissues, including brain tissue. Considering the possibility that LGF could be used as a therapeutic agent in Parkinson’s disease, we analyzed its potential neuroregenerative and/or neuroprotective activity when peripherally administered to unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. For these studies, rats subjected to nigrostriatal lesions were treated intraperitoneally twice a week with LGF (5 microg/rat) for 3 weeks. Animals were sacrificed 4 weeks after the last LGF treatment. The results show that LGF stimulates sprouting of tyrosine hydroxylase-positive terminals and increases tyrosine hydroxylase and dopamine transporter expression, as well as dopamine levels in the denervated striatum of 6-OHDA-lesioned rats. In this structure, LGF activates microglia and raises tumor necrosis factor-alpha protein levels, which have been reported to have a role in neuroregeneration and neuroprotection. Besides, LGF stimulates the phosphorylation of MAPK/ERK1/2 and CREB, and regulates the expression of proteins which are critical for cell survival such as Bcl2 and Akt. Because LGF partially protects dopamine neurons from 6-OHDA neurotoxicity in the substantia nigra, and reduces motor deficits in these animals, we propose LGF as a novel factor that may be useful in the treatment of Parkinson’s disease. PMID:23861803

  16. Brain lesion detection in MRI with fuzzy and geostatistical models.

    PubMed

    Pham, Tuan D

    2010-01-01

    Automated image detection of white matter changes of the brain is essentially helpful in providing a quantitative measure for studying the association of white matter lesions with other types of biomedical data. Such study allows the possibility of several medical hypothesis validations which lead to therapeutic treatment and prevention. This paper presents a new clustering-based segmentation approach for detecting white matter changes in magnetic resonance imaging with particular reference to cognitive decline in the elderly. The proposed method is formulated using the principles of fuzzy c-means algorithm and geostatistics.

  17. Toward online modeling for lesion visualization and monitoring in cardiac ablation therapy.

    PubMed

    Linte, Cristian A; Camp, Jon J; Holmes, David R; Rettmann, Maryam E; Robb, Richard A

    2013-01-01

    Despite extensive efforts to enhance catheter navigation, limited research has been done to visualize and monitor the tissue lesions created during ablation in the attempt to provide feedback for effective therapy. We propose a technique to visualize the temperature distribution and extent of induced tissue injury via an image-based model that uses physiological tissue parameters and relies on heat transfer principles to characterize lesion progression in near real time. The model was evaluated both numerically and experimentally using ex vivo bovine muscle samples while emulating a clinically relevant ablation protocol. Results show agreement to within 5 degreeC between the model-predicted and experimentally measured end-ablation tissue temperatures, as well as comparable predicted and observed lesion characteristics. The model yields temperature and lesion updates in near real-time, thus providing reasonably accurate and sufficiently fast monitoring for effective therapy.

  18. Fish biomarkers for environmental monitoring: An integrated model supporting enzyme activity and histopathological lesions

    NASA Astrophysics Data System (ADS)

    Neta, Raimunda Nonata Fortes Carvalho; Torres Junior, Audalio Rebelo

    2014-10-01

    We present a mathematical model describing the association between glutathione-S-transferase activity and brachial lesions in the catfish, Sciades herzbergii (Ariidae) from a polluted port. The catfish were sampled from a port known to be contaminated with heavy metals and organic compounds and from a natural reserve in São Marcos Bay, Brazil. Two biomarkers, hepatic glutathione S-transferase (GST) activity and histopathological lesions, in gills tissue were measured. The values for GST activity were modeled with the occurrence of branchial lesions by fitting a third order polynomial. Results from the mathematical model indicate that GST activity has a strong polynomial relationship with the occurrence of branchial lesions in both the wet and the dry seasons, but only at the polluted port site. The model developed in this study indicates that branchial and hepatic lesions are initiated when GST activity reaches 2.15 μmol min-1 mg protein-1. Beyond this limit, GST activity decreased to very low levels and irreversible histopathological lesions occurred. This mathematical model provides a realistic approach to analyze predictive biomarkers of environmental health status.

  19. AAV.shRNA-mediated downregulation of ROCK2 attenuates degeneration of dopaminergic neurons in toxin-induced models of Parkinson's disease in vitro and in vivo.

    PubMed

    Saal, Kim-Ann; Koch, Jan C; Tatenhorst, Lars; Szegő, Eva M; Ribas, Vinicius Toledo; Michel, Uwe; Bähr, Mathias; Tönges, Lars; Lingor, Paul

    2015-01-01

    Parkinson's disease (PD) is a neurodegenerative disorder with prominent neuronal cell death in the substantia nigra (SN) and other parts of the brain. Previous studies in models of traumatic and neurodegenerative CNS disease showed that pharmacological inhibition of Rho-associated kinase (ROCK), a molecule involved in inhibitory signaling in the CNS, by small-molecule inhibitors improves neuronal survival and increases regeneration. Most small-molecule inhibitors, however, offer only limited target specificity and also inhibit other kinases, including both ROCK isoforms. To establish the role of the predominantly brain-expressed ROCK2 isoform in models of regeneration and PD, we used adeno-associated viral vectors (AAV) to specifically knockdown ROCK2 in neurons. Rat primary midbrain neurons (PMN) were transduced with AAV expressing short-hairpin-RNA (shRNA) against ROCK2 and LIM-domain kinase 1 (LIMK1), one of the downstream targets of ROCK2. While knock-down of ROCK2 and LIMK1 both enhanced neurite regeneration in a traumatic scratch lesion model, only ROCK2-shRNA protected PMN against 1-methyl-4-phenylpyridinium (MPP+) toxicity. Moreover, AAV.ROCK2-shRNA increased levels of the pro-survival markers Bcl-2 and phospho-Erk1. In vivo, AAV.ROCK2-shRNA vectors were injected into the ipsilateral SN and a unilateral 6-OHDA striatal lesion was performed. After four weeks, behavioral, immunohistochemical and biochemical alterations were investigated. Downregulation of ROCK2 protected dopaminergic neurons in the SN from 6-OHDA-induced degeneration and resulted in significantly increased TH-positive neuron numbers. This effect, however, was confined to nigral neuronal somata as striatal terminal density, dopamine and metabolite levels were not significantly preserved. Interestingly, motor behavior was improved in the ROCK2-shRNA treated animals compared to control after four weeks. Our studies thus confirm ROCK2 as a promising therapeutic target in models of PD and

  20. 5-Hydroxy-tryptophan for the treatment of L-DOPA-induced dyskinesia in the rat Parkinson's disease model.

    PubMed

    Tronci, Elisabetta; Lisci, Carlo; Stancampiano, Roberto; Fidalgo, Camino; Collu, Maria; Devoto, Paola; Carta, Manolo

    2013-12-01

    The serotonin system has recently emerged as an important player in the appearance of L-DOPA-induced dyskinesia (LID) in experimental models of Parkinson's disease, as it provides an unregulated source of L-DOPA-derived dopamine release in the dopamine-depleted striatum. Accordingly, toxin lesion or pharmacological silencing of serotonin neurons suppressed LID in the rat and monkey models of Parkinson's disease. However, 5-HT1 receptor agonists were also found to partially reduce the therapeutic effect of L-DOPA. In this study, we evaluated whether enhancement of the serotonin tone induced by the administration of the serotonin precursor 5-hydroxy-tryptophan (5-HTP) could affect induction and expression of LID, as well as the therapeutic effect of L-DOPA, in 6-OHDA-lesioned rats. Drug naïve and L-DOPA-primed 6-OHDA-lesioned rats were chronically treated with a daily injection of L-DOPA (6 mg/kg plus benserazide, s.c.) alone, or in combination with 5-HTP (24-48 mg/kg, i.p.). The abnormal involuntary movements (AIMs) test, as well as the stepping and the motor activity tests, were performed during the chronic treatments. Results showed that 5-HTP reduced the appearance of LID of about 50% at both tested doses. A partial reduction of the therapeutic effect of L-DOPA was seen with the higher but not with the lower dose of 5-HTP. 5-HTP 24 mg/kg was also able to reduce the expression of dyskinesia in L-DOPA-primed dyskinetic rats, to a similar extent than in L-DOPA-primed rats. Importantly, the antidyskinetic effect of 5-HTP 24 mg/kg does not appear to be due to a competition with L-DOPA for crossing the blood-brain barrier; in fact, similar L-DOPA striatal levels were found in L-DOPA only and L-DOPA plus 5-HTP 24 mg/kg treated animals. These data further confirm the involvement of the serotonin system in the appearance of LID, and suggest that 5-HTP may be useful to counteract the appearance of dyskinesia in Parkinson's disease patients.

  1. Histopathological Analogies in Chronic Pulmonary Lesions between Cattle and Humans: Basis for an Alternative Animal Model

    PubMed Central

    Ramírez-Romero, Rafael; Nevárez-Garza, Alicia M.; Rodríguez-Tovar, Luis E.; Wong-González, Alfredo; Ledezma-Torres, Rogelio A.; Hernández-Vidal, Gustavo

    2012-01-01

    Most of the natural cases of pneumonia in feedlot cattle are characterized by a longer clinical course due to chronic lung lesions. Microscopically, these lesions include interstitial fibroplasia, bronchitis, bronchiectasis, bronchiolitis obliterans, and epithelial metaplasia of the airways. Herein, the aim was to review, under a medical perspective, the pathologic mechanisms operating in these chronic pneumonic lesions in calves. Based on the similarities of these changes to those reported in bronchiolitis obliterans/organising pneumonia (BO/OP) and chronic obstructive pulmonary disease (COPD) in human beings, calves are proposed as an alternative animal model. PMID:22629176

  2. Atlas-based segmentation of pathological MR brain images using a model of lesion growth.

    PubMed

    Cuadra, Meritxell Bach; Pollo, Claudio; Bardera, Anton; Cuisenaire, Olivier; Villemure, Jean-Guy; Thiran, Jean-Philippe

    2004-10-01

    We propose a method for brain atlas deformation in the presence of large space-occupying tumors, based on an a priori model of lesion growth that assumes radial expansion of the lesion from its starting point. Our approach involves three steps. First, an affine registration brings the atlas and the patient into global correspondence. Then, the seeding of a synthetic tumor into the brain atlas provides a template for the lesion. The last step is the deformation of the seeded atlas, combining a method derived from optical flow principles and a model of lesion growth. Results show that a good registration is performed and that the method can be applied to automatic segmentation of structures and substructures in brains with gross deformation, with important medical applications in neurosurgery, radiosurgery, and radiotherapy.

  3. Effects of zingerone [4-(4-hydroxy-3-methoxyphenyl)-2-butanone] and eugenol [2-methoxy-4-(2-propenyl)phenol] on the pathological progress in the 6-hydroxydopamine-induced Parkinson's disease mouse model.

    PubMed

    Kabuto, Hideaki; Yamanushi, Tomoko T

    2011-12-01

    Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the nigrostriatal system and dopamine (DA) depletion in the striatum. The most popular therapeutic medicine for treating PD, 3-(3,4-Dihydroxyphenyl)-L-alanine (L-DOPA), has adverse effects, such as dyskinesia and disease acceleration. As superoxide (·O(2)(-)) and hydroxyl radical (·OH) have been implicated in the pathogenesis of PD, free radical scavenging and antioxidants have attracted attention as agents to prevent disease progression. Rodents injected with 6-hydroxydopamine (6-OHDA) intracerebroventricularly are considered to be a good animal model of PD. Zingerone and eugenol, essential oils extracted from ginger and cloves, are known to have free radical scavenging and antioxidant effects. Therefore, we examined the effects of zingerone and eugenol on the behavioral problems in mouse model and on the DA concentration and antioxidant activities in the striatum after 6-OHDA administration and L-DOPA treatment. Daily oral administration of eugenol/zingerone and injection of L-DOPA intraperitoneally for 4 weeks following a single 6-OHDA injection did not improve abnormal behaviors induced by L-DOPA treatment. 6-OHDA reduced the DA level in the striatum; surprisingly, zingerone and eugenol enhanced the reduction of striatal DA and its metabolites. Zingerone decreased catalase activity, and increased glutathione peroxidase activity and the oxidized L-ascorbate level in the striatum. We previously reported that pre-treatment with zingerone or eugenol prevents 6-OHDA-induced DA depression by preventing lipid peroxidation. However, the present study shows that post-treatment with these substances enhanced the DA decrease. These substances had adverse effects dependent on the time of administration relative to model PD onset. These results suggest that we should be wary of ingesting these spice elements after the onset of PD symptoms.

  4. Correlation between model observer and human observer performance in CT imaging when lesion location is uncertain

    NASA Astrophysics Data System (ADS)

    Leng, Shuai; Yu, Lifeng; Chen, Lingyun; Ramirez Giraldo, Juan C.; McCollough, Cynthia H.

    2012-03-01

    The purpose of this study is to investigate how well model observer can correlate with human observer in the lesion detection and localization task when the location of lesion is uncertain in CT imaging. A 35 × 26 cm oblong-shaped water phantom was scanned with and without two cylindrical rods (3 mm and 5 mm diameters) to simulate lesions with - 15HU contrast. Scans were repeated 100 times with the rods and 100 times without for each of 4 dose levels. Signal and background images were generated by selecting ROIs with 128x128 pixels, with the location of signal in each ROI randomly distributed. Human observer studies were conducted as three medical physicists identified the presence or absence of lesion, indicated the lesion location in each image and scored confidence level with a 6-point scale. ROC curves were fitted and area under curve (AUC) was calculated. The same data set was also analyzed using a Channelized Hottelling model observer with Gabor channels. Internal noise was added to the test variables for model observer study. AUC of ROC and LROC curves were calculated using non-parametric approach. The performance of human observer and model observer was compared. The Peason's product-moment correlation coefficients were 0.994 and 0.998 for 3mm and 5mm diameter lesions in ROC analysis and 0.987 and 0.999 in LROC analysis, indicating that model observer performance was highly correlated with the human observer performance for different size of lesions and different dose levels when signal location is uncertain. These results provide the potential of using model observer that correlates with human observer to assess CT image quality, optimize scanning protocol and reduce radiation dose.

  5. detecting multiple sclerosis lesions with a fully bioinspired visual attention model

    NASA Astrophysics Data System (ADS)

    Villalon-Reina, Julio; Gutierrez-Carvajal, Ricardo; Thompson, Paul M.; Romero-Castro, Eduardo

    2013-11-01

    The detection, segmentation and quantification of multiple sclerosis (MS) lesions on magnetic resonance images (MRI) has been a very active field for the last two decades because of the urge to correlate these measures with the effectiveness of pharmacological treatment. A myriad of methods has been developed and most of these are non specific for the type of lesions and segment the lesions in their acute and chronic phases together. On the other hand, radiologists are able to distinguish between several stages of the disease on different types of MRI images. The main motivation of the work presented here is to computationally emulate the visual perception of the radiologist by using modeling principles of the neuronal centers along the visual system. By using this approach we are able to detect the lesions in the majority of the images in our population sample. This type of approach also allows us to study and improve the analysis of brain networks by introducing a priori information.

  6. Location- and lesion-dependent estimation of background tissue complexity for anthropomorphic model observer

    NASA Astrophysics Data System (ADS)

    Avanaki, Ali R. N.; Espig, Kathryn; Knippel, Eddie; Kimpe, Tom R. L.; Xthona, Albert; Maidment, Andrew D. A.

    2016-03-01

    In this paper, we specify a notion of background tissue complexity (BTC) as perceived by a human observer that is suited for use with model observers. This notion of BTC is a function of image location and lesion shape and size. We propose four unsupervised BTC estimators based on: (i) perceived pre- and post-lesion similarity of images, (ii) lesion border analysis (LBA; conspicuous lesion should be brighter than its surround), (iii) tissue anomaly detection, and (iv) mammogram density measurement. The latter two are existing methods we adapt for location- and lesion-dependent BTC estimation. To validate the BTC estimators, we ask human observers to measure BTC as the visibility threshold amplitude of an inserted lesion at specified locations in a mammogram. Both human-measured and computationally estimated BTC varied with lesion shape (from circular to oval), size (from small circular to larger circular), and location (different points across a mammogram). BTCs measured by different human observers are correlated (ρ=0.67). BTC estimators are highly correlated to each other (0.84lesion shape or size, estimated BTC by LBA changes in the same direction as human-measured BTC. A generalization of proposed methods for viewing breast tomosynthesis sequences in cine mode is outlined. The proposed estimators, as-is or customized to a specific human observer, may be used to construct a BTC-aware model observer, with applications such as optimization of contrast-enhanced medical imaging systems, and creation of a diversified image dataset with characteristics of a desired population.

  7. Delayed dominant-negative TNF gene therapy halts progressive loss of nigral dopaminergic neurons in a rat model of Parkinson's disease.

    PubMed

    Harms, Ashley S; Barnum, Christopher J; Ruhn, Kelly A; Varghese, Steve; Treviño, Isaac; Blesch, Armin; Tansey, Malú G

    2011-01-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder typified by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Recent evidence indicates that neuroinflammation may play a critical role in the pathogenesis of PD, particularly tumor necrosis factor (TNF). We have previously shown that soluble TNF (solTNF) is required to mediate robust degeneration induced by 6-hydroxydopamine (6-OHDA) or lipopolysaccharide. What remains unknown is whether TNF inhibition can attenuate the delayed and progressive phase of neurodegeneration. To test this, rats were injected in the SNpc with lentivirus encoding dominant-negative TNF (lenti-DN-TNF) 2 weeks after receiving a 6-OHDA lesion. Remarkably, when examined 5 weeks after the initial 6-OHDA lesion, no further loss of nigral DA neurons was observed. Lenti-DN-TNF also attenuated microglial activation. Together, these data suggest that TNF is likely a critical mediator of nigral DA neuron death during the delayed and progressive phase of neurodegeneration, and that microglia may be the principal cell type involved. These promising findings provide compelling reasons to perform DN-TNF gene transfer studies in nonhuman primates with the long-term goal of using it in the clinic to prevent the delayed and progressive degeneration of DA neurons that gives rise to motor symptoms in PD.

  8. Delayed Dominant-Negative TNF Gene Therapy Halts Progressive Loss of Nigral Dopaminergic Neurons in a Rat Model of Parkinson's Disease

    PubMed Central

    Harms, Ashley S; Barnum, Christopher J; Ruhn, Kelly A; Varghese, Steve; Treviño, Isaac; Blesch, Armin; Tansey, Malú G

    2011-01-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder typified by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Recent evidence indicates that neuroinflammation may play a critical role in the pathogenesis of PD, particularly tumor necrosis factor (TNF). We have previously shown that soluble TNF (solTNF) is required to mediate robust degeneration induced by 6-hydroxydopamine (6-OHDA) or lipopolysaccharide. What remains unknown is whether TNF inhibition can attenuate the delayed and progressive phase of neurodegeneration. To test this, rats were injected in the SNpc with lentivirus encoding dominant-negative TNF (lenti-DN-TNF) 2 weeks after receiving a 6-OHDA lesion. Remarkably, when examined 5 weeks after the initial 6-OHDA lesion, no further loss of nigral DA neurons was observed. Lenti-DN-TNF also attenuated microglial activation. Together, these data suggest that TNF is likely a critical mediator of nigral DA neuron death during the delayed and progressive phase of neurodegeneration, and that microglia may be the principal cell type involved. These promising findings provide compelling reasons to perform DN-TNF gene transfer studies in nonhuman primates with the long-term goal of using it in the clinic to prevent the delayed and progressive degeneration of DA neurons that gives rise to motor symptoms in PD. PMID:20959812

  9. A Mechanical and Biochemical Model of Intimal Atherosclerotic Lesions

    NASA Astrophysics Data System (ADS)

    Fok, Pak-Wing; Vandiver, Rebecca

    2014-03-01

    We investigate a 1D axisymmetric model of intimal hyperplasia using hyperelasticity theory. Our model incorporates growth of the intima due to cell proliferation which in turn is driven by the release of a cytokine such as Platelet-Derived Growth Factor (PDGF). The main novelty of our model is that the growth rate is tied to local stresses and the local concentration of PDGF. The resulting system is a triple free boundary problem with different regions of the vessel wall having different homeostatic stress, depending on the local PDGF concentration. This system is coupled to force-balance equations that yield distributions for the stress and deformation. We find that rapid intimal thickening coupled to a quiescent media puts the intima in a state of compression and results in slow time scales of evolution. Our results are compared with intima-media thickness measurements of carotid arteries from previous clinical studies. Funded by a Simons Collaboration Grant.

  10. Chronic Spinal Cord Electrical Stimulation Protects Against 6-hydroxydopamine Lesions

    NASA Astrophysics Data System (ADS)

    Yadav, Amol P.; Fuentes, Romulo; Zhang, Hao; Vinholo, Thais; Wang, Chi-Han; Freire, Marco Aurelio M.; Nicolelis, Miguel A. L.

    2014-01-01

    Although L-dopa continues to be the gold standard for treating motor symptoms of Parkinson's disease (PD), it presents long-term complications. Deep brain stimulation is effective, but only a small percentage of idiopathic PD patients are eligible. Based on results in animal models and a handful of patients, dorsal column stimulation (DCS) has been proposed as a potential therapy for PD. To date, the long-term effects of DCS in animal models have not been quantified. Here, we report that DCS applied twice a week in rats treated with bilateral 6-OHDA striatal infusions led to a significant improvement in symptoms. DCS-treated rats exhibited a higher density of dopaminergic innervation in the striatum and higher neuronal cell count in the substantia nigra pars compacta compared to a control group. These results suggest that DCS has a chronic therapeutical and neuroprotective effect, increasing its potential as a new clinical option for treating PD patients.

  11. HPV-16 infection and cervical cancer: modeling the influence of duration of infection and precancerous lesions.

    PubMed

    Baussano, Iacopo; Ronco, Guglielmo; Segnan, Nereo; French, Katherine; Vineis, Paolo; Garnett, Geoff P

    2010-03-01

    The patterns of transmission, clearance, and progression of HPV infection and the related precancerous lesions are key to accurately model cervical cancer epidemiology and prevention. We have developed an age-structured dynamic model of the transmission of HPV-16 infection. This mathematical model accounts, for the first time, for the effect of infection and precancerous lesions duration on the natural history of HPV-16 infection and precancerous lesions. The model's output has been fitted to contemporaneous sets of data from Turin, Italy, to estimate parameters that have had been indirectly tested by comparing them with other estimates reported in the literature. The average probability of HPV-16 infection transmission per sexual partnership was about 40%. The HPV-16 clearance and progression rates decreased as the length of time with infection increased, clearance ranging between 1.6 per woman-year (in the first 6 months of infection) and 0.036 (after more than 6 years of infection), and progression between 0.072 and 0.018 per woman-year. The rate of clearance of precancerous lesions (CIN2+) was inversely dependent on age, while the progression of CIN2+ toward invasive cervical cancer increased as the precancerous lesions persisted. The present study also suggests that an exclusive role of women's age in shaping the rate of progression to cancer is unlikely. These results should inform future analyses. Including more accurately the role of the duration of infection and precancerous lesions as determinants of the cervical cancer occurrence in models of cervical cancer control may influence predictors of the effectiveness of intervention strategies.

  12. Promotion of endodontic lesions in rats by a novel extraradicular biofilm model using obturation materials.

    PubMed

    Kuremoto, Katsutaka; Noiri, Yuichiro; Ishimoto, Takuya; Yoneda, Naomichi; Yamamoto, Reiko; Maezono, Hazuki; Nakano, Takayoshi; Hayashi, Mikako; Ebisu, Shigeyuki

    2014-07-01

    Although extraradicular biofilm formation is related to refractory periapical periodontitis, the mechanism of extraradicular biofilm development, as well as its effect on periapical lesions, is unknown. Therefore, we aimed to develop an in vivo extraradicular biofilm model in rats and to identify and quantify extraradicular biofilm-forming bacteria while investigating the effect of extraradicular biofilms on periapical lesions. Periapical lesions were induced by exposing the pulpal tissue of the mandibular first molars of male Wistar rats to their oral environment. Four weeks later, gutta-percha points were excessively inserted into the mesial root canals of the right first molars (experimental sites) but not the left first molars (control sites). After 6 and 8 weeks of pulp exposure, the presence of extraradicular biofilms was confirmed histomorphologically, and biofilm-forming bacteria were identified by using classical culture methods. The biofilms were observed in the extraradicular area of the experimental sites. Similar species were detected both inside and outside the root canals. The bacterial count, quantified by real-time PCR assays, in the extraradicular area gradually increased in the experimental sites until 20 weeks after pulp exposure. After 8 weeks of pulp exposure, the periapical lesion volume that was measured by micro-computed tomography was significantly larger in the experimental sites than in the control sites (P < 0.05 by Welch's t test). These results suggest that we developed an extraradicular biofilm model in rats and that extraradicular biofilms affect developing periapical lesions.

  13. Promotion of Endodontic Lesions in Rats by a Novel Extraradicular Biofilm Model Using Obturation Materials

    PubMed Central

    Kuremoto, Katsutaka; Ishimoto, Takuya; Yoneda, Naomichi; Yamamoto, Reiko; Maezono, Hazuki; Nakano, Takayoshi; Hayashi, Mikako; Ebisu, Shigeyuki

    2014-01-01

    Although extraradicular biofilm formation is related to refractory periapical periodontitis, the mechanism of extraradicular biofilm development, as well as its effect on periapical lesions, is unknown. Therefore, we aimed to develop an in vivo extraradicular biofilm model in rats and to identify and quantify extraradicular biofilm-forming bacteria while investigating the effect of extraradicular biofilms on periapical lesions. Periapical lesions were induced by exposing the pulpal tissue of the mandibular first molars of male Wistar rats to their oral environment. Four weeks later, gutta-percha points were excessively inserted into the mesial root canals of the right first molars (experimental sites) but not the left first molars (control sites). After 6 and 8 weeks of pulp exposure, the presence of extraradicular biofilms was confirmed histomorphologically, and biofilm-forming bacteria were identified by using classical culture methods. The biofilms were observed in the extraradicular area of the experimental sites. Similar species were detected both inside and outside the root canals. The bacterial count, quantified by real-time PCR assays, in the extraradicular area gradually increased in the experimental sites until 20 weeks after pulp exposure. After 8 weeks of pulp exposure, the periapical lesion volume that was measured by micro-computed tomography was significantly larger in the experimental sites than in the control sites (P < 0.05 by Welch's t test). These results suggest that we developed an extraradicular biofilm model in rats and that extraradicular biofilms affect developing periapical lesions. PMID:24747900

  14. Electrode radius predicts lesion radius during radiofrequency energy heating. Validation of a proposed thermodynamic model

    SciTech Connect

    Haines, D.E.; Watson, D.D.; Verow, A.F. )

    1990-07-01

    Myocardial heating by transcatheter delivery of radiofrequency (RF) energy has been proposed as an effective means of arrhythmia ablation. A thermodynamic model describing the radial temperature gradient at steady state during RF-induced heating is proposed. If one assumes that RF power output is adjusted to maintain a constant electrode-tissue interface temperature at all times, then this thermodynamic model predicts that the radius of the RF-induced lesion will be directly proportional to the electrode radius. A total of 76 RF-induced lesions were created in a model of isolated canine right ventricular free wall perfused and superfused with oxygenated Krebs-Henseleit buffer. Electrode radius was varied between 0.75 and 2.25 mm. RF energy (500 kHz) was delivered for 90 seconds, and the power output was adjusted to maintain a constant electrode-tissue interface temperature of 60 degrees C. A strong linear correlation was observed between electrode radius and lesion radius in two dimensions: transverse (p = 0.0001, r = 0.85) and transmural (p = 0.0001, r = 0.89). With these data, the temperature correlation with irreversible myocardial injury in this model was calculated at 46.6-48.8 degrees C. Therefore, the proposed thermodynamic model closely predicts the observed relation between electrode radius and lesion size during RF myocardial heating.

  15. Effects of clozapine on memory function in the rat neonatal hippocampal lesion model of schizophrenia.

    PubMed

    Levin, Edward D; Christopher, N Channelle

    2006-03-01

    Clozapine is an effective atypical antipsychotic drug used to treat schizophrenia. It has the advantage of producing fewer extrapyramidal motor side effects than typical antipsychotic drugs such as haloperidol. Schizophrenia involves more than the hallmark symptom of psychosis. Substantial cognitive impairment is also seen. Effective drug treatments against the cognitive impairment of schizophrenia need to be developed. The current study was conducted to determine the effects of clozapine on working memory in the rat neonatal hippocampal lesion model of schizophrenia, which includes symptoms of cognitive impairment. Infant Sprague-Dawley rats were given ibotenic acid lesions of the hippocampus on day 7 of age (using the day of birth as day 0). Controls were given vehicle infusions. In adulthood, the rats were trained on the 8-arm radial maze using the win-shift procedure. After 6 sessions of training, the lesioned rats and their controls were administered repeated injections of saline or clozapine (2.5 mg/kg) for the next 12 sessions of training. The females had significant radial-arm maze choice accuracy impairments caused by either clozapine or the hippocampal lesion, but the combination of the two treatments had no additive effect. The males showed a different pattern of effects. Intact males did not show a significant clozapine-induced impairment, whereas males with hippocampal lesions did show significant clozapine-induced impairment although hippocampal lesions by themselves did not significantly impair male choice accuracy. These data show that clozapine can cause memory impairment and it potentiates rather than reverses hippocampal lesion-induced deficits. There are critical sex-related differences in these effects.

  16. A new murine model of stress-induced complex atherosclerotic lesions

    PubMed Central

    Najafi, Amir H.; Aghili, Nima; Tilan, Justin U.; Andrews, James A.; Peng, XinZhi; Lassance-Soares, Roberta M.; Sood, Subeena; Alderman, Lee O.; Abe, Ken; Li, Lijun; Kolodgie, Frank D.; Virmani, Renu; Zukowska, Zofia; Epstein, Stephen E.; Burnett, Mary Susan

    2013-01-01

    SUMMARY The primary purpose of this investigation was to determine whether ApoE−/− mice, when subjected to chronic stress, exhibit lesions characteristic of human vulnerable plaque and, if so, to determine the time course of such changes. We found that the lesions were remarkably similar to human vulnerable plaque, and that the time course of lesion progression raised interesting insights into the process of plaque development. Lard-fed mixed-background ApoE−/− mice exposed to chronic stress develop lesions with large necrotic core, thin fibrous cap and a high degree of inflammation. Neovascularization and intraplaque hemorrhage are observed in over 80% of stressed animals at 20 weeks of age. Previously described models report a prevalence of only 13% for neovascularization observed at a much later time point, between 36 and 60 weeks of age. Thus, our new stress-induced model of advanced atherosclerotic plaque provides an improvement over what is currently available. This model offers a tool to further investigate progression of plaque phenotype to a more vulnerable phenotype in humans. Our findings also suggest a possible use of this stress-induced model to determine whether therapeutic interventions have effects not only on plaque burden, but also, and importantly, on plaque vulnerability. PMID:23324329

  17. Numerical modelling of tooth enamel subsurface lesion formation induced by dental plaque.

    PubMed

    Ilie, O; van Turnhout, A G; van Loosdrecht, M C M; Picioreanu, C

    2014-01-01

    Using a one-dimensional mathematical model that couples tooth demineralisation and remineralisation with metabolic processes occurring in the dental plaque, two mechanisms for subsurface lesion formation were evaluated. It was found that a subsurface lesion can develop only as the result of alternating periods of demineralisation (acid attack during sugar consumption) and remineralisation (resting period) in tooth enamel with uniform mineral composition. It was also shown that a minimum plaque thickness that can induce an enamel lesion exists. The subsurface lesion formation can also be explained by assuming the existence of a fluoride-containing layer at the tooth surface that decreases enamel solubility. A nearly constant thickness of the surface layer was obtained with both proposed mechanisms. Sensitivity analysis showed that surface layer formation is strongly dependent on the length of remineralisation and demineralisation cycles. The restoration period is very important and the numerical simulations support the observation that often consumption of sugars is a key factor in caries formation. The calculated profiles of mineral content in enamel are similar to those observed experimentally. Most probably, both studied mechanisms interact in vivo in the process of caries development, but the simplest explanation for subsurface lesion formation remains the alternation between demineralisation and remineralisation cycles without any pre-imposed gradients.

  18. A low cost training phantom model for radio-guided localization techniques in occult breast lesions.

    PubMed

    Aydogan, Fatih; Mallory, Melissa Anne; Tukenmez, Mustafa; Sagara, Yasuaki; Ozturk, Erkan; Ince, Yavuz; Celik, Varol; Akca, Tamer; Golshan, Mehra

    2015-09-01

    Radio-guided localization (RGL) for identifying occult breast lesions has been widely accepted as an alternative technique to other localization methods, including those using wire guidance. An appropriate phantom model would be an invaluable tool for practitioners interested in learning the technique of RGL prior to clinical application. The aim of this study was to devise an inexpensive and reproducible training phantom model for RGL. We developed a simple RGL phantom model imitating an occult breast lesion from inexpensive supplies including a pimento olive, a green pea and a turkey breast. The phantom was constructed for a total cost of less than $20 and prepared in approximately 10 min. After the first model's construction, we constructed approximately 25 additional models and demonstrated that the model design was easily reproducible. The RGL phantom is a time- and cost-effective model that accurately simulates the RGL technique for non-palpable breast lesions. Future studies are warranted to further validate this model as an effective teaching tool.

  19. Enhanced frustrative nonreward effect following 6-hydroxydopamine lesions of the lateral septum in the rat.

    PubMed

    Taghzouti, K; Le Moal, M; Simon, H

    1985-12-01

    The effect of local injections of 6-hydroxydopamine (6-OHDA) into the lateral septum was tested in a paradigm known to lead to an energizing behavior, through a possible frustrative effect, induced by partial or total omission of reward in hungry rats. Biochemical assays in the septum showed that 6-OHDA reduced endogenous dopamine and, to a lesser extent, noradrenaline concentrations and left intact noncatecholaminergic neurons such as serotoninergic terminals. The first behavioral experiment was conducted in a double straight alley. The animals were submitted to three phases of testing with differing degrees of reinforcement: (a) an acquisition phase, in which the reinforcement was continuously delivered in the goal box of the two alleys, (b) a partial reinforced phase, in which animals received 50% partial reinforcement in the first alley and continuous reinforcement in the second alley, and (c) an extinction phase performed in one alley without any reinforcement. Animals with lesions ran faster for food than controls in the partial reinforcement or extinction situation, although there was no difference between the two groups in the acquisition phase of the continuous schedule of reinforcement or in the 50% reinforced trials of the partial reinforcement phase. The two groups also behaved similarly after the first six trials of the extinction phase. In a second experiment, the animals were tested in a lever-press conditioning task. Animals with lesions and control animals learned this task equally well, both with respect to the number of lever presses and the time to obtain a fixed number of food pellets.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. Restoring Behavior via Inverse Neurocontroller in a Lesioned Cortical Spiking Model Driving a Virtual Arm

    PubMed Central

    Dura-Bernal, Salvador; Li, Kan; Neymotin, Samuel A.; Francis, Joseph T.; Principe, Jose C.; Lytton, William W.

    2016-01-01

    Neural stimulation can be used as a tool to elicit natural sensations or behaviors by modulating neural activity. This can be potentially used to mitigate the damage of brain lesions or neural disorders. However, in order to obtain the optimal stimulation sequences, it is necessary to develop neural control methods, for example by constructing an inverse model of the target system. For real brains, this can be very challenging, and often unfeasible, as it requires repeatedly stimulating the neural system to obtain enough probing data, and depends on an unwarranted assumption of stationarity. By contrast, detailed brain simulations may provide an alternative testbed for understanding the interactions between ongoing neural activity and external stimulation. Unlike real brains, the artificial system can be probed extensively and precisely, and detailed output information is readily available. Here we employed a spiking network model of sensorimotor cortex trained to drive a realistic virtual musculoskeletal arm to reach a target. The network was then perturbed, in order to simulate a lesion, by either silencing neurons or removing synaptic connections. All lesions led to significant behvaioral impairments during the reaching task. The remaining cells were then systematically probed with a set of single and multiple-cell stimulations, and results were used to build an inverse model of the neural system. The inverse model was constructed using a kernel adaptive filtering method, and was used to predict the neural stimulation pattern required to recover the pre-lesion neural activity. Applying the derived neurostimulation to the lesioned network improved the reaching behavior performance. This work proposes a novel neurocontrol method, and provides theoretical groundwork on the use biomimetic brain models to develop and evaluate neurocontrollers that restore the function of damaged brain regions and the corresponding motor behaviors. PMID:26903796

  1. Differential pattern of motor impairments in neurotoxic, environmental and inflammation-driven rat models of Parkinson's disease.

    PubMed

    Naughton, Carol; Moriarty, Niamh; Feehan, Jennifer; O'Toole, Daniel; Dowd, Eilís

    2016-01-01

    One of the reasons proposed for the paucity of drug discovery for Parkinson's disease is the lack of relevant animal models of the condition. Parkinson's disease has been modelled extensively using the selective neurotoxin, 6-hydroxydopamine (6-OHDA). However, as this model bears little etiological resemblance to the human condition, there has been a drive to develop models with improved etiological validity. Two such models are those induced by the pesticide, rotenone, and the inflammagen, lipopolysaccharide (LPS). However, to date, these models have been poorly characterised in terms of their motor profiles and have never been directly compared to the more established models. Thus, the aim of this study was to characterise the behavioural profile of the rotenone and LPS models, and to compare them with the 6-OHDA model. Animals underwent baseline testing on the Stepping, Whisker, Corridor and Cylinder Tests of motor function. They were then grouped for unilateral intra-striatal infusion of 6-OHDA, rotenone or LPS. Motor testing continued for ten weeks after which the rats were processed for immunohistochemical analysis of nigrostriatal integrity. We found that, although all neurotoxins induced a similar level of nigrostriatal neurodegeneration, neither the rotenone nor LPS models were associated with amphetamine-induced rotation, and they were associated with significantly less pronounced and stable impairments in the spontaneous tasks than the 6-OHDA model. In conclusion, this study demonstrates key differences in the pattern of motor dysfunction induced by Parkinsonian neurotoxins which should be taken into consideration when selecting the most appropriate model for Parkinson's disease preclinical studies.

  2. Application of radiosurgical techniques to produce a primate model of brain lesions

    PubMed Central

    Kunimatsu, Jun; Miyamoto, Naoki; Ishikawa, Masayori; Shirato, Hiroki; Tanaka, Masaki

    2015-01-01

    Behavioral analysis of subjects with discrete brain lesions provides important information about the mechanisms of various brain functions. However, it is generally difficult to experimentally produce discrete lesions in deep brain structures. Here we show that a radiosurgical technique, which is used as an alternative treatment for brain tumors and vascular malformations, is applicable to create non-invasive lesions in experimental animals for the research in systems neuroscience. We delivered highly focused radiation (130–150 Gy at ISO center) to the frontal eye field (FEF) of macaque monkeys using a clinical linear accelerator (LINAC). The effects of irradiation were assessed by analyzing oculomotor performance along with magnetic resonance (MR) images before and up to 8 months following irradiation. In parallel with tissue edema indicated by MR images, deficits in saccadic and smooth pursuit eye movements were observed during several days following irradiation. Although initial signs of oculomotor deficits disappeared within a month, damage to the tissue and impaired eye movements gradually developed during the course of the subsequent 6 months. Postmortem histological examinations showed necrosis and hemorrhages within a large area of the white matter and, to a lesser extent, in the adjacent gray matter, which was centered at the irradiated target. These results indicated that the LINAC system was useful for making brain lesions in experimental animals, while the suitable radiation parameters to generate more focused lesions need to be further explored. We propose the use of a radiosurgical technique for establishing animal models of brain lesions, and discuss the possible uses of this technique for functional neurosurgical treatments in humans. PMID:25964746

  3. A Weibull-PBPK model for assessing risk of arsenic-induced skin lesions in children.

    PubMed

    Liao, Chung-Min; Lin, Tzu-Ling; Chen, Szu-Chieh

    2008-03-25

    Chronic arsenic exposure and skin lesions (keratosis and hyperpigmentation) are inextricably linked. This paper was to quantify the children skin lesions risks and to further recommend safe drinking water arsenic standard based on reported arsenic epidemiological data. We linked the Weibull dose-response function and a physiologically based pharmacokinetic (PBPK) model to estimate safe drinking water arsenic concentrations and to perform the risk characterization. We calculated odds ratios (ORs) to assess the relative magnitude of the effect of the arsenic exposure on the likelihood of the prevalence of children skin lesions by calculating proposed Weibull-based prevalence ratios of exposed to control groups associated with the age group-specific PBPK model predicted dimethylarsinite (MMA(III)) levels in urine. Positive relationships between arsenic exposures and cumulative prevalence ratios of skin lesions were found using Weibull dose-response model (r2=0.91-0.96). We reported that the safe drinking water arsenic standards were recommended to be 2.2 and 1 microg/L for male and 6 and 2.8 microg/L for female in 0-6 and 7-18 years age groups, respectively, based on hyperpigmentation with an excess risk of 10(-3) for a 75 years lifetime exposure. Risk predictions indicate that estimated ORs have 95% confidence intervals of 1.33-5.12, 1.74-19.15, and 2.81-19.27 based on mean drinking water arsenic contents of 283.19, 282.65, and 468.81 microg/L, respectively, in West Bengal, India, Bangladesh, and southwestern Taiwan. Our findings also suggest that increasing urinary monomethylarsonic acid (MMA) levels are associated with an increase in risks of arsenic-induced children skin lesions.

  4. C-peptide promotes lesion development in a mouse model of arteriosclerosis.

    PubMed

    Vasic, Dusica; Marx, Nikolaus; Sukhova, Galina; Bach, Helga; Durst, Renate; Grüb, Miriam; Hausauer, Angelina; Hombach, Vinzenz; Rottbauer, Wolfgang; Walcher, Daniel

    2012-04-01

    Patients with insulin resistance and early type 2 diabetes exhibit an increased propensity to develop a diffuse and extensive pattern of arteriosclerosis. Typically, these patients show elevated serum levels of the proinsulin cleavage product C-peptide and immunohistochemical data from our group revealed C-peptide deposition in early lesions of these individuals. Moreover, in vitro studies suggest that C-peptide could promote atherogenesis. This study examined whether C-peptide promotes vascular inflammation and lesion development in a mouse model of arteriosclerosis. ApoE-deficient mice on a high fat diet were treated with C-peptide or control injections for 12 weeks and the effect on lesion size and plaque composition was analysed. C-peptide treatment significantly increased C-peptide blood levels by 4.8-fold without having an effect on glucose or insulin levels, nor on the lipid profile. In these mice, C-peptide deposition in atherosclerotic plaques was significantly increased compared with controls. Moreover, lesions of C-peptide-treated mice contained significantly more macrophages (1.6 ± 0.3% versus 0.7 ± 0.2% positive area; P < 0.01) and more vascular smooth muscle cells (4.8 ± 0.6% versus 2.4 ± 0.3% positive area; P < 0.01). Finally, lipid deposition measured by Oil-red-O staining in the aortic arch was significantly higher in the C-peptide group compared with controls. Our results demonstrate that elevated C-peptide levels promote inflammatory cell infiltration and lesion development in ApoE-deficient mice without having metabolic effects. These data obtained in a mouse model of arteriosclerosis support the hypothesis that C-peptide may have an active role in atherogenesis in patients with diabetes and insulin resistance.

  5. Molecular and structural evaluation of dentin caries-like lesions produced by different artificial models.

    PubMed

    Pacheco, Larissa Ferreira; Banzi, Éfani Caroline de Freitas; Rodrigues, Eliana; Soares, Luís Eduardo Silva; Pascon, Fernanda Miori; Correr-Sobrinho, Lourenço; Puppin-Rontani, Regina Maria

    2013-01-01

    This study evaluated structural and molecular issues of dentin caries-like lesions produced by different artificial models (ACL) compared with natural caries lesions (NCL). One hundred twenty-four sound occlusal dentin blocks and 47 carious blocks were obtained and surface hardness was analyzed (SH1). They were assigned to groups according to ACL: GB: Biological; GC: Chemical; GIS: In situ; GNC: natural caries (control). Blocks from groups 1, 2 and 3 were submitted to caries lesion induction. NCL and ACL blocks were submitted to surface hardness (SH 2), FT-Raman and µEDXRF analysis. All blocks were longitudinally sectioned and one of the halves was submitted to cross-sectional hardness (CSH) and the other to SEM analysis. SH1 and SH2 data were submitted to t test (unpaired and paired, respectively), CSH and SEM data to two-way and one-way ANOVA respectively, and Tukey and t tests, respectively (p<0.05). Data from FT-Raman/µEDXRF were submitted to one-way ANOVA and Dunnett multiple-comparisons test (a=0.05). GB and GNC showed lowest SH2 values that were significantly different from GC and GIS. Regarding CSH, GB and GNC showed no significant difference between them. SEM showed similar caries lesion depth for GB and GNC, being significantly higher than for GC and GIS. µEDXRF showed similar values of calcium and phosphate for GB and GNC; GNC values were significantly different from GIS. No significant difference was found among the groups concerning phosphate, carbonate and CH bonds values. For collagen type I, GC values were significantly different compared to other groups. It may be concluded that caries-like lesions produced by GB were the closest model to NCL.

  6. Anodal transcranial direct current stimulation relieves the unilateral bias of a rat model of Parkinson's disease.

    PubMed

    Li, Yiyan; Tian, Xulong; Qian, Long; Yu, Xuehong; Jiang, Weiwei

    2011-01-01

    The unilaterally lesioned rat model of Parkinson's disease which fails to orient to the food stimuli presented on the contralateral side of its preferential side of body could be induced by the injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB). We employed transcranial direct current stimulation (tDCS, current intensity: 80 μA, and 40 μA; anodal electrode area: 3.14 mm(2); stimulation time: 30 minutes) over the M1 area to relieve the ipsilateral bias in the rat model. A corridor test was set to count the ipsilateral bias of the rats. In this experiment, 30 Sprague-Dawley rats (80 μA: n = 8, 40 μA: n = 8, sham: n = 7, healthy control: n = 7) were chosen for the corridor test and the tDCS session. The lesioned rats exhibited increased ipsilateral bias 4 weeks after the lesion surgery (P < 0.01), and the anodal tDCS with the active electrode on the lesioned side relieved the ipsilateral bias significantly (P < 0.01) immediately after the surgery and the improvement lasted for nearly 1 day. The rats in the group of 80 μA exhibited more significant changes than the 40 μA group after one day. After all the experiments, the histological process showed no neurotrauma led by the tDCS. In conclusion, the modulatory function of the cortical excitability of the tDCS may awaken the compensatory mechanisms and the response mechanisms which modulate the loss of the brain function. Further studies should be done to provide more evidence about the assumption.

  7. A New Surgical Model of Skeletal Muscle Injuries in Rats Reproduces Human Sports Lesions.

    PubMed

    Contreras-Muñoz, P; Fernández-Martín, A; Torrella, R; Serres, X; De la Varga, M; Viscor, G; Järvinen, T A H; Martínez-Ibáñez, V; Peiró, J L; Rodas, G; Marotta, M

    2016-03-01

    Skeletal muscle injuries are the most common sports-related injuries in sports medicine. In this work, we have generated a new surgically-induced skeletal muscle injury in rats, by using a biopsy needle, which could be easily reproduced and highly mimics skeletal muscle lesions detected in human athletes. By means of histology, immunofluorescence and MRI imaging, we corroborated that our model reproduced the necrosis, inflammation and regeneration processes observed in dystrophic mdx-mice, a model of spontaneous muscle injury, and realistically mimicked the muscle lesions observed in professional athletes. Surgically-injured rat skeletal muscles demonstrated the longitudinal process of muscle regeneration and fibrogenesis as stated by Myosin Heavy Chain developmental (MHCd) and collagen-I protein expression. MRI imaging analysis demonstrated that our muscle injury model reproduces the grade I-II type lesions detected in professional soccer players, including edema around the central tendon and the typically high signal feather shape along muscle fibers. A significant reduction of 30% in maximum tetanus force was also registered after 2 weeks of muscle injury. This new model represents an excellent approach to the study of the mechanisms of muscle injury and repair, and could open new avenues for developing innovative therapeutic approaches to skeletal muscle regeneration in sports medicine.

  8. Simulating a lesion in a basis function model of spatial representations: comparison with hemineglect.

    PubMed

    Pouget, A; Sejnowski, T J

    2001-07-01

    The basis function theory of spatial representations explains how neurons in the parietal cortex can perform nonlinear transformations from sensory to motor coordinates. The authors present computer simulations showing that unilateral parietal lesions leading to a neuronal gradient in basis function maps can account for the behavior of patients with hemineglect, including (a) neglect in line cancellation and line bisection experiments; (b) neglect in multiple frames of reference simultaneously; (c) relative neglect, a form of what is sometime called object-centered neglect; and (d) neglect without optic ataxia. Contralateral neglect arises in the model because the lesion produces an imbalance in the salience of stimuli that is modulated by the orientation of the body in space. These results strongly support the basis function theory for spatial representations in humans and provide a computational model of hemineglect at the single-cell level.

  9. Towards patient-specific modelling of lesion formation during radiofrequency catheter ablation for atrial fibrillation

    PubMed Central

    Soor, Navjeevan; Morgan, Ross; Varela, Marta; Aslanidi, Oleg V.

    2017-01-01

    Radiofrequency catheter ablation procedures are a first-line method of clinical treatment for atrial fibrillation. However, they suffer from suboptimal success rates and are also prone to potentially serious adverse effects. These limitations can be at least partially attributed to the inter- and intra- patient variations in atrial wall thickness, and could be mitigated by patient-specific approaches to the procedure. In this study, a modelling approach to optimising ablation procedures in subject-specific 3D atrial geometries was applied. The approach enabled the evaluation of optimal ablation times to create lesions for a given wall thickness measured from MRI. A nonliner relationship was revealed between the thickness and catheter contact time required for fully transmural lesions. Hence, our approach based on MRI reconstruction of the atrial wall combined with subject-specific modelling of ablation can provide useful information for improving clinical procedures.

  10. Application of Fluoro-Jade C in acute and chronic neurodegeneration models: utilities and staining differences.

    PubMed

    Ehara, Ayuka; Ueda, Shuichi

    2009-12-29

    Recent neuropathological studies have shown that Fluoro-Jade C (FJC), an anionic fluorescent dye, is a good marker of degenerating neurons. However, those studies have mostly examined acute rather than chronic models of neurodegeneration. We therefore compared FJC staining using the intrastriatal 6-hydroxydopamine (6-OHDA)-injected rat as an acute model and the zitter rat as a chronic model, as both show dopaminergic (DA) neurodegeneration. In the 6-OHDA-injected rat, FJC-positive neurons were found in the substantia nigra pars compacta (SNc) before the loss of tyrosine hydroxylase (TH)-positive DA neurons. In the zitter rat, FJC-labeled fibers were first detected at 1 month old (1M) and were considerably increased in the striatum at 4M, whereas FJC-labeled cell bodies were found at 4M, but not at 1M in the SNc. Furthermore, FJC-labeled neurons of the zitter rat showed TH-immunoreactivity in fibers, but little in cell bodies, while those from the 6-OHDA-injected rat showed TH-immunoreactivity even in the cell bodies. These results demonstrate that FJC is a useful tool for detecting chronically degenerating neurons, and suggest that intracellular substances bound to FJC may accumulate in the cell bodies from fibers at a slower rate in the chronic model than in the acute model.

  11. A heat transfer model of skin tissue for the detection of lesions: sensitivity analysis.

    PubMed

    Cetingül, M Pirtini; Herman, C

    2010-10-07

    In this paper, we study the transient thermal response of skin layers to determine to which extent the surface temperature distribution reflects the properties of subsurface structures, such as benign or malignant lesions. Specifically, we conduct a detailed sensitivity analysis to interpret the changes in the surface temperature distribution as a function of variations in thermophysical properties, blood perfusion rate, metabolic heat generation and thicknesses of skin layers, using a multilayer computational model. These properties can vary from individual to individual or depend on location, external and internal influences, and in certain situations accurate property data are not available in the literature. Therefore, the uncertainties in these data could potentially affect the accuracy of the interpretation/diagnosis of a lesion in a clinical setting. In this study, relevant parameters were varied within characteristic physiological ranges, and differences in the surface temperature response were quantified. It was observed that variations in these parameters have a small influence on the surface temperature distribution. Analysis using this multilayer model was further conducted to determine the sensitivity of transient thermal response to different lesion sizes. This work validates the idea of examining the transient thermal response obtained using a thermal imaging system with the objective of lesion identification. The modeling effort and the sensitivity analysis reported in this paper comprise a portion of a comprehensive research effort involving experimentation on a skin phantom model as well as measurements on patients in a clinical setting, that are currently underway. One of the preliminary results from the ongoing clinical trial is also included to demonstrate the feasibility of the proposed approach.

  12. A robust region-based active contour model with point classification for ultrasound breast lesion segmentation

    NASA Astrophysics Data System (ADS)

    Liu, Zhihua; Zhang, Lidan; Ren, Haibing; Kim, Ji-Yeun

    2013-02-01

    Lesion segmentation is one of the key technologies for computer-aided diagnosis (CAD) system. In this paper, we propose a robust region-based active contour model (ACM) with point classification to segment high-variant breast lesion in ultrasound images. First, a local signed pressure force (LSPF) function is proposed to classify the contour points into two classes: local low contrast class and local high contrast class. Secondly, we build a sub-model for each class. For low contrast class, the sub-model is built by combining global energy with local energy model to find a global optimal solution. For high contrast class, the sub-model is just the local energy model for its good level set initialization. Our final energy model is built by adding the two sub-models. Finally, the model is minimized and evolves the level set contour to get the segmentation result. We compare our method with other state-of-art methods on a very large ultrasound database and the result shows that our method can achieve better performance.

  13. Fasudil Decreases Lesion Burden in a Murine Model of Cerebral Cavernous Malformation Disease

    PubMed Central

    McDonald, David A.; Shi, Changbin; Shenkar, Robert; Stockton, Rebecca A.; Liu, Feifei; Ginsberg, Mark H.; Marchuk, Douglas A.; Awad, Issam A.

    2011-01-01

    Background and Purpose Cerebral cavernous malformations (CCMs) are characterized by grossly dilated capillaries, associated with vascular leak and hemorrhage, and occur in sporadic or inherited (autosomal dominant) forms with mutations in one of three gene loci (CCM 1, 2 or 3). We previously reported that the CCM1 protein (KRIT1) localizes to endothelial cell-cell junctions and loss of KRIT1 leads to junctional instability associated with activation of RhoA and its effector Rho kinase (ROCK). Although ROCK inhibition has been proposed as potential therapy for CCM, there has been no demonstration of a therapeutic effect on CCM lesion genesis in vivo. Methods Our recently generated a model of CCM1 disease (Ccm1+/−Msh2−/−) was treated with ROCK inhibitor fasudil (100 mg/kg/day administered in drinking water from weaning to 5 months of age), or placebo, and blindly assessed CCM lesion burden by systematic survey of animals’ brains. For comparison, we also assessed therapeutic effect in previously described Ccm2+/−Trp53−/− mice, treated with the same dose and duration of fasudil and placebo. Results Fasudil treated Ccm1+/−Msh2−/− mice had a significantly decreased prevalence of CCM lesions compared to placebo controls. Lesions in treated animals were smaller and less likely associated with hemorrhage, inflammation and endothelial proliferation, and exhibited decreased expression of ROCK activation biomarkers. A therapeutic effect was also documented in Ccm2+/−Trp53−/− mice. Conclusion This represents the first report of therapeutic benefit of pharmacological therapy in development and progression of CCMs, and indicates that ROCK activation is a critical step in CCM lesion genesis and maturation. PMID:22034008

  14. Evaluation of the chemical model of vestibular lesions induced by arsanilate in rats

    SciTech Connect

    Vignaux, G.; Chabbert, C.; Gaboyard-Niay, S.; Travo, C.; Machado, M.L.; Denise, P.; Comoz, F.; Hitier, M.; Landemore, G.; Philoxène, B.; Besnard, S.

    2012-01-01

    Several animal models of vestibular deficits that mimic the human pathology phenotype have previously been developed to correlate the degree of vestibular injury to cognate vestibular deficits in a time-dependent manner. Sodium arsanilate is one of the most commonly used substances for chemical vestibular lesioning, but it is not well described in the literature. In the present study, we used histological and functional approaches to conduct a detailed exploration of the model of vestibular lesions induced by transtympanic injection of sodium arsanilate in rats. The arsanilate-induced damage was restricted to the vestibular sensory organs without affecting the external ear, the oropharynx, or Scarpa's ganglion. This finding strongly supports the absence of diffusion of arsanilate into the external ear or Eustachian tubes, or through the eighth cranial nerve sheath leading to the brainstem. One of the striking observations of the present study is the complete restructuring of the sensory epithelia into a non sensory epithelial monolayer observed at 3 months after arsanilate application. This atrophy resembles the monolayer epithelia observed postmortem in the vestibular epithelia of patients with a history of lesioned vestibular deficits such as labyrinthectomy, antibiotic treatment, vestibular neuritis, or Ménière's disease. In cases of Ménière's disease, aminoglycosides, and platinum-based chemotherapy, vestibular hair cells are destroyed, regardless of the physiopathological process, as reproduced with the arsanilate model of vestibular lesion. These observations, together with those presented in this study of arsanilate vestibular toxicity, suggest that this atrophy process relies on a common mechanism of degeneration of the sensory epithelia.

  15. Sudden Death Following Selective Neuronal Lesions in the Rat Nucleus Tractus Solitarii

    PubMed Central

    Talman, William T.; Lin, Li-Hsien

    2013-01-01

    In efforts to assess baroreflex and cardiovascular responses in rats in which substance P (SP) or catecholamine transmission had been eliminated we studied animals after bilateral injections into the nucleus tractus solitarii (NTS) of SP or stabilized SP (SSP) conjugated to saporin (SP-SAP or SSP-SAP respectively) or SAP conjugated to an antibody to dopamine-β-hydroxylase (anti-DBH-SAP). We found that SP- and SSP-SAP eliminated NTS neurons that expressed the SP neurokinin-1 receptor (NK1R) while anti-DBH-SAP eliminated NTS neurons expressing tyrosine hydroxylase (TH) and DBH. The toxins were selective. Thus SP-or SSP-SAP did not eliminate TH/DBH neurons and anti-DBH-SAP did not eliminate NK1R neurons in the NTS. Each toxin, however, led to chronic lability of arterial blood pressure, diminished baroreflex function, cardiac ventricular irritability, coagulation necrosis of cardiac myocytes and, in some animals, sudden death associated with asystole. However, when TH/DBH neurons were targeted and eliminated by injection of 6-hydroxydopamine (6-OHDA), none of the cardiovascular or cardiac changes occurred. The studies reviewed here reveal that selective lesions of the NTS lead to altered baroreflex control and to cardiac changes that may lead to sudden death. Though the findings could support a role for SP or catecholamines in baroreflex transmission neither is proven in that NK1R colocalizes with glutamate receptors. Thus neurons with both are lost when treated with SP- or SSP-SAP. In addition, loss of catecholamine neurons after treatment with 6-OHDA does not affect cardiovascular control. Thus, the effect of the toxins may depend on an action of SAP independent of the effects of the SAP conjugates on targeted neuronal types. PMID:23245583

  16. Detection of questionable occlusal carious lesions using an electrical bioimpedance method with fractional electrical model

    NASA Astrophysics Data System (ADS)

    Morais, A. P.; Pino, A. V.; Souza, M. N.

    2016-08-01

    This in vitro study evaluated the diagnostic performance of an alternative electric bioimpedance spectroscopy technique (BIS-STEP) detect questionable occlusal carious lesions. Six specialists carried out the visual (V), radiography (R), and combined (VR) exams of 57 sound or non-cavitated occlusal carious lesion teeth classifying the occlusal surfaces in sound surface (H), enamel caries (EC), and dentinal caries (DC). Measurements were based on the current response to a step voltage excitation (BIS-STEP). A fractional electrical model was used to predict the current response in the time domain and to estimate the model parameters: Rs and Rp (resistive parameters), and C and α (fractional parameters). Histological analysis showed caries prevalence of 33.3% being 15.8% hidden caries. Combined examination obtained the best traditional diagnostic results with specificity = 59.0%, sensitivity = 70.9%, and accuracy = 60.8%. There were statistically significant differences in bioimpedance parameters between the H and EC groups (p = 0.016) and between the H and DC groups (Rs, p = 0.006; Rp, p = 0.022, and α, p = 0.041). Using a suitable threshold for the Rs, we obtained specificity = 60.7%, sensitivity = 77.9%, accuracy = 73.2%, and 100% of detection for deep lesions. It can be concluded that BIS-STEP method could be an important tool to improve the detection and management of occlusal non-cavitated primary caries and pigmented sites.

  17. The Impact of Exercise on the Vulnerability of Dopamine Neurons to Cell Death in Animal Models of Parkinson’s Disease

    DTIC Science & Technology

    2006-07-01

    and methamphetamine Our basic assumption is that protective treatments alter both post-translational and translational events so as to reduce the...the MN9D cells, which included changes in gene expression, alterations in protein synthesis , and post-translational state. Although we have not yet...cellular models. • Identified several of the mechanisms underlying preconditioning by 6-OHDA and methamphetamine in an in vitro model. • Replicated

  18. Serological validation of an alveolar echinococcosis rat model with a single hepatic lesion

    PubMed Central

    YAMASHITA, Masamichi; IMAGAWA, Tomohiro; SAKO, Yasuhito; OKAMOTO, Munehiro; YANAGIDA, Tetsuya; OKAMOTO, Yoshiharu; TSUKA, Takeshi; OSAKI, Tomohiro; ITO, Akira

    2016-01-01

    Serology is important for the diagnosis and follow-up of human alveolar echinococcosis (AE). However, patient conditions are highly variable among those with AE, and antibody responses in serological follow-up have not been well-defined. We recently described a new AE rat model established by implantation of small AE tissue into a single arbitrary location in the liver; no metastasis and dissemination were observed. In the present study, we examined the serological characteristics in our rat model before and after surgical treatment. The results showed that antibody responses against crude antigens were increased at one month after transplantation and similar to those of other model animals. For the antigen Em18, antibody responses were slower in our rat model than in other animal models. After surgical resection, changes in antibody responses against Em18 were similar to those observed in human patients with AE. Because of the slow growth of lesions, establishment of a single hepatic lesion and patterns of antibody responses, our rat model may be useful for clarifying follow-up serodiagnoses in human AE and determining the mechanisms of multi-organ involvement by primary infection with oncospheres rather than metastasis. PMID:27890868

  19. Neuroprotective effects of swimming training in a mouse model of Parkinson's disease induced by 6-hydroxydopamine.

    PubMed

    Goes, A T R; Souza, L C; Filho, C B; Del Fabbro, L; De Gomes, M G; Boeira, S P; Jesse, C R

    2014-01-03

    Parkinson's disease (PD) is characterized by progressive dopamine (DA) depletion in the striatum. Exercise has been shown to be a promising non-pharmacological approach to reduce the risk of neurodegeneration diseases. This study was designed to investigate the potential neuroprotective effect of swimming training (ST) in a mouse model of PD induced by 6-hydroxydopamine (6-OHDA) in mice. The present study demonstrated that a 4-week ST was effective in attenuating the following impairments resulting from 6-OHDA exposure: (i) depressive-like behavior in the tail suspension test; (ii) increase in the number of falls in the rotarod test; (iii) impairment on long-term memory in the object recognition test; (iv) increase of the reactive species and interleukin 1-beta (IL-1β) levels; (v) inhibition of the glutathione peroxidase (GPx) activity; (vi) rise of the glutathione reductase (GR) and glutathione S-transferase (GST) activities and vii) decrease of DA, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels. The mechanisms involved in this study are the modulation of GPx, GR and GST activities as well as IL-1β level in a PD model induced by 6-OHDA, protecting against the decrease of DA, DOPAC and HVA levels in the striatum of mice. These findings reinforce that one of the effects induced by exercise on neurodegenerative disease, such as PD, is due to antioxidant and anti-inflammatory properties. We suggest that exercise attenuates cognitive and motor declines, depression, oxidative stress, and neuroinflammation induced by 6-OHDA supporting the hypothesis that exercise can be used as a non-pharmacological tool to reduce the symptoms of PD.

  20. Comparison of models to identify lame cows based on gait and lesion scores, and limb movement variables.

    PubMed

    Rajkondawar, P G; Liu, M; Dyer, R M; Neerchal, N K; Tasch, U; Lefcourt, A M; Erez, B; Varner, M A

    2006-11-01

    Bovine lameness results in pain and suffering in cattle and economic loss for producers. A system for automatically detecting lame cows was developed recently that measures vertical force components attributable to individual limbs. These measurements can be used to calculate a number of limb movement variables. The objective of this investigation was to explore whether gait scores, lesion scores, or combined gait and lesion scores were more effectively captured by a set of 5 limb movement variables. A set of 700 hind limb examinations was used to create gait-based, lesion-based, and combined (gait- and lesion-based) models. Logistic regression models were constructed using 1, 2, or 3 d of measurements. Resulting models were tested on cows not used in modeling. The accuracy of lesion-score models was superior to that of gait-score models; lesion-based models generated greater values of areas under the receiving operating characteristic curves (range 0.75 to 0.84) and lower mean-squared errors (0.13 to 0.16) compared with corresponding values for the gait-based models (0.63 to 0.73 and 0.26 to 0.31 for receiving operating characteristic and mean-squared errors, respectively). These results indicate that further model development and investigation could generate automated and objective methods of lameness detection in dairy cattle.

  1. A novel thiol antioxidant that crosses the blood brain barrier protects dopaminergic neurons in experimental models of Parkinson's disease.

    PubMed

    Bahat-Stroomza, Merav; Gilgun-Sherki, Yossi; Offen, Daniel; Panet, Hana; Saada, Ann; Krool-Galron, Nili; Barzilai, Aari; Atlas, Daphne; Melamed, Eldad

    2005-02-01

    It is believed that oxidative stress (OS) plays an important role in the loss of dopaminergic nigrostriatal neurons in Parkinson's disease (PD) and that treatment with antioxidants might be neuroprotective. However, most currently available antioxidants cannot readily penetrate the blood brain barrier after systemic administration. We now report that AD4, the novel low molecular weight thiol antioxidant and the N-acytel cysteine (NAC) related compound, is capable of penetrating the brain and protects neurons in general and especially dopaminergic cells against various OS-generating neurotoxins in tissue cultures. Moreover, we found that treatment with AD4 markedly decreased the damage of dopaminergic neurons in three experimental models of PD. AD4 suppressed amphetamine-induced rotational behaviour in rats with unilateral 6-OHDA-induced nigral lesion. It attenuated the reduction in striatal dopamine levels in mice treated with 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP). It also reduced the dopaminergic neuronal loss following chronic intrajugular administration of rotenone in rats. Our findings suggest that AD4 is a novel potential new neuroprotective drug that might be effective at slowing down nigral neuronal degeneration and illness progression in patients with PD.

  2. Color diffusion model for active contours - an application to skin lesion segmentation.

    PubMed

    Ivanovici, Mihai; Stoica, Diana

    2012-01-01

    Most of the existing diffusion models are defined for gray-scale images. We propose a diffusion model for color images to be used as external energy for active contours. Our diffusion model is based on the first-order moment of the correlation integral expressed using ΔE distances in the CIE Lab color space. We use a multi-scale approach for active contours, the diffusion being independently computed at various scales. We validate the model on synthetic images, including multi-fractal color textures, as well as medical images representing melanoma. We conclude that the proposed diffusion model is valid for use in skin lesion segmentation in color images using active contours.

  3. A new background distribution-based active contour model for three-dimensional lesion segmentation in breast DCE-MRI

    SciTech Connect

    Liu, Hui; Liu, Yiping; Qiu, Tianshuang; Zhao, Zuowei; Zhang, Lina

    2014-08-15

    Purpose: To develop and evaluate a computerized semiautomatic segmentation method for accurate extraction of three-dimensional lesions from dynamic contrast-enhanced magnetic resonance images (DCE-MRIs) of the breast. Methods: The authors propose a new background distribution-based active contour model using level set (BDACMLS) to segment lesions in breast DCE-MRIs. The method starts with manual selection of a region of interest (ROI) that contains the entire lesion in a single slice where the lesion is enhanced. Then the lesion volume from the volume data of interest, which is captured automatically, is separated. The core idea of BDACMLS is a new signed pressure function which is based solely on the intensity distribution combined with pathophysiological basis. To compare the algorithm results, two experienced radiologists delineated all lesions jointly to obtain the ground truth. In addition, results generated by other different methods based on level set (LS) are also compared with the authors’ method. Finally, the performance of the proposed method is evaluated by several region-based metrics such as the overlap ratio. Results: Forty-two studies with 46 lesions that contain 29 benign and 17 malignant lesions are evaluated. The dataset includes various typical pathologies of the breast such as invasive ductal carcinoma, ductal carcinomain situ, scar carcinoma, phyllodes tumor, breast cysts, fibroadenoma, etc. The overlap ratio for BDACMLS with respect to manual segmentation is 79.55% ± 12.60% (mean ± s.d.). Conclusions: A new active contour model method has been developed and shown to successfully segment breast DCE-MRI three-dimensional lesions. The results from this model correspond more closely to manual segmentation, solve the weak-edge-passed problem, and improve the robustness in segmenting different lesions.

  4. The L-type channel antagonist isradipine is neuroprotective in a mouse model of Parkinson’s disease

    PubMed Central

    Ilijic, E; Guzman, JN; Surmeier, DJ

    2011-01-01

    The motor symptoms of Parkinson’s disease (PD) are due to the progressive loss of dopamine (DA) neurons in substantia nigra pars compacta (SNc). Nothing is known to slow the progression of the disease, making the identification of potential neuroprotective agents of great clinical importance. Previous studies using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD have shown that antagonism of L-type Ca2+ channels protects SNc DA neurons. However, this was not true in a 6-hydroxydopamine (6-OHDA) model. One potential explanation for this discrepancy is that protection in the 6-OHDA model requires greater antagonism of Cav1.3 L-type Ca2+ channels thought to underlie vulnerability and this was not achievable with the low affinity dihydropyridine (DHP) antagonist used. To test this hypothesis, the DHP with the highest affinity for Cav1.3 L-type channels – isradipine – was systemically administered and then the DA toxin 6-OHDA injected intrastriatally. Twenty-five days later, neuroprotection and plasma concentration of isradipine were determined. This analysis revealed that isradipine produced a dose-dependent sparing of DA fibers and cell bodies at concentrations achievable in humans, suggesting that isradipine is a potentially viable neuroprotective agent for PD. PMID:21515375

  5. Assessment of a Diagnostic Predictive Probability Model Provided by a Multispectral Digital Skin Lesion Analysis Device for Melanoma and Other High-risk Pigmented Lesions and its Impact on Biopsy Decisions

    PubMed Central

    Yoo, Jane; Tucker, Natalie; White, Richard; Rigel, Darrell S.

    2014-01-01

    Objective: Risk prediction models for primary malignant melanoma thus far have relied on qualitative patient information. The authors propose a quantitative diagnostic predictive probability model using Multispectral Digital Skin Lesion Analysis for melanoma and other high-risk pigmented lesions and evaluate its effectiveness optimizing biopsy decisions by dermatologists. Design: Data from 1,632 pigmented lesions analyzed by a Multispectral Digital Skin Lesion Analysis device were used to perform a logistic regression analysis. This new quantitative melanoma or melanoma/atypical melanocytic hyperplasia/high-grade dysplastic nevus probability model was then evaluated to determine its impact on dermatologist decisions to biopsy pigmented lesions clinically suggestive of melanoma. Participants were given an electronic keypad and answered “yes” or “no” if they would biopsy each of 12 pigmented lesions when presented first with patient history, clinical images, and dermoscopic images and again when subsequently shown Multispectral Digital Skin Lesion Analysis data. Setting/participants: Study of 191 dermatologists at a medical conference. Measurements: Sensitivity, specificity, biopsy accuracy, overall biopsy rate, and percentage dermatologists biopsying all five melanomas. Results: Dermatologists were significantly more sensitive, specific, and accurate while decreasing overall biopsy rates with Multispectral Digital Skin Lesion Analysis probability information. Conclusion: Integration of Multispectral Digital Skin Lesion Analysis probability information in the biopsy evaluation and selection process of pigmented lesions has the potential to improve melanoma sensitivity of dermatologists without the concomitant costs associated with additional biopsies being performed. PMID:25584133

  6. Sparse Codebook Model of Local Structures for Retrieval of Focal Liver Lesions Using Multiphase Medical Images

    PubMed Central

    Han, Xian-Hua; Xu, Yingying; Lin, Lanfen; Hu, Hongjie; Jin, Chongwu

    2017-01-01

    Characterization and individual trait analysis of the focal liver lesions (FLL) is a challenging task in medical image processing and clinical site. The character analysis of a unconfirmed FLL case would be expected to benefit greatly from the accumulated FLL cases with experts' analysis, which can be achieved by content-based medical image retrieval (CBMIR). CBMIR mainly includes discriminated feature extraction and similarity calculation procedures. Bag-of-Visual-Words (BoVW) (codebook-based model) has been proven to be effective for different classification and retrieval tasks. This study investigates an improved codebook model for the fined-grained medical image representation with the following three advantages: (1) instead of SIFT, we exploit the local patch (structure) as the local descriptor, which can retain all detailed information and is more suitable for the fine-grained medical image applications; (2) in order to more accurately approximate any local descriptor in coding procedure, the sparse coding method, instead of K-means algorithm, is employed for codebook learning and coded vector calculation; (3) we evaluate retrieval performance of focal liver lesions (FLL) using multiphase computed tomography (CT) scans, in which the proposed codebook model is separately learned for each phase. The effectiveness of the proposed method is confirmed by our experiments on FLL retrieval. PMID:28293255

  7. Spontaneous Healing of Mycobacterium ulcerans Lesions in the Guinea Pig Model

    PubMed Central

    Silva-Gomes, Rita; Marcq, Elly; Trigo, Gabriela; Gonçalves, Carine M.; Longatto-Filho, Adhemar; Castro, António G.; Pedrosa, Jorge; Fraga, Alexandra G.

    2015-01-01

    Buruli Ulcer (BU) is a necrotizing skin disease caused by Mycobacterium ulcerans infection. BU is characterized by a wide range of clinical forms, including non-ulcerative cutaneous lesions that can evolve into severe ulcers if left untreated. Nevertheless, spontaneous healing has been reported to occur, although knowledge on this process is scarce both in naturally infected humans and experimental models of infection. Animal models are useful since they mimic different spectrums of human BU disease and have the potential to elucidate the pathogenic/protective pathway(s) involved in disease/healing. In this time-lapsed study, we characterized the guinea pig, an animal model of resistance to M. ulcerans, focusing on the macroscopic, microbiological and histological evolution throughout the entire experimental infectious process. Subcutaneous infection of guinea pigs with a virulent strain of M. ulcerans led to early localized swelling, which evolved into small well defined ulcers. These macroscopic observations correlated with the presence of necrosis, acute inflammatory infiltrate and an abundant bacterial load. By the end of the infectious process when ulcerative lesions healed, M. ulcerans viability decreased and the subcutaneous tissue organization returned to its normal state after a process of continuous healing characterized by tissue granulation and reepethelialization. In conclusion, we show that the experimental M. ulcerans infection of the guinea pig mimics the process of spontaneous healing described in BU patients, displaying the potential to uncover correlates of protection against BU, which can ultimately contribute to the development of new prophylactic and therapeutic strategies. PMID:26625302

  8. Anti-high mobility group box 1 antibody exerts neuroprotection in a rat model of Parkinson's disease.

    PubMed

    Sasaki, Tatsuya; Liu, Keyue; Agari, Takashi; Yasuhara, Takao; Morimoto, Jun; Okazaki, Mihoko; Takeuchi, Hayato; Toyoshima, Atsuhiko; Sasada, Susumu; Shinko, Aiko; Kondo, Akihiko; Kameda, Masahiro; Miyazaki, Ikuko; Asanuma, Masato; Borlongan, Cesario V; Nishibori, Masahiro; Date, Isao

    2016-01-01

    The high mobility group box-1 (HMGB1) exists as an architectural nuclear protein in the normal state, but displays an inflammatory cytokine-like activity in the extracellular space under pathological condition. Inflammation in the pathogenesis of Parkinson's disease (PD) has been documented. In this study, we investigated the involvement of HMGB1 in the pathology and the neuroprotective effects of neutralizing anti-HMGB1 monoclonal antibody (mAb) on an animal model of PD. Adult female Sprague-Dawley rats were initially injected with 6-hydroxydopmaine (6-OHDA, 20 μg/4 μl) into the right striatum, then anti-HMGB1 mAb (1 mg/kg), or control mAb was intravenously administered immediately, at 6 and 24 h after 6-OHDA injection. The treatment with anti-HMGB1 mAb significantly preserved dopaminergic neurons in substantia nigra pars compacta and dopaminergic terminals inherent in the striatum, and attenuated PD behavioral symptoms compared to the control mAb-treated group. HMGB1 was retained in the nucleus of neurons and astrocytes by inhibiting the proinflammation-induced oxidative stress in the anti-HMGB1 mAb-treated group, whereas HMGB1 translocation was observed in neurons at 1 day and astrocytes at 7 days after 6-OHDA injection in the control mAb-treated group. Anti-HMGB1 mAb inhibited the activation of microglia, disruption of blood-brain-barrier (BBB), and the expression of inflammation cytokines such as IL-1β and IL-6. These results suggested that HMGB1 released from neurons and astrocytes was at least partly involved in the mechanism and pathway of degeneration of dopaminergic neurons induced by 6-OHDA exposure. Intravenous administration of anti-HMGB1 mAb stands as a novel therapy for PD possibly acting through the suppression of neuroinflammation and the attenuation of disruption of BBB associated with the disease.

  9. Modeling and simulation of HIFU induced lesions using different treatment pattern

    NASA Astrophysics Data System (ADS)

    Qiao, Shan; Shen, Guofeng; Bai, Jingfeng; Chen, Yazhu

    2012-10-01

    Long heating time is needed to ablate a large area using high intensity focused ultrasound, while multiple-focus pattern or single-focus scan is used. This process may cause unexpected temperature rise in pre-focal regions, which can distort acoustic propagation and affect lesion formations. This article simulates this process by using a thermo-acoustic model, which is based on linear acoustic equations and the heat transfer equation, considering parameter variations due to temperature rising of media on the propagation path. Perfect matched layer (PML) technique is introduced for the absorb boundary condition. Finite difference time-domain (FDTD) method is applied to solve the thermo-acoustic model. The simulations that describe lesion formations in multiple-layer media with different treatment patterns-single focus, multiple-focus and single-focus scan are investigated respectively. These simulations indicate that distortions can be serious with single-focus scan method. Additionally, the single-focus scan patterns applying different interval time length are also simulated. The results imply that the proper interval time can minimize the ultrasound distribution distortion caused by pre-focal heating.

  10. Photodynamic therapy for the treatment of metastatic lesions in bone: studies in rat and porcine models

    NASA Astrophysics Data System (ADS)

    Burch, S.; Bisland, Stuart K.; Siewerdsen, Jeff; Bogaards, Arjen; Moseley, Douglas; Yee, A.; Finkelstein, J.; Wilson, Brian

    2004-06-01

    This study represents the first reported use of photodynamic therapy in bone and specifically, as a treatment for spinal metastases. A metastatic model in rat confirmed the efficacy of benzoporphyrin derivative-monoacid-mediated PDT for treating lesions within the spine and appendicular bone. Fluorimetry confirmed the selective accumulation of drug into the tumor(s) at 3 hours post-injection. 48 hrs post light delivery into the vertebral body of the rat spine loss of bioluminescent signal and histological analyses of sectioned spine confirmed MT-1 tumor cell kill in vivo as previously confirmed in vitro using an established cell viability assay. Porcine vertebrae provided a model comparable to that of human for light propagation and PDT response. Light measurements were recorded at 2.5 mm increments as the detector probe was retracted out of the vertebral body away from a diffusing fiber at 70-90° planar angle to it. At 30 minutes or 1hr post BPD-MA administration (6 mg/m2), light (648 J, 150 mW/cm, 690 nm) was delivered to vertebrae L1 and/or L2. Vertebrae were harvested and sectioned for histology 48 hrs following PDT. Light propagation was plotted as distance (μm) from the emitting source. Results support the application of PDT to the treatment of primary or metastatic lesions within bone.

  11. [High-frequency electro-acupuncture stimulation modulates intracerebral γ-aminobutyric acid content in rat model of Parkinson's disease].

    PubMed

    Du, Jing; Sun, Zuo-Li; Jia, Jun; Wang, Xuan; Wang, Xiao-Min

    2011-08-25

    The purpose of the present study is to observe the effect of electro-acupuncture (EA) stimulation on intracerebral neurotransmitters in a rat model of Parkinson's disease (PD), and explore the possible mechanism. We used 6-hydroxydopamine (6-OHDA) injection in medial forebrain bundle (MFB) in the right brain of Sprague Dawley (SD) rat to establish the parkinsonian rat model, and randomly divided the PD rats into model and 100 Hz EA stimulation groups (n =10 in each group). EA stimulation group received 4 courses of EA stimulation on Baihui (GV-20) and Dazhui (GV-14) acupuncture points. Moreover, ten rats were randomly selected as sham operation group, only receiving normal saline (NS) injection in MFB. Then apomorphine (APO)-induced rotational behavior in different groups was recorded, and the contents of γ-aminobutyric acid (GABA) in the brain were analyzed with high pressure/performance liquid chromatography-electrochemical detection (HPLC-ECD). The results showed that model group exhibited abnormal rotational behavior with APO treatment, suggesting the successful establishment of PD model. Compared with sham operation group, model group showed increased GABA contents in cortex and striatum, as well as decreased GABA content in ventral midbrain, on the lesioned side. EA stimulation could effectively ameliorate the abnormal rotational behavior of PD rat. Compared with the model group, EA stimulation decreased the ratio of GABA content on the lesioned side to that on unlesioned side in the cortex, while increased the ratios in the striatum and cerebellum. However, there was no difference of the ratio in the ventral midbrain among three groups. These results suggest high-frequency EA stimulation significantly improves the abnormal behavior of PD rats, which may exert through enhancing the inhibitory effect of cerebellum-basal ganglia-cortical loop on motor center.

  12. Tio2-dopamine complex implanted unilaterally in the caudate nucleus improves motor activity and behavior function of rats with induced hemiparkinsonism.

    PubMed

    Vergara-Aragón, Patricia; Domínguez-Marrufo, Leonardo Eduardo; Ibarra-Guerrero, Patricia; Hernandez-Ramírez, Heidi; Hernández-Téllez, Beatriz; López-Martínez, Irma Elena; Sánchez-Cervantes, Ivonne; Santiago-Jacinto, Patricia; García-Macedo, Jorge Alberto; Valverde-Aguilar, Guadalupe; Santiago, Julio

    2011-01-01

    Parkinson's disease (PD) is characterized by malfunction of dopaminergic systems, and the current symptomatic treatment is to replace lost dopamine. For investigating mechanisms of pathogenesis and alternative treatments to compensate lack of dopamine (DA) activity in PD, the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD has been useful, these animals display apomorphine-induced contralateral rotational behavior, when they are examined after lesion. The purpose of this study was to assess Titania-dopamine (TiO2-DA) complexes implanted on the caudate nucleus for diminishing motor behavior alterations of the 6-OHDA rat model. Rats with 6-OHDA unilateral lesions received TiO2 alone or TiO2-DA implants, and were tested for open field (OF) gross motor crossing and rearing behaviors, and apomorphine-induced rotation (G) behavior. TiO2 complex have no effects on rearing OF and G behaviors, and a significant reducing effect on crossing motor behavior of normal rats compared to control non-treated rats throughout 56 days of observation. Interestingly, TiO2-DA treatment significant recovered motor crossing and rearing behaviors in 6-OHDA-lesioned rats, and diminished the G behaviors during 56 days of examination. Additionally, in the 6-OHDA-lesioned rats TiO2 treatment had a moderate recovering effect only on crossing behavior compared to lesioned non treated rats. Our results suggest that continuous release of dopamine in the caudate nucleus from TiO2-DA complex is capable of reversing gross motor deficits observed in the 6-OHDA-lesioned rat model of PD. Thistype of delivery system of DA represents a promising therapy for PD in humans.

  13. Automatic coronary lumen segmentation with partial volume modeling improves lesions' hemodynamic significance assessment

    NASA Astrophysics Data System (ADS)

    Freiman, M.; Lamash, Y.; Gilboa, G.; Nickisch, H.; Prevrhal, S.; Schmitt, H.; Vembar, M.; Goshen, L.

    2016-03-01

    The determination of hemodynamic significance of coronary artery lesions from cardiac computed tomography angiography (CCTA) based on blood flow simulations has the potential to improve CCTA's specificity, thus resulting in improved clinical decision making. Accurate coronary lumen segmentation required for flow simulation is challenging due to several factors. Specifically, the partial-volume effect (PVE) in small-diameter lumina may result in overestimation of the lumen diameter that can lead to an erroneous hemodynamic significance assessment. In this work, we present a coronary artery segmentation algorithm tailored specifically for flow simulations by accounting for the PVE. Our algorithm detects lumen regions that may be subject to the PVE by analyzing the intensity values along the coronary centerline and integrates this information into a machine-learning based graph min-cut segmentation framework to obtain accurate coronary lumen segmentations. We demonstrate the improvement in hemodynamic significance assessment achieved by accounting for the PVE in the automatic segmentation of 91 coronary artery lesions from 85 patients. We compare hemodynamic significance assessments by means of fractional flow reserve (FFR) resulting from simulations on 3D models generated by our segmentation algorithm with and without accounting for the PVE. By accounting for the PVE we improved the area under the ROC curve for detecting hemodynamically significant CAD by 29% (N=91, 0.85 vs. 0.66, p<0.05, Delong's test) with invasive FFR threshold of 0.8 as the reference standard. Our algorithm has the potential to facilitate non-invasive hemodynamic significance assessment of coronary lesions.

  14. Locally adaptive MR intensity models and MRF-based segmentation of multiple sclerosis lesions

    NASA Astrophysics Data System (ADS)

    Galimzianova, Alfiia; Lesjak, Žiga; Likar, Boštjan; Pernuš, Franjo; Špiclin, Žiga

    2015-03-01

    Neuroimaging biomarkers are an important paraclinical tool used to characterize a number of neurological diseases, however, their extraction requires accurate and reliable segmentation of normal and pathological brain structures. For MR images of healthy brains the intensity models of normal-appearing brain tissue (NABT) in combination with Markov random field (MRF) models are known to give reliable and smooth NABT segmentation. However, the presence of pathology, MR intensity bias and natural tissue-dependent intensity variability altogether represent difficult challenges for a reliable estimation of NABT intensity model based on MR images. In this paper, we propose a novel method for segmentation of normal and pathological structures in brain MR images of multiple sclerosis (MS) patients that is based on locally-adaptive NABT model, a robust method for the estimation of model parameters and a MRF-based segmentation framework. Experiments on multi-sequence brain MR images of 27 MS patients show that, compared to whole-brain model and compared to the widely used Expectation-Maximization Segmentation (EMS) method, the locally-adaptive NABT model increases the accuracy of MS lesion segmentation.

  15. Automatic iterative segmentation of multiple sclerosis lesions using Student's t mixture models and probabilistic anatomical atlases in FLAIR images.

    PubMed

    Freire, Paulo G L; Ferrari, Ricardo J

    2016-06-01

    Multiple sclerosis (MS) is a demyelinating autoimmune disease that attacks the central nervous system (CNS) and affects more than 2 million people worldwide. The segmentation of MS lesions in magnetic resonance imaging (MRI) is a very important task to assess how a patient is responding to treatment and how the disease is progressing. Computational approaches have been proposed over the years to segment MS lesions and reduce the amount of time spent on manual delineation and inter- and intra-rater variability and bias. However, fully-automatic segmentation of MS lesions still remains an open problem. In this work, we propose an iterative approach using Student's t mixture models and probabilistic anatomical atlases to automatically segment MS lesions in Fluid Attenuated Inversion Recovery (FLAIR) images. Our technique resembles a refinement approach by iteratively segmenting brain tissues into smaller classes until MS lesions are grouped as the most hyperintense one. To validate our technique we used 21 clinical images from the 2015 Longitudinal Multiple Sclerosis Lesion Segmentation Challenge dataset. Evaluation using Dice Similarity Coefficient (DSC), True Positive Ratio (TPR), False Positive Ratio (FPR), Volume Difference (VD) and Pearson's r coefficient shows that our technique has a good spatial and volumetric agreement with raters' manual delineations. Also, a comparison between our proposal and the state-of-the-art shows that our technique is comparable and, in some cases, better than some approaches, thus being a viable alternative for automatic MS lesion segmentation in MRI.

  16. Impact of Prostate Inflammation on Lesion Development in the POET3+Pten+/− Mouse Model of Prostate Carcinogenesis

    PubMed Central

    Burcham, Grant N.; Cresswell, Gregory M.; Snyder, Paul W.; Chen, Long; Liu, Xiaoqi; Crist, Scott A.; Henry, Michael D.; Ratliff, Timothy L.

    2015-01-01

    Evidence linking prostatitis and prostate cancer development is contradictory. To study this link, the POET3 mouse, an inducible model of prostatitis, was crossed with a Pten-loss model of prostate cancer (Pten+/−) containing the ROSA26 luciferase allele to monitor prostate size. Prostatitis was induced, and prostate bioluminescence was tracked over 12 months, with lesion development, inflammation, and cytokine expression analyzed at 4, 8, and 12 months and compared with mice without induction of prostatitis. Acute prostatitis led to more proliferative epithelium and enhanced bioluminescence. However, 4 months after initiation of prostatitis, mice with induced inflammation had lower grade pre-neoplastic lesions. A trend existed toward greater development of carcinoma 12 months after induction of inflammation, including one of two mice with carcinoma developing perineural invasion. Two of 18 mice at the later time points developed lesions with similarities to proliferative inflammatory atrophy, including one mouse with associated carcinoma. Pten+/− mice developed spontaneous inflammation, and prostatitis was similar among groups of mice at 8 and 12 months. Analyzed as one cohort, lesion number and grade were positively correlated with prostatitis. Specifically, amounts of CD11b+Gr1+ cells were correlated with lesion development. These results support the hypothesis that myeloid-based inflammation is associated with lesion development in the murine prostate, and previous bouts of CD8-driven prostatitis may promote invasion in the Pten+/− model of cancer. PMID:25455686

  17. Computer-assisted lesion detection system for stomach screening using stomach shape and appearance models

    NASA Astrophysics Data System (ADS)

    Midoh, Y.; Nakamura, M.; Takashima, M.; Nakamae, K.; Fujioka, H.

    2007-03-01

    In Japan, stomach cancer is one of the three most common causes of death from cancer. Since periodic health checks of stomach X-rays have become more widely carried out, the physicians' burdens have been increasing in the mass screening to detect initial symptoms of a disease. For the purpose of automatic diagnosis, we try to develop a computer-assisted lesion detection system for stomach screening. The proposed system has two databases. One is the stomach shape database that consists of the computer graphics stomach 3D models based on biomechanics simulation and their projected 2D images. The other is the normal appearance database that is constructed by learning patterns in a normal patient training set. The stomach contour is extracted from an X-ray image including a barium filled region by the following steps. Firstly, the approximated stomach region is obtained by nonrigid registration based on mutual information. We define nonrigid transformation as one that includes translations, rotations, scaling, air-barium interface and weights of eigenvectors determined by principal components analysis in the stomach shape database. Secondly, the accurate stomach contour is extracted from the gradient of an image by using the Dynamic Programming. After then, stomach lesions are detected by inspecting whether the Mahalanobis distance from the mean in the normal appearance database is longer than a suitable value on the extracted stomach contour. We applied our system to 75 X-ray images of barium-filled stomach to show its validity.

  18. Effect of carbon dioxide laser treatment on lesion progression in an intraoral model

    NASA Astrophysics Data System (ADS)

    Featherstone, John D. B.; Fried, Daniel; Gansky, Stuart A.; Stookey, George K.; Dunipace, Ann J.

    2001-04-01

    Previous studies have shown that pretreatment of dental enamel by specific carbon dioxide laser conditions inhibited subsequent progression of caries-like lesions in vitro. The aim of the present study was to use an intra-oral model to determine whether similar inhibition is observed in the human mouth. A cross over study with 23 subjects and three regimens was used. Pre-formed varies-like lesions were made in extracted human enamel and exposed intra-orally in partial dentures in each subject to A) placebo dentifrice and no laser treatment, B) placebo dentifrice following laser pretreatment, or C) sodium fluoride dentifrice and no laser treatment during each of three study periods. Samples were assessed by micro radiography to compare the mineral loss before and after each treatment and drive a net change in mineral value. Overall P was not significantly different form L but both P and L were different from F. For those subjects who demineralized in P, L and F were significantly better than P, with L showing an 84 percent inhibition of further demineralization, but no enhancement of demineralization.

  19. Protective effects of leflunomide on renal lesions in a rat model if diabetic nephropathy.

    PubMed

    Zhang, Qing; Ji, Yongqiang; Lv, Wei; He, Tianwei; Wang, Jianping

    2016-01-01

    Diabetic nephropathy is one of the most common chronic complications of diabetes with poor efficacy of clinical treatment. This study investigated the protective effects of leflunomide, a new immunosuppressant, on tubulointerstitial lesions in a rat model of diabetic nephropathy. Diabetes was induced with streptozotocin (STZ, 50 mg/kg) by intraperitoneal injection in male Wistar rats. Two weeks after STZ injection, diabetic rats were treated daily for 8 weeks with low (5 mg/kg) and high dose (10 mg/kg) of leflunomide, and benazepril hydrochloride (4 mg/kg) as a positive control. In diabetic rats, the 24-h urine volume, urine protein and microalbumin, blood creatinine and urea nitrogen significantly increased, which were attenuated by leflunomide treatment in a dose-dependent manner (all p < 0.05). The increase of kidney weight/body weight and the histopathological findings of tubulointerstitial lesion in diabetic rats were mitigated by leflunomide treatment. Immunohistochemistry study and real-time polymerase chain reaction results demonstrated that osteopontin (OPN), transforming growth factor beta 1 (TGF-β1), α-smooth muscle actin and CD68 expression in the renal tubulointerstitial region were significantly increased in the diabetic rats, while these increases were inhibited by leflunomide treatment. These findings suggest that leflunomide protects the kidney injury of diabetic rats might through its inhibition of OPN/TGF-β1 mediated extracellular matrix deposition and tubulointerstitial fibrosis, as well as its inhibition on tubular epithelial-myofibroblast transdifferentiation.

  20. Five myofibrillar lesion types in eccentrically challenged, unloaded rat adductor longus muscle--a test model

    NASA Technical Reports Server (NTRS)

    Thompson, J. L.; Balog, E. M.; Fitts, R. H.; Riley, D. A.

    1999-01-01

    Sarcomere disruptions are observed in the adductor longus (AL) muscles following voluntary reloading of spaceflown and hindlimb suspension unloaded (HSU) rat, which resemble lesions in eccentrically challenged muscle. We devised and tested an eccentric contraction (ECCON) test system for the 14-day HSU rat AL. Six to 7 hours following ECCON, ALs were fixed to allow immunostaining and electron microscopy (EM). Toluidine blue-stained histology semithin sections were screened for lesion density (#/mm2). Serial semithin sections from the ECCON group were characterized for myosin immunointensity of lesions. Five myofibrillar lesion types were identified in histological semithin sections: focal contractions; wide A-bands; opaque areas; missing A-bands; and hyperstretched sarcomeres. Lesion density by type was greater for ECCON than NonECCON ALs (P< or =0.05; focal contractions and opaque regions). Lesion density (#-of-all-five-types/mm2) was significantly different (ECCON: 23.91+/-10.58 vs. NonECCON: 5.48+/-1.28, P< or =0.05; ECCON vs. SHAM: 0.00+/-0.00; P< or = 0.025). PostECCON optimal tension decreased (Poi-drop, 17.84+/-4.22%) and was correlated to lesion density (R2=0.596), but prestretch tension demonstrated the highest correlation with lesion density (R2=0.994). In lesions, the darkly staining A-band lost the normally organized thick filament alignment to differing degrees across the different lesion types. Ranking the five lesion types by a measure of lesion length deformation (hypercontracted to hyperstretched) at the light microscopy level, related to the severity of thick filament registry loss across the lesion types at the electron microscopic level. This ranking suggested that the five lesion types seen in semithin sections at the light level represented a lesion progression sequence and paralleled myosin immunostaining loss as the distorted A-band filaments spread across the hyperlengthening lesion types. Lesion ultrastructure indicated damage involved

  1. A central neuropathic pain model by DSP-4 induced lesion of noradrenergic neurons: preliminary report.

    PubMed

    Kudo, Takashi; Kushikata, Tetsuya; Kudo, Mihoko; Kudo, Tsuyoshi; Hirota, Kazuyoshi

    2010-09-06

    Neuropathic pain models are classified as central and peripheral pain models. Although various peripheral neuropathic pain models are established, central pain models are based only on spinal cord injury. DSP-4 is a competitive inhibitor of norepinephrine uptake that selectively degenerates the locus coeruleus (LC)-noradrenergic neurons projection to the cerebral cortex and hippocampus. In the present study, we have tested whether lesion of LC-noradrenergic neurons by ip DSP-4 (0, 10, 30, 50 mg/kg, n=7 each) could provide a new central neuropathic pain model in rats using a hot-plate and tail-flick tests. DSP-4 significantly reduced the hot-plate latency and norepinephrine contents especially in the coerulean regions. However, DSP-4 did not change tail-flick latency. There are significant correlations of the latency in the hot-plate test with norepinephrine contents in the cerebral cortex (r=0.432, p=0.022), the hippocampus (r=0.465, p=0.013) and the pons (r=0.400, p=0.035) but not with those in the hypothalamus and the spinal cord. As response to hot-plate and tail-flick implies supra-spinal process and spinal reflex, respectively, central neuropathic pain may be facilitated by DSP-4 depleting LC-noradrenergic neurons although the present data are preliminary.

  2. Dopaminergic Lesions of the Dorsolateral Striatum in Rats Increase Delay Discounting in an Impulsive Choice Task

    PubMed Central

    Tedford, Stephanie E.; Persons, Amanda L.; Napier, T. Celeste

    2015-01-01

    Dysregulated dopamine transmission in striatal circuitry is associated with impulsivity. The current study evaluated the influence of dopaminergic inputs to the dorsolateral striatum on impulsive choice, one aspect of impulsive behavior. We implemented an operant task that measures impulsive choice in rats via delay discounting wherein intracranial self-stimulation (ICSS) was used as the positive reinforcer. To do so, rats were anesthetized to allow implanting of a stimulating electrode within the lateral hypothalamus of one hemisphere and bilateral dorsal striatal injections of the dopaminergic toxin, 6-OHDA (lesioned) or its vehicle (sham). Following recovery, rats were trained in a delay discounting task wherein they selected between a small ICSS current presented immediately after lever pressing, and a large ICSS current presented following a 0 to 15s delay upon pressing the alternate lever. Task acquisition and reinforcer discrimination were similar for lesioned and sham rats. All rats exhibited an initial preference for the large reinforcer, and as the delay was increased, preference for the large reinforcer was decreased indicating that the subjective value of the large reinforcer was discounted as a function of delay time. However, this discounting effect was significantly enhanced in lesioned rats for the longer delays. These data reveal a contribution of dopaminergic inputs to the dorsolateral striatum on impulsive choice behavior, and provide new insights into neural substrates underlying discounting behaviors. PMID:25927685

  3. ALCAR Exerts Neuroprotective and Pro-Neurogenic Effects by Inhibition of Glial Activation and Oxidative Stress via Activation of the Wnt/β-Catenin Signaling in Parkinsonian Rats.

    PubMed

    Singh, Sonu; Mishra, Akanksha; Shukla, Shubha

    2016-09-01

    Oxidative stress and neuroinflammation are known causative factors in progressive degeneration of dopaminergic (DAergic) neurons in Parkinson's disease (PD). Neural stem cells (NSCs) contribute in maintaining brain plasticity; therefore, survival of NSCs and neuroblasts during neurodegenerative process becomes important in replenishing the pool of mature neuronal population. Acetyl-L-carnitine (ALCAR), present in almost all body cells, increases endogenous antioxidants and regulates bioenergetics. Currently, no information is available about the putative mechanism and neuroprotective effects of ALCAR in 6-hydroxydopamine (6-OHDA)-induced rat model of PD-like phenotypes. Herein, we investigated the effect of ALCAR on death/survival of DAergic neurons, neuroblasts and NSCs and associates mechanism of neuroprotection in 6-OHDA-induced rat model of PD-like phenotypes. ALCAR (100 mg/kg/day, intraperitoneal (i.p.)) treatment started 3 days prior to 6-OHDA lesioning and continued for another 14 day post-lesioning. We found that ALCAR pretreatment in 6-OHDA-lesioned rats increased expression of neurogenic and the Wnt pathway genes in the striatum and substantia nigra pars compacta (SNpc) region. It suppressed the glial cell activation, improved antioxidant status, increased NSC/neuroblast population and rescued the DAergic neurons in nigrostriatal pathway. ALCAR pretreatment in 6-OHDA-lesioned rats decreased GSK-3β activation and increased nuclear translocation of β-catenin. Functional deficits were restored following ALCAR pretreatment in 6-OHDA-lesioned rats as demonstrated by improved motor coordination and rotational behaviour, confirming protection of DAergic innervations in lesioned striatum. These results indicate that ALCAR exerts neuroprotective effects through the activation of Wnt/β-catenin pathway, suggesting its therapeutic use to treat neurodegenerative diseases by enhancing regenerative capacity.

  4. Example based lesion segmentation

    NASA Astrophysics Data System (ADS)

    Roy, Snehashis; He, Qing; Carass, Aaron; Jog, Amod; Cuzzocreo, Jennifer L.; Reich, Daniel S.; Prince, Jerry; Pham, Dzung

    2014-03-01

    Automatic and accurate detection of white matter lesions is a significant step toward understanding the progression of many diseases, like Alzheimer's disease or multiple sclerosis. Multi-modal MR images are often used to segment T2 white matter lesions that can represent regions of demyelination or ischemia. Some automated lesion segmentation methods describe the lesion intensities using generative models, and then classify the lesions with some combination of heuristics and cost minimization. In contrast, we propose a patch-based method, in which lesions are found using examples from an atlas containing multi-modal MR images and corresponding manual delineations of lesions. Patches from subject MR images are matched to patches from the atlas and lesion memberships are found based on patch similarity weights. We experiment on 43 subjects with MS, whose scans show various levels of lesion-load. We demonstrate significant improvement in Dice coefficient and total lesion volume compared to a state of the art model-based lesion segmentation method, indicating more accurate delineation of lesions.

  5. Optical changes as a marker for lesion size estimation during radio frequency ablation: a model study

    NASA Astrophysics Data System (ADS)

    Eriksson, Ola; Wardell, Karin

    2001-06-01

    Stereotactic radiofrequency (RF)-lesioning in the central part of the brain is performed on patients that, for instance, have severe movement or psychiatric disorders. The size of the generated lesion can to some extent be controlled by RF-generator settings such as temperature and time as well as the electrode configuration. Today, MR- imaging and CT are the essential diagnostic methods to confirm the lesion size in vivo. The aim of this study was to investigate whether it is possible to use changes in the reflected light intensity and laser Doppler flowmetry as a marker for size estimation during RF-lesioning.

  6. Dehydroepiandrosterone sulfate is neuroprotective when administered either before or after injury in a focal cortical cold lesion model.

    PubMed

    Juhász-Vedres, Gabriella; Rózsa, Eva; Rákos, Gabriella; Dobszay, Márton B; Kis, Zsolt; Wölfling, János; Toldi, József; Párducz, Arpád; Farkas, Tamás

    2006-02-01

    Dehydroepiandrosterone and its sulfate (DHEAS) are sex hormone precursors that exert marked neurotrophic and/or neuroprotective activity in the central nervous system. The present study evaluated the effects of DHEAS and 17beta-estradiol (E2) in a focal cortical cold lesion model, in which DHEAS (50 mg/kg, sc) and E2 (35 mg/kg, sc) were administered either as pretreatment (two subsequent injections 1 d and 1 h before lesion induction) or posttreatment (immediately after lesion induction). The focal cortical cold lesion was induced in the primary motor cortex by means of a cooled copper cylinder placed directly onto the cortical surface. One hour later, the animals were killed, the brains cut into 0.4-mm-thick slices, and the sections stained with 1% triphenyltetrazolium chloride. The volume of the hemispheric lesion was calculated for each animal. The results demonstrated that the lesion area was significantly attenuated in both the DHEAS- and E2- pre- and posttreated groups and that in the presence of letrozole, a nonsteroidal aromatase inhibitor, no neuroprotection was observed, suggesting that the beneficial effect of DHEAS on the cold injury might depend on the conversion of DHEAS to E2 within the brain. It is concluded that even a single posttraumatic administration of DHEAS may be of substantial therapeutic benefit in the treatment of focal brain injury with vasogenic edema.

  7. Non-invasive neurochemical analysis of focal excitotoxic lesions in models of neurodegenerative illness using spectroscopic imaging.

    PubMed

    Jenkins, B G; Brouillet, E; Chen, Y C; Storey, E; Schulz, J B; Kirschner, P; Beal, M F; Rosen, B R

    1996-05-01

    Water-suppressed chemical shift magnetic resonance imaging was used to detect neurochemical alterations in vivo in neurotoxin-induced rat models of Huntington's and Parkinson's disease. The toxins were: N-methyl-4-phenylpyridinium (MPP+), aminooxyacetic acid (AOAA), 3-nitropropionic acid (3-NP), malonate, and azide. Local or systemic injection of these compounds caused secondary excitotoxic lesions by selective inhibition of mitochondrial respiration that gave rise to elevated lactate concentrations in the striatum. In addition, decreased N-acetylaspartate (NAA) concentrations were noted at the lesion site over time. Measurements of lactate washout kinetics demonstrated that t1/2 followed the order: 3-NP approximately MPP+ > AOAA approximately malonate, which parallels the expected lifetimes of the neurotoxins based on their mechanisms of action. Further increases in lactate were also caused by intravenous infusion of glucose. At least part of the excitotoxicity is mediated through indirect glutamate pathways because lactate production and lesion size were diminished using unilateral decortectomies (blockade of glutamatergic input) or glutamate antagonists (MK-801). Lesion size and lactate were also diminished by energy repletion with ubiquinone and nicotinamide. Lactate measurements determined by magnetic resonance agreed with biochemical measurements made using freeze clamp techniques. Lesion size as measured with MR, although larger by 30%, agreed well with lesion size determined histologically. These experiments provide evidence for impairment of intracellular energy metabolism leading to indirect excitotoxicity for all the compounds mentioned before and demonstrate the feasibility of small-volume metabolite imaging for in vivo neurochemical analysis.

  8. Bee Venom Alleviates Motor Deficits and Modulates the Transfer of Cortical Information through the Basal Ganglia in Rat Models of Parkinson’s Disease

    PubMed Central

    Maurice, Nicolas; Deltheil, Thierry; Melon, Christophe; Degos, Bertrand; Mourre, Christiane

    2015-01-01

    Recent evidence points to a neuroprotective action of bee venom on nigral dopamine neurons in animal models of Parkinson’s disease (PD). Here we examined whether bee venom also displays a symptomatic action by acting on the pathological functioning of the basal ganglia in rat PD models. Bee venom effects were assessed by combining motor behavior analyses and in vivo electrophysiological recordings in the substantia nigra pars reticulata (SNr, basal ganglia output structure) in pharmacological (neuroleptic treatment) and lesional (unilateral intranigral 6-hydroxydopamine injection) PD models. In the hemi-parkinsonian 6-hydroxydopamine lesion model, subchronic bee venom treatment significantly alleviates contralateral forelimb akinesia and apomorphine-induced rotations. Moreover, a single injection of bee venom reverses haloperidol-induced catalepsy, a pharmacological model reminiscent of parkinsonian akinetic deficit. This effect is mimicked by apamin, a blocker of small conductance Ca2+-activated K+ (SK) channels, and blocked by CyPPA, a positive modulator of these channels, suggesting the involvement of SK channels in the bee venom antiparkinsonian action. In vivo electrophysiological recordings in the substantia nigra pars reticulata (basal ganglia output structure) showed no significant effect of BV on the mean neuronal discharge frequency or pathological bursting activity. In contrast, analyses of the neuronal responses evoked by motor cortex stimulation show that bee venom reverses the 6-OHDA- and neuroleptic-induced biases in the influence exerted by the direct inhibitory and indirect excitatory striatonigral circuits. These data provide the first evidence for a beneficial action of bee venom on the pathological functioning of the cortico-basal ganglia circuits underlying motor PD symptoms with potential relevance to the symptomatic treatment of this disease. PMID:26571268

  9. Interleukin-6 receptor alpha blockade improves skin lesions in a murine model of systemic lupus erythematosus.

    PubMed

    Birner, Peter; Heider, Susanne; Petzelbauer, Peter; Wolf, Peter; Kornauth, Christoph; Kuroll, Madeleine; Merkel, Olaf; Steiner, Günter; Kishimoto, Tadamitsu; Rose-John, Stefan; Soleiman, Afschin; Moriggl, Richard; Kenner, Lukas

    2016-04-01

    Systemic lupus erythematosus (SLE) is an autoimmune disease, characterized by antinuclear autoantibodies (ANA) and immunocomplexes, commonly affecting kidneys, skin, heart, lung or even the brain. We have shown that JunB(Δep) mice develop a SLE phenotype linked to increased epidermal Interleukin (IL)-6 secretion. Blocking of IL-6 receptor alpha (IL-6Rα) is considered as therapeutic strategy for the treatment of SLE. JunB(Δep) and wild-type mice were treated for short (5 weeks) or long term (21 weeks) with the IL-6Rα-blocking antibody MR16-1. Skin and kidney of mice were investigated by histology and immunofluorescence, and in addition, kidneys were analysed by electron microscopy. Furthermore, soluble IL-6R (sIL-6R), antihistone and antinucleosome antibodies levels were measured and associated with disease parameters. Treatment with MR16-1 resulted in significant improvement of SLE-like skin lesions in JunB(Δep) mice, compared to untreated mice. The sIL-6R amount upon long-term treatment with MR16-1 was significantly higher in JunB(Δep) versus untreated JunB(Δep) (P = 0.034) or wild-type mice (P = 0.034). MR16-1 treatment over these time spans did not significantly improve kidney pathology of immunoglobulin deposits causing impaired function. Significantly higher antihistone (P = 0.028) and antinucleosome antibody levels (P = 0.028) were measured in MR16-1-treated JunB(Δep) mice after treatment compared to levels before therapy. In conclusion, blockade of IL-6Rα improves skin lesions in a murine SLE model, but does not have a beneficial effect on autoimmune-mediated kidney pathology. Inhibition of IL-6R signalling might be helpful in lupus cases with predominant skin involvement, but combinatorial treatment might be required to restrain autoantibodies.

  10. An NR2B-Dependent Decrease in the Expression of trkB Receptors Precedes the Disappearance of Dopaminergic Cells in Substantia Nigra in a Rat Model of Presymptomatic Parkinson's Disease

    PubMed Central

    Riquelme, Eduardo; Abarca, Jorge; Campusano, Jorge M.; Bustos, Gonzalo

    2012-01-01

    Compensatory changes occurring during presymptomatic stages of Parkinson's disease (PD) would explain that the clinical symptoms of the disease appear late, when the degenerative process is quite advanced. Several data support the proposition that brain-derived neurotrophic factor (BDNF) could play a role in these plastic changes. In the present study, we evaluated the expression of the specific BDNF receptor, trkB, in a rat model of presymptomatic PD generated by intrastriatal injection of the neurotoxin 6-OHDA. Immunohistochemical studies revealed a decrease in trkB expression in SN pars compacta (SNc) seven days after 6-OHDA injection. At this time point, no change in the number of tyrosine hydroxylase (TH) immunoreactive (TH-IR) cells is detected, although a decrease is evident 14 days after neurotoxin injection. The decrease in TH-positive cells and trkB expression in SNc was significantly prevented by systemic administration of Ifenprodil, a specific antagonist of NR2B-containing NMDA receptors. Therefore, an NR2B-NMDA receptor-dependent decrease in trkB expression precedes the disappearance of TH-IR cells in SNc in response to 6-OHDA injection. These results support the idea that a functional coupling between NMDA receptors and BDNF/trkB signalling may be important for the maintenance of the dopaminergic phenotype in SNc during presymptomatic stages of PD. PMID:22720191

  11. IMaGe: Iterative Multilevel Probabilistic Graphical Model for Detection and Segmentation of Multiple Sclerosis Lesions in Brain MRI.

    PubMed

    Subbanna, Nagesh; Precup, Doina; Arnold, Douglas; Arbel, Tal

    2015-01-01

    In this paper, we present IMaGe, a new, iterative two-stage probabilistic graphical model for detection and segmentation of Multiple Sclerosis (MS) lesions. Our model includes two levels of Markov Random Fields (MRFs). At the bottom level, a regular grid voxel-based MRF identifies potential lesion voxels, as well as other tissue classes, using local and neighbourhood intensities and class priors. Contiguous voxels of a particular tissue type are grouped into regions. A higher, non-lattice MRF is then constructed, in which each node corresponds to a region, and edges are defined based on neighbourhood relationships between regions. The goal of this MRF is to evaluate the probability of candidate lesions, based on group intensity, texture and neighbouring regions. The inferred information is then propagated to the voxel-level MRF. This process of iterative inference between the two levels repeats as long as desired. The iterations suppress false positives and refine lesion boundaries. The framework is trained on 660 MRI volumes of MS patients enrolled in clinical trials from 174 different centres, and tested on a separate multi-centre clinical trial data set with 535 MRI volumes. All data consists of T1, T2, PD and FLAIR contrasts. In comparison to other MRF methods, such as, and a traditional MRF, IMaGe is much more sensitive (with slightly better PPV). It outperforms its nearest competitor by around 20% when detecting very small lesions (3-10 voxels). This is a significant result, as such lesions constitute around 40% of the total number of lesions.

  12. Effects of lesions of the subthalamic nucleus/zona incerta area and dorsomedial striatum on attentional set-shifting in the rat.

    PubMed

    Tait, David S; Phillips, Janice M; Blackwell, Andrew D; Brown, Verity J

    2017-03-14

    Patients with Parkinson's disease (PD) show cognitive impairments, including difficulty in shifting attention between perceptual dimensions of complex stimuli. Inactivation of the subthalamic nucleus (STN) has been shown to be effective in ameliorating the motor abnormalities associated with striatal dopamine (DA) depletion, but it is possible that STN inactivation might result in additional, perhaps attentional, deficits. This study examined the effects of: DA depletion from the dorsomedial striatum (DMS); lesions of the STN area; and the effects of the two lesions together, on the ability to shift attentional set in the rat. In a single session, rats performed the intradimensional/extradimensional (ID/ED) test of attentional set-shifting. This comprises a series of seven, two-choice discriminations, including acquisitions of novel discriminations in which the relevant stimulus is either in the currently attended dimension (ID) or the currently unattended dimension (ED shift) and reversals (REVs) following each acquisition stage. Bilateral lesions were made by injection of 6-hydroxydopamine (6-OHDA) into the DMS, resulting in a selective impairment in reversal learning. Large bilateral ibotenic acid lesions centered on the STN resulted in an increase in trials to criterion in the initial stages, but learning rate improved within the session. There was no evidence of a 'cost' of set-shifting - the ED stage was completed in fewer trials than the ID stage - and neither was there a cost of reversal learning. Strikingly, combined lesions of both regions did not resemble the effects of either lesion alone and resulted in no apparent deficits.

  13. In vivo T2* weighted MRI visualizes cardiac lesions in murine models of acute and chronic viral myocarditis

    PubMed Central

    Helluy, Xavier; Sauter, Martina; Ye, Yu-Xiang; Lykowsky, Gunthard; Kreutner, Jakob; Yilmaz, Ali; Jahns, Roland; Boivin, Valerie; Kandolf, Reinhard; Jakob, Peter M.; Hiller, Karl-Heinz; Klingel, Karin

    2017-01-01

    Objective Acute and chronic forms of myocarditis are mainly induced by virus infections. As a consequence of myocardial damage and inflammation dilated cardiomyopathy and chronic heart failure may develop. The gold standard for the diagnosis of myocarditis is endomyocardial biopsies which are required to determine the etiopathogenesis of cardiac inflammatory processes. However, new non-invasive MRI techniques hold great potential in visualizing cardiac non-ischemic inflammatory lesions at high spatial resolution, which could improve the investigation of the pathophysiology of viral myocarditis. Results Here we present the discovery of a novel endogenous T2* MRI contrast of myocardial lesions in murine models of acute and chronic CVB3 myocarditis. The evaluation of infected hearts ex vivo and in vivo by 3D T2w and T2*w MRI allowed direct localization of virus-induced myocardial lesions without any MRI tracer or contrast agent. T2*w weighted MRI is able to detect both small cardiac lesions of acute myocarditis and larger necrotic areas at later stages of chronic myocarditis, which was confirmed by spatial correlation of MRI hypointensity in myocardium with myocardial lesions histologically. Additional in vivo and ex vivo MRI analysis proved that the contrast mechanism was due to a strong paramagnetic tissue alteration in the vicinity of myocardial lesions, effectively pointing towards iron deposits as the primary contributor of contrast. The evaluation of the biological origin of the MR contrast by specific histological staining and transmission electron microscopy revealed that impaired iron metabolism primarily in mitochondria caused iron deposits within necrotic myocytes, which induces strong magnetic susceptibility in myocardial lesions and results in strong T2* contrast. Conclusion This T2*w MRI technique provides a fast and sensitive diagnostic tool to determine the patterns and the severity of acute and chronic enteroviral myocarditis and the precise

  14. Hyperproliferation of normally quiescent keratinocytes in non-lesional psoriatic skin due to high calcium concentration (an organotypic culture model).

    PubMed

    Szabó, Anna Kenderessy; Bos, J D; Das, P K

    2002-01-01

    Calcium plays an important role in the regulation of different functions of keratinocytes. In the present work we studied the effect of different extracellular calcium concentrations (0.01 mM-2.0 mM) on the proliferation and differentiation of human keratinocytes in normal human and non-lesional psoriatic skin. Using explant culture model, the proliferative and differentiated subsets of keratinocytes were detected by specific antibodies related to cell proliferation [beta-1 integrin (CD29), proliferating cell antigen (Ki67), proliferating cell nuclear antigen (PCNA)] and differentiation [differentiated cell cytokeratins (K1/K10) and differentiating cell antigen (lectin Ulex europaius agglutinin, UEA-1)]. After 4 days of culturing at high Ca2+ (2.0 mM) we observed marked hyperproliferation among the normally quiescent keratinocytes of non-lesional psoriatic skin. In normal uncultured and cultured skin and in uncultured and two-day-cultured non-lesional psoriatic skin both at normal (1.2 mM) and at high (2.0 mM) Ca2+ concentration only one layer of basal CD29+/Ki67+/K1/K10-/UEA-1- cell was observed. In sections from non-lesional psoriatic skin cultured for 4 days in the presence of high Ca2+ (2.0 mM) this cell population has expanded from at least three layers above the basement membrane. This expanded cell population of the 4-day high Ca2+ cultured non-lesional skin showed clear PCNA positive staining on frozen sections with the strongest positivity among the most basal localized cells. These data suggest that (i) extracellular Ca2+ concentration can influence the proliferation of basal ("stem") keratinocytes, (ii) the proliferative response to high Ca2+ concentration of psoriatic non-lesional basal keratinocytes differs from that of normal basal keratinocytes, (iv) changes in the extracellular Ca2+ milieu might play a role in the induction of the hyperproliferative psoriatic lesion.

  15. Deconstructing empathy: Neuroanatomical dissociations between affect sharing and prosocial motivation using a patient lesion model.

    PubMed

    Shdo, Suzanne M; Ranasinghe, Kamalini G; Gola, Kelly A; Mielke, Clinton J; Sukhanov, Paul V; Miller, Bruce L; Rankin, Katherine P

    2017-02-14

    Affect sharing and prosocial motivation are integral parts of empathy that are conceptually and mechanistically distinct. We used a neurodegenerative disease (NDG) lesion model to examine the neural correlates of these two aspects of real-world empathic responding. The study enrolled 275 participants, including 44 healthy older controls and 231 patients diagnosed with one of five neurodegenerative diseases (75 Alzheimer's disease, 58 behavioral variant frontotemporal dementia (bvFTD), 42 semantic variant primary progressive aphasia (svPPA), 28 progressive supranuclear palsy, and 28 non-fluent variant primary progressive aphasia (nfvPPA). Informants completed the Revised Self-Monitoring Scale's Sensitivity to the Expressive Behavior of Others (RSMS-EX) subscale and the Interpersonal Reactivity Index's Empathic Concern (IRI-EC) subscale describing the typical empathic behavior of the participants in daily life. Using regression modeling of the voxel based morphometry of T1 brain scans prepared using SPM8 DARTEL-based preprocessing, we isolated the variance independently contributed by the affect sharing and the prosocial motivation elements of empathy as differentially measured by the two scales. We found that the affect sharing component uniquely correlated with volume in right>left medial and lateral temporal lobe structures, including the amygdala and insula, that support emotion recognition, emotion generation, and emotional awareness. Prosocial motivation, in contrast, involved structures such as the nucleus accumbens (NaCC), caudate head, and inferior frontal gyrus (IFG), which suggests that an individual must maintain the capacity to experience reward, to resolve ambiguity, and to inhibit their own emotional experience in order to effectively engage in spontaneous altruism as a component of their empathic response to others.

  16. Gabapentin attenuates hyperexcitability in the freeze-lesion model of developmental cortical malformation

    PubMed Central

    Andresen, Lauren; Hampton, David; Taylor, Amaro; Morel, Lydie; Yang, Yongjie; Maguire, Jamie; Dulla, Chris G.

    2014-01-01

    Developmental cortical malformations are associated with a high incidence of drug-resistant epilepsy. The underlying epileptogenic mechanisms, however, are poorly understood. In rodents, cortical malformations can be modeled using neonatal freeze-lesion (FL), which has been shown to cause in vitro cortical hyperexcitability. Here, we investigated the therapeutic potential of gabapentin, a clinically used anticonvulsant and analgesic, in preventing FL-induced in vitro and in vivo hyperexcitability. Gabapentin has been shown to disrupt the interaction of thrombospondin (TSP) with α2δ-1, an auxiliary calcium channel subunit. TSP/ α2δ-1 signaling has been shown to drive the formation of excitatory synapses during cortical development and following injury. Gabapentin has been reported to have neuroprotective and anti-epileptogenic effects in other models associated with increased TSP expression and reactive astrocytosis. We found that both TSP and α2δ-1 were transiently upregulated following neonatal FL. We therefore designed a one-week GBP treatment paradigm to block TSP/ α2δ-1 signaling during the period of their upregulation. GBP treatment prevented epileptiform activity following FL, as assessed by both glutamate biosensor imaging and field potential recording. GBP also attenuated FL-induced increases in mEPSC frequency at both P7 and 28. Additionally, GBP treated animals had decreased in vivo kainic acid (KA)-induced seizure activity. Taken together these results suggest gabapentin treatment immediately after FL can prevent the formation of a hyperexcitable network and may have therapeutic potential to minimize epileptogenic processes associated with developmental cortical malformations. PMID:25158291

  17. Pharmacological targeting of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth in the mouse model of lymphangioleiomyomatosis.

    PubMed

    Atochina-Vasserman, Elena N; Abramova, Elena; James, Melane L; Rue, Ryan; Liu, Amy Y; Ersumo, Nathan Tessema; Guo, Chang-Jiang; Gow, Andrew J; Krymskaya, Vera P

    2015-12-15

    Pulmonary lymphangioleiomyomatosis (LAM), a rare progressive lung disease associated with mutations of the tuberous sclerosis complex 2 (Tsc2) tumor suppressor gene, manifests by neoplastic growth of LAM cells, induction of cystic lung destruction, and respiratory failure. LAM severity correlates with upregulation in serum of the prolymphangiogenic vascular endothelial growth factor D (VEGF-D) that distinguishes LAM from other cystic diseases. The goals of our study was to determine whether Tsc2 deficiency upregulates VEGF-D, and whether axitinib, the Food and Drug Administration-approved small-molecule inhibitor of VEGF receptor (VEGFR) signaling, will reduce Tsc2-null lung lesion growth in a mouse model of LAM. Our data demonstrate upregulation of VEGF-D in the serum and lung lining in mice with Tsc2-null lesions. Progressive growth of Tsc2-null lesions induces recruitment and activation of inflammatory cells and increased nitric oxide production. Recruited cells isolated from the lung lining of mice with Tsc2-null lesions demonstrate upregulated expression of provasculogenic Vegfa, prolymphangiogenic Figf, and proinflammatory Nos2, Il6, and Ccl2 genes. Importantly, axitinib is an effective inhibitor of Tsc2-null lesion growth and inflammatory cell recruitment, which correlates with reduced VEGF-D levels in serum and lung lining. Our data demonstrate that pharmacological inhibition of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth, attenuates recruitment and activation of inflammatory cells, and reduces VEGF-D levels systemically and in the lung lining. Our study suggests a potential therapeutic benefit of inhibition of VEGFR signaling for treatment of LAM.

  18. Accentuated behavioral sensitization to nicotine in the neonatal ventral hippocampal lesion model of schizophrenia.

    PubMed

    Berg, Sarah A; Chambers, R Andrew

    2008-06-01

    The prevalence of smoking in schizophrenia patients far exceeds that in the general population. Increased vulnerability to nicotine and other drug addictions in schizophrenia may reflect the impact of developmental limbic abnormalities on cortical-striatal mediation of behavioral changes associated with drug use. Rats with neonatal ventral hippocampal lesions (NVHLs), a neurodevelopmental model of schizophrenia, have previously been shown to exhibit altered patterns of behavioral sensitization to both cocaine and ethanol. This study explored nicotine sensitization in NVHLs by testing locomotor activity of NVHL vs. SHAM-operated controls over 3 weeks in response to nicotine (0.5 mg/kg) or saline injections (s.c.) followed by a nicotine challenge delivered to all rats 2 weeks later. At the beginning of the initial injection series, post-injection locomotor activation was indistinguishable among all treatment groups. However, nicotine but not saline injections produced a progressive sensitization effect that was greater in NVHLs compared to SHAMs. In the challenge session, rats with previous nicotine history showed enhanced locomotor activation to nicotine when compared to drug naïve rats, with NVHL-nicotine rats showing the greatest degree of activity overall. These results demonstrate that NVHLs exhibit altered short- and long-term sensitization profiles to nicotine, similar to altered long-term sensitization profiles produced by cocaine and ethanol. Collectively, these findings suggest the neurodevelopmental underpinnings of schizophrenia produce enhanced behavioral sensitization to addictive drugs as an involuntary and progressive neurobehavioral process, independent of the acute psychoactive properties uniquely attributed to nicotine, cocaine, or alcohol.

  19. Striatal Glutamate and GABA after High Frequency Subthalamic Stimulation in Parkinsonian Rat

    PubMed Central

    Lee, Kyung Jin; Shim, Insop; Sung, Jae Hoon; Hong, Jae Taek; Kim, Il sup; Cho, Chul Bum

    2017-01-01

    Objective High frequency stimulation (HFS) of the subthalamic nucleus (STN) is recognized as an effective treatment of advanced Parkinson’s disease. However, the neurochemical basis of its effects remains unknown. The aim of this study is to investigate the effects of STN HFS in intact and 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian rat model on changes of principal neurotransmitters, glutamate, and gamma-aminobutyric acid (GABA) in the striatum. Methods The authors examined extracellular glutamate and GABA change in the striatum on sham group, 6-OHDA group, and 6-OHDA plus deep brain stimulation (DBS) group using microdialysis methods. Results High-pressure liquid chromatography was used to quantify glutamate and GABA. The results show that HFS-STN induces a significant increase of extracellular glutamate and GABA in the striatum of 6-OHDA plus DBS group compared with sham and 6-OHDA group. Conclusion Therefore, the clinical results of STN-HFS are not restricted to the direct STN targets but involve widespread adaptive changes within the basal ganglia. PMID:28264233

  20. Involvement of TNF-α converting enzyme in the development of psoriasis-like lesions in a mouse model.

    PubMed

    Sato, Kenji; Takaishi, Mikiro; Tokuoka, Shota; Sano, Shigetoshi

    2014-01-01

    TNF-α plays a crucial role in psoriasis; therefore, TNF inhibition has become a gold standard for the treatment of psoriasis. TNF-α is processed from a membrane-bound form by TNF-α converting enzyme (TACE) to soluble form, which exerts a number of biological activities. EGF receptor (EGFR) ligands, including heparin-binding EGF-like growth factor (HB-EGF), amphiregulin and transforming growth factor (TGF)-α are also TACE substrates and are psoriasis-associated growth factors. Vascular endothelial growth factor (VEGF), one of the downstream molecules of EGFR and TNF signaling, plays a key role in angiogenesis for developing psoriasis. In the present study, to assess the possible role of TACE in the pathogenesis of psoriasis, we investigated the involvement of TACE in TPA-induced psoriasis-like lesions in K5.Stat3C mice, which represent a mouse model of psoriasis. In this mouse model, TNF-α, amphiregulin, HB-EGF and TGF-α were significantly up-regulated in the skin lesions, similar to human psoriasis. Treatment of K5.Stat3C mice with TNF-α or EGFR inhibitors attenuated the skin lesions, suggesting the roles of TACE substrates in psoriasis. Furthermore, the skin lesions of K5.Stat3C mice showed down-regulation of tissue inhibitor of metalloproteinase-3, an endogenous inhibitor of TACE, and an increase in soluble TNF-α. A TACE inhibitor abrogated EGFR ligand-dependent keratinocyte proliferation and VEGF production in vitro, suggesting that TACE was involved in both epidermal hyperplasia and angiogenesis during psoriasis development. These results strongly suggest that TACE contributes to the development of psoriatic lesions through releasing two kinds of psoriasis mediators, TNF-α and EGFR ligands. Therefore, TACE could be a potential therapeutic target for the treatment of psoriasis.

  1. Animal models of Parkinson's disease: a source of novel treatments and clues to the cause of the disease

    PubMed Central

    Duty, Susan; Jenner, Peter

    2011-01-01

    Animal models of Parkinson's disease (PD) have proved highly effective in the discovery of novel treatments for motor symptoms of PD and in the search for clues to the underlying cause of the illness. Models based on specific pathogenic mechanisms may subsequently lead to the development of neuroprotective agents for PD that stop or slow disease progression. The array of available rodent models is large and ranges from acute pharmacological models, such as the reserpine- or haloperidol-treated rats that display one or more parkinsonian signs, to models exhibiting destruction of the dopaminergic nigro-striatal pathway, such as the classical 6-hydroxydopamine (6-OHDA) rat and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models. All of these have provided test beds in which new molecules for treating the motor symptoms of PD can be assessed. In addition, the emergence of abnormal involuntary movements (AIMs) with repeated treatment of 6-OHDA-lesioned rats with L-DOPA has allowed for examination of the mechanisms responsible for treatment-related dyskinesia in PD, and the detection of molecules able to prevent or reverse their appearance. Other toxin-based models of nigro-striatal tract degeneration include the systemic administration of the pesticides rotenone and paraquat, but whilst providing clues to disease pathogenesis, these are not so commonly used for drug development. The MPTP-treated primate model of PD, which closely mimics the clinical features of PD and in which all currently used anti-parkinsonian medications have been shown to be effective, is undoubtedly the most clinically-relevant of all available models. The MPTP-treated primate develops clear dyskinesia when repeatedly exposed to L-DOPA, and these parkinsonian animals have shown responses to novel dopaminergic agents that are highly predictive of their effect in man. Whether non-dopaminergic drugs show the same degree of predictability of response is a matter of debate. As our

  2. A modeling-based assessment of acousto-optic sensing for monitoring high-intensity focused ultrasound lesion formation

    NASA Astrophysics Data System (ADS)

    Adams, Matthew Tyler

    Real-time acousto-optic (AO) sensing---a dual-wave modality that combines ultrasound with diffuse light to probe the optical properties of turbid media---has been demonstrated to non-invasively detect changes in ex vivo tissue optical properties during high-intensity focused ultrasound (HIFU) exposure. The AO signal indicates the onset of lesion formation and predicts resulting lesion volumes. Although proof-of-concept experiments have been successful, many of the underlying parameters and mechanisms affecting thermally induced optical property changes and the AO detectability of HIFU lesion formation are not well understood. In thesis, a numerical simulation was developed to model the AO sensing process and capture the relevant acoustic, thermal, and optical transport processes. The simulation required data that described how optical properties changed with heating. Experiments were carried out where excised chicken breast was exposed to thermal bath heating and changes in the optical absorption and scattering spectra (500 nm--1100 nm) were measured using a scanning spectrophotometer and an integrating sphere assembly. Results showed that the standard thermal dose model currently used for guiding HIFU treatments needs to be adjusted to describe thermally induced optical property changes. To model the entire AO process, coupled models were used for ultrasound propagation, tissue heating, and diffusive light transport. The angular spectrum method was used to model the acoustic field from the HIFU source. Spatial-temporal temperature elevations induced by the absorption of ultrasound were modeled using a finite-difference time-domain solution to the Pennes bioheat equation. The thermal dose model was then used to determine optical properties based on the temperature history. The diffuse optical field in the tissue was then calculated using a GPU-accelerated Monte Carlo algorithm, which accounted for light-sound interactions and AO signal detection. The simulation was

  3. Effects of thalamic hemorrhagic lesions on explicit and implicit learning during the acquisition and retrieval phases in an animal model of central post-stroke pain.

    PubMed

    Wang, Cheng Chung; Shih, Hsi-Chien; Shyu, Bai Chuang; Huang, Andrew Chih Wei

    2017-01-15

    Hemorrhagic stroke has many symptoms, including central pain, learning and memory impairments, motor deficits, language problems, emotional disturbances, and social maladjustment. Lesions of the ventral basal complex (VBC) of the thalamus elicit thermal and mechanical hyperalgesia, forming an animal model of central post-stroke pain (CPSP). However, no research has yet examined the involvement of learning and memory in CPSP using an animal model. The present study examined whether VBC lesions affect motor function, conditioned place preference (CPP; implicit memory), and spatial learning (explicit memory) in the acquisition and retrieval phases. The results showed that rats with VBC lesions exhibited thermal hyperalgesia in the acquisition and retrieval phases, indicating that these lesions can induce CPSP. During these phases, the rats with VBC lesions exhibited enhanced (morphine-induced) CPP learning. These lesions did not affect the rats' total distance travelled, time spent, or velocity in the spatial learning tasks. The lesions also did not affect motor function in the rotarod task. Altogether, VBC lesions resulted in CPSP and facilitated CPP (implicit memory). However, the lesions did not affect spatial learning (explicit memory) or motor function. The relationship between CPSP and learning and memory is important for patients who suffer from such central pain. The implications of the present study may provide insights into helping reduce CPSP and its associated symptoms.

  4. Brain Lesions

    MedlinePlus

    ... MRI scans, brain lesions appear as dark or light spots that don't look like normal brain tissue. Usually, a brain lesion is an incidental finding unrelated to the condition or symptom that led to the imaging test in the first place. ...

  5. Your perspective and my benefit: multiple lesion models of self-other integration strategies during social bargaining.

    PubMed

    Melloni, Margherita; Billeke, Pablo; Baez, Sandra; Hesse, Eugenia; de la Fuente, Laura; Forno, Gonzalo; Birba, Agustina; García-Cordero, Indira; Serrano, Cecilia; Plastino, Angelo; Slachevsky, Andrea; Huepe, David; Sigman, Mariano; Manes, Facundo; García, Adolfo M; Sedeño, Lucas; Ibáñez, Agustín

    2016-09-27

    Recursive social decision-making requires the use of flexible, context-sensitive long-term strategies for negotiation. To succeed in social bargaining, participants' own perspectives must be dynamically integrated with those of interactors to maximize self-benefits and adapt to the other's preferences, respectively. This is a prerequisite to develop a successful long-term self-other integration strategy. While such form of strategic interaction is critical to social decision-making, little is known about its neurocognitive correlates. To bridge this gap, we analysed social bargaining behaviour in relation to its structural neural correlates, ongoing brain dynamics (oscillations and related source space), and functional connectivity signatures in healthy subjects and patients offering contrastive lesion models of neurodegeneration and focal stroke: behavioural variant frontotemporal dementia, Alzheimer's disease, and frontal lesions. All groups showed preserved basic bargaining indexes. However, impaired self-other integration strategy was found in patients with behavioural variant frontotemporal dementia and frontal lesions, suggesting that social bargaining critically depends on the integrity of prefrontal regions. Also, associations between behavioural performance and data from voxel-based morphometry and voxel-based lesion-symptom mapping revealed a critical role of prefrontal regions in value integration and strategic decisions for self-other integration strategy. Furthermore, as shown by measures of brain dynamics and related sources during the task, the self-other integration strategy was predicted by brain anticipatory activity (alpha/beta oscillations with sources in frontotemporal regions) associated with expectations about others' decisions. This pattern was reduced in all clinical groups, with greater impairments in behavioural variant frontotemporal dementia and frontal lesions than Alzheimer's disease. Finally, connectivity analysis from functional

  6. Gastroprotective effect of the ethanolic extract of Parkia platycephala Benth. leaves against acute gastric lesion models in rodents.

    PubMed

    Fernandes, Hélio B; Silva, Francilene V; Passos, Flávia Franceli B; Bezerra, Roosevelt D S; Chaves, Mariana H; Oliveira, Francisco A; Oliveira, Rita C Meneses

    2010-01-01

    Parkia platycephala Benth. (Leguminosae--Mimosoideae), popularly known as "visgueira", fava bean tree or "fava-de-bolota", is widely found in the Northern and Northeastern regions of Brazil. Its pods are used as cattle food supplement in the drought period. Compounds with a gastroprotective activity were obtained from the genus Parkia. Therefore, this study aimed at investigating the gastroprotective effect of the ethanolic extract of Parkia platycephala Benth. leaves (Pp-EtOH), as well as evaluating its possible mechanisms of action in experimental ulcer induction models. Lesions were induced by absolute ethanol, ethanol-HCl, ischemia-reperfusion and indomethacin in rodents. Pp-EtOH showed a protective effect in the lesion models (66, 48 and 52%, respectively), but it was not able to protect gastric mucosa against indomethacin-induced lesions. Results show a possible participation of the NO-synthase pathway in the gastroprotection and an antioxidant activity, by the increase of the catalase activity. The participation of prostaglandins and potassium channels sensitive to ATP in the gastroprotective effect of Pp-EtOH seems less likely to occur. More comprehensive studies, therefore, should be carried out to elucidate the antiulcerative effects of this promising natural product against this gastrointestinal disorder.

  7. The effect of low frequency stimulation of the pedunculopontine tegmental nucleus on basal ganglia in a rat model of Parkinson's disease.

    PubMed

    Park, Eunkyoung; Song, Inho; Jang, Dong Pyo; Kim, In Young

    2014-08-08

    The pedunculopontine nucleus (PPN) has recently been introduced as an alternative target to the subthalamic nucleus (STN) or globus pallidus internus (GPi) for the treatment of advanced Parkinson's disease with severe and medically intractable axial symptoms such as gait and postural impairment. However, it is little known about how electrical stimulation of the PPN affects control of neuronal activities between the PPN and basal ganglia. We examined how low frequency stimulation of the pedunculopontine tegmental nucleus (PPTg) affects control of neuronal activities between the PPN and basal ganglia in 6-OHDA lesioned rats. In order to identify the effect of low frequency stimulation on the PPTg, neuronal activity in both the STN and substantia nigra par reticulata (SNr) were recorded and subjected to quantitative analysis, including analysis of firing rates and firing patterns. In this study, we found that the firing rates of the STN and SNr were suppressed during low frequency stimulation of the PPTg. However, the firing pattern, in contrast to the firing rate, did not exhibit significant changes in either the STN or SNr of 6-OHDA lesioned rats during low frequency stimulation of the PPTg. In addition, we also found that the firing rate of STN and SNr neurons displaying burst and random pattern were decreased by low frequency stimulation of PPTg, while the neurons displaying regular pattern were not affected. These results indicate that low frequency stimulation of the PPTg affects neuronal activity in both the STN and SNr, and may represent electrophysiological efficacy of low frequency PPN stimulation.

  8. PARP Inhibition Attenuates Histopathological Lesion in Ischemia/Reperfusion Renal Mouse Model after Cold Prolonged Ischemia

    PubMed Central

    del Moral, Raimundo M. G.; Gómez-Morales, Mercedes; Aguilar, David; Caballero, Trinidad; Aneiros-Fernández, Jose; Caba-Molina, Mercedes; Rodríguez-Martínez, Mª  Dolores; Peralta, Andreina; Galindo-Moreno, Pablo; Osuna, Antonio; Oliver, F. Javier

    2013-01-01

    We test the hypothesis that PARP inhibition can decrease acute tubular necrosis (ATN) and other renal lesions related to prolonged cold ischemia/reperfusion (IR) in kidneys preserved at 4°C in University of Wisconsin (UW) solution. Material and Methods. We used 30 male Parp1+/+ wild-type and 15 male Parp10/0 knockout C57BL/6 mice. Fifteen of these wild-type mice were pretreated with 3,4-dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinolinone (DPQ) at a concentration of 15 mg/kg body weight, used as PARP inhibitor. Subgroups of mice were established (A: IR 45 min/6 h; B: IR + 48 h in UW solution; and C: IR + 48 h in UW solution plus DPQ). We processed samples for morphological, immunohistochemical, ultrastructural, and western-blotting studies. Results. Prolonged cold ischemia time in UW solution increased PARP-1 expression and kidney injury. Preconditioning with PARP inhibitor DPQ plus DPQ supplementation in UW solution decreased PARP-1 nuclear expression in renal tubules and renal damage. Parp10/0 knockout mice were more resistant to IR-induced renal lesion. In conclusion, PARP inhibition attenuates ATN and other IR-related renal lesions in mouse kidneys under prolonged cold storage in UW solution. If confirmed, these data suggest that pharmacological manipulation of PARP activity may have salutary effects in cold-stored organs at transplantation. PMID:24319370

  9. Intra-lesional injection of the novel PKC activator EBC-46 rapidly ablates tumors in mouse models.

    PubMed

    Boyle, Glen M; D'Souza, Marjorie M A; Pierce, Carly J; Adams, Ryan A; Cantor, Aaron S; Johns, Jenny P; Maslovskaya, Lidia; Gordon, Victoria A; Reddell, Paul W; Parsons, Peter G

    2014-01-01

    Intra-lesional chemotherapy for treatment of cutaneous malignancies has been used for many decades, allowing higher local drug concentrations and less toxicity than systemic agents. Here we describe a novel diterpene ester, EBC-46, and provide preclinical data supporting its use as an intra-lesional treatment. A single injection of EBC-46 caused rapid inflammation and influx of blood, followed by eschar formation and rapid tumor ablation in a range of syngeneic and xenograft models. EBC-46 induced oxidative burst from purified human polymorphonuclear cells, which was prevented by the Protein Kinase C inhibitor bisindolylmaleimide-1. EBC-46 activated a more specific subset of PKC isoforms (PKC-βI, -βII, -α and -γ) compared to the structurally related phorbol 12-myristate 13-acetate (PMA). Although EBC-46 showed threefold less potency for inhibiting cell growth than PMA in vitro, it was more effective for cure of tumors in vivo. No viable tumor cells were evident four hours after injection by ex vivo culture. Pharmacokinetic profiles from treated mice indicated that EBC-46 was retained preferentially within the tumor, and resulted in significantly greater local responses (erythema, oedema) following intra-lesional injection compared with injection into normal skin. The efficacy of EBC-46 was reduced by co-injection with bisindolylmaleimide-1. Loss of vascular integrity following treatment was demonstrated by an increased permeability of endothelial cell monolayers in vitro and by CD31 immunostaining of treated tumors in vivo. Our results demonstrate that a single intra-lesional injection of EBC-46 causes PKC-dependent hemorrhagic necrosis, rapid tumor cell death and ultimate cure of solid tumors in pre-clinical models of cancer.

  10. Intra-Lesional Injection of the Novel PKC Activator EBC-46 Rapidly Ablates Tumors in Mouse Models

    PubMed Central

    Pierce, Carly J.; Adams, Ryan A.; Cantor, Aaron S.; Johns, Jenny P.; Maslovskaya, Lidia; Gordon, Victoria A.; Reddell, Paul W.; Parsons, Peter G.

    2014-01-01

    Intra-lesional chemotherapy for treatment of cutaneous malignancies has been used for many decades, allowing higher local drug concentrations and less toxicity than systemic agents. Here we describe a novel diterpene ester, EBC-46, and provide preclinical data supporting its use as an intra-lesional treatment. A single injection of EBC-46 caused rapid inflammation and influx of blood, followed by eschar formation and rapid tumor ablation in a range of syngeneic and xenograft models. EBC-46 induced oxidative burst from purified human polymorphonuclear cells, which was prevented by the Protein Kinase C inhibitor bisindolylmaleimide-1. EBC-46 activated a more specific subset of PKC isoforms (PKC-βI, -βII, -α and -γ) compared to the structurally related phorbol 12-myristate 13-acetate (PMA). Although EBC-46 showed threefold less potency for inhibiting cell growth than PMA in vitro, it was more effective for cure of tumors in vivo. No viable tumor cells were evident four hours after injection by ex vivo culture. Pharmacokinetic profiles from treated mice indicated that EBC-46 was retained preferentially within the tumor, and resulted in significantly greater local responses (erythema, oedema) following intra-lesional injection compared with injection into normal skin. The efficacy of EBC-46 was reduced by co-injection with bisindolylmaleimide-1. Loss of vascular integrity following treatment was demonstrated by an increased permeability of endothelial cell monolayers in vitro and by CD31 immunostaining of treated tumors in vivo. Our results demonstrate that a single intra-lesional injection of EBC-46 causes PKC-dependent hemorrhagic necrosis, rapid tumor cell death and ultimate cure of solid tumors in pre-clinical models of cancer. PMID:25272271

  11. Intranigral administration of substance P receptor antagonist attenuated levodopa-induced dyskinesia in a rat model of Parkinson's disease.

    PubMed

    Yang, Xinxin; Zhao, Hui; Shi, Hongjuan; Wang, Xiaoying; Zhang, Shenyang; Zhang, Zunsheng; Zu, Jie; Zhang, Wei; Shen, Xia; Cui, Guiyun; Hua, Fang

    2015-09-01

    Levodopa (L-dopa) remains the most effective drug in the treatment of Parkinson's disease (PD). However, L-dopa-induced dyskinesia (LID) has hindered its use for PD patients. The mechanisms of LID are not fully understood. Substance P (SP) receptor antagonist has been shown to reduce parkinsonism in animal models of PD, and ameliorate LID in PD rats. But the concrete mechanism is not fully understood. To address this issue, we produced a rat model of PD using 6-hydroxydompamine (6-OHDA) injections, and valid PD rats were intranigrally administrated with different doses of SP receptor antagonist LY303870 (5 nmol/day, 10 nmol/day and 20 nmol/day) following L-dopa (6 mg/kg/day, i.p.) plus benserazide (12 mg/kg/day, i.p.) for 23 days. We found that nigral SP levels were increased on days 3, 7 and 14 and decreased on day 21 after 6-hydroxydompamine lesions. But nigral SP levels kept increasing after repeated L-dopa administration in PD rats. Intranigral administration of low and moderate LY303870 reduced abnormal involuntary movements (AIMs) while improving motor deficits in PD rats treated with L-dopa plus benserazide. Microdialysis revealed that LY303870 (10 nmol/day) treatment attenuated the increase of striatal dopamine and the reduction of γ-aminobutyric acid in ventromedial thalamus of PD rats primed with L-dopa. Additionally, LY303870 (10 nmol/day) treatment prior to L-dopa administration reduced the phosphorylated levels of dopamine- and cyclic adenosine monophosphate-regulated phosphoprotein of 32 kDa at Thr 34 and extracellular signal-regulated kinases 1/2 as well as the levels of activity-regulated cytoskeleton-associated protein and Penk in L-dopa-primed PD rats. Taken together, these data showed that low and moderate SP receptor antagonists LY303870 could ameliorate LID via neurokinin 1 receptor without affecting therapeutic effect of L-dopa.

  12. Depth of lesion model in children and adolescents with moderate to severe traumatic brain injury: use of SPGR MRI to predict severity and outcome

    PubMed Central

    Grados, M; Slomine, B; Gerring, J; Vasa, R; Bryan, N; Denckla, M

    2001-01-01

    OBJECTIVES—The utility of a depth of lesion classification using an SPGR MRI sequence in children with moderate to severe traumatic brain injury (TBI) was examined. Clinical and depth of lesion classification measures of TBI severity were used to predict neurological and functional outcome after TBI.
METHODS—One hundred and six children, aged 4 to 19, with moderate to severe TBI admitted to a rehabilitation unit had an SPGR MRI sequence obtained 3 months afterTBI. Acquired images were analyzed for location, number, and size of lesions. The Glasgow coma scale (GCS) was the clinical indicator of severity. The deepest lesion present was used for depth of lesion classification. Speed of injury was inferred from the type of injury. The disability rating scale at the time of discharge from the rehabilitation unit (DRS1) and at 1 year follow up (DRS2) were functional outcome measures.
RESULTS—The depth of lesion classification was significantly correlated with GCS severity, number of lesions, and both functional measures, DRS1 and DRS2. This result was more robust for time 1, probably due to the greater number of psychosocial factors impacting on functioning at time 2. Lesion volume was not correlated with the depth of lesion model. In multivariate models, depth of lesion was most predictive of DRS1, whereas GCS was most predictive of DRS2.
CONCLUSIONS—A depth of lesion classification of TBI severity may have clinical utility in predicting functional outcome in children and adolescents with moderate to severe TBI.

 PMID:11181858

  13. Differential behavioral reinforcement effects of dopamine receptor agonists in the rat with bilateral lesion of the posterior ventral tegmental area.

    PubMed

    Ouachikh, Omar; Dieb, Wisam; Durif, Franck; Hafidi, Aziz

    2013-09-01

    Dopamine dysregulation syndrome in Parkinson's disease has been attributed to dopamine replacement therapies and/or a lesion of the dopaminergic system. The dopaminergic neuronal loss targets the substantia nigra and the ventral tegmental area (VTA). We hypothesize that dopamine replacement therapy is responsible for the potential reinforcement effect in Parkinson's disease by acting on the neuronal reward circuitry. Therefore this study was designed to explore the potential motivational effect of dopamine replacement therapy in bilateral VTA-lesioned animals. The posterior (p)VTA, which project to the nucleus accumbens (NAc) constitutes the major dopamine neuronal circuitry implicated in addictive disorders. Using the conditioned place preference (CPP) behavioral paradigm, we investigated the motivational effects of dopamine receptor agonists, and cocaine in rat with a 6-OHDA bilateral lesion of the pVTA. Amongst the dopamine receptor agonists used in this study only the D2R and D3R agonists (bromocriptine, PD128907 and pramipexole), induced a significant CPP in pVTA-lesioned animals. Dopamine receptor agonists did not induce behavioral sensitization in sham animals. Moreover, confocal D2R immunostaining analysis showed a significant increase in the number of D2R per cell body in the NAc shell of pVTA lesioned rats compared to sham. This result correlated, for the first time, the dopamine receptor agonists effect with DR2 overexpression in the NAc shell of pVTA-lesioned rats. In addition, cocaine, which is known to increase dopamine release, induced behavioral sensitization in sham group but not in dopamine deprived group. Thus, the later result highlighted the importance of pVTA-NAc dopaminergic pathway in positive reinforcements. Altogether these data suggested that the implication of the dopamine replacement therapy in the appearance of dopamine dysregulation syndrome in Parkinson's disease is probably due to both neuronal degeneration in the posterior VTA and

  14. Alterations in primary motor cortex neurotransmission and gene expression in hemi-Parkinsonian rats with drug-induced dyskinesia

    PubMed Central

    Lindenbach, David; Conti, Melissa M.; Ostock, Corinne Y.; Dupre, Kristin B.; Bishop, Christopher

    2015-01-01

    Treatment of Parkinson’s disease (PD) with dopamine replacement relieves symptoms of poverty of movement, but often causes drug-induced dyskinesias. Accumulating clinical and pre-clinical evidence suggests that the primary motor cortex (M1) is involved in the pathophysiology of PD and that modulating cortical activity may be a therapeutic target in PD and dyskinesia. However, surprisingly little is known about how M1 neurotransmitter tone or gene expression are altered in PD, dyskinesia or associated animal models. The present study utilized the rat unilateral 6-hydroxydopamine (6-OHDA) model of PD / dyskinesia to characterize structural and functional changes taking place in M1 monoamine innervation and gene expression. 6-OHDA caused dopamine pathology in M1, although the lesion was less severe than in the striatum. Rats with 6-OHDA lesions showed a PD motor impairment and developed dyskinesia when given L-DOPA or the D1 receptor agonist, SKF81297. M1 expression of two immediate-early genes (c-Fos and ARC) was strongly enhanced by either L-DOPA or SKF81297. At the same time, expression of genes specifically involved in glutamate and GABA signaling were either modestly affected or unchanged by lesion and/or treatment. We conclude that M1 neurotransmission and signal transduction in the rat 6-OHDA model of PD / dyskinesia mirror features of human PD, supporting the utility of the model to study M1 dysfunction in PD and the elucidation of novel pathophysiological mechanisms and therapeutic targets. PMID:26363150

  15. Alterations in primary motor cortex neurotransmission and gene expression in hemi-parkinsonian rats with drug-induced dyskinesia.

    PubMed

    Lindenbach, D; Conti, M M; Ostock, C Y; Dupre, K B; Bishop, C

    2015-12-03

    Treatment of Parkinson's disease (PD) with dopamine replacement relieves symptoms of poverty of movement, but often causes drug-induced dyskinesias. Accumulating clinical and pre-clinical evidence suggests that the primary motor cortex (M1) is involved in the pathophysiology of PD and that modulating cortical activity may be a therapeutic target in PD and dyskinesia. However, surprisingly little is known about how M1 neurotransmitter tone or gene expression is altered in PD, dyskinesia or associated animal models. The present study utilized the rat unilateral 6-hydroxydopamine (6-OHDA) model of PD/dyskinesia to characterize structural and functional changes taking place in M1 monoamine innervation and gene expression. 6-OHDA caused dopamine pathology in M1, although the lesion was less severe than in the striatum. Rats with 6-OHDA lesions showed a PD motor impairment and developed dyskinesia when given L-DOPA or the D1 receptor agonist, SKF81297. M1 expression of two immediate-early genes (c-Fos and ARC) was strongly enhanced by either L-DOPA or SKF81297. At the same time, expression of genes specifically involved in glutamate and GABA signaling were either modestly affected or unchanged by lesion and/or treatment. We conclude that M1 neurotransmission and signal transduction in the rat 6-OHDA model of PD/dyskinesia mirror features of human PD, supporting the utility of the model to study M1 dysfunction in PD and the elucidation of novel pathophysiological mechanisms and therapeutic targets.

  16. Embryonic Cell Grafts in a Culture Model of Spinal Cord Lesion: Neuronal Relay Formation Is Essential for Functional Regeneration

    PubMed Central

    Tscherter, Anne; Heidemann, Martina; Kleinlogel, Sonja; Streit, Jürg

    2016-01-01

    Presently there exists no cure for spinal cord injury (SCI). However, transplantation of embryonic tissue into spinal cord (SC) lesions resulted in axon outgrowth across the lesion site and some functional recovery, fostering hope for future stem cell therapies. Although in vivo evidence for functional recovery is given, the exact cellular mechanism of the graft support remains elusive: either the grafted cells provide a permissive environment for the host tissue to regenerate itself or the grafts actually integrate functionally into the host neuronal network reconnecting the separated SC circuits. We tested the two hypotheses in an in vitro SC lesion model that is based on propagation of activity between two rat organotypic SC slices in culture. Transplantation of dissociated cells from E14 rat SC or forebrain (FB) re-established the relay of activity over the lesion site and thus, provoked functional regeneration. Combining patch-clamp recordings from transplanted cells with network activity measurements from the host tissue on multi-electrode arrays (MEAs) we here show that neurons differentiate from the grafted cells and integrate into the host circuits. Optogenetic silencing of neurons developed from transplanted embryonic mouse FB cells provides clear evidence that they replace the lost neuronal connections to relay and synchronize activity between the separated SC circuits. In contrast, transplantation of neurospheres (NS) induced neither the differentiation of mature neurons from the grafts nor an improvement of functional regeneration. Together these findings suggest, that the formation of neuronal relays from grafted embryonic cells is essential to re-connect segregated SC circuits. PMID:27708562

  17. Improved bleeding scores using Gelfoam(®) Powder with incremental concentrations of bovine thrombin in a swine liver lesion model.

    PubMed

    Morse, Dennis C; Silva, Elif; Bartrom, Jolee; Young, Kelli; Bass, Eric J; Potter, David; Bieber, Trevor

    2016-10-01

    Topical hemostatic agents are used intra-operatively to prevent uncontrolled bleeding. Gelfoam(®) Powder contains a hemostatic agent prepared from purified pork skin gelatin, the efficacy of which is increased when combined with thrombin. However, the effect of increasing concentrations of thrombin on resultant hemostasis is not known. This study sought to evaluate the ability of various concentrations of thrombin in combination with Gelfoam Powder to control bleeding using a swine liver lesion model. Ten pigs underwent a midline laparotomy. Circular lesions were created in the left medial, right medial, and left lateral lobes; six lesions per lobe. Gelfoam Powder was hydrated with Thrombin-JMI(®) diluted to 250, 375, and 770 IU/mL. Each concentration was applied to two lesion sites per lobe. Bleeding scores were measured at 3, 6, 9, and 12 min using a 6-point system; comparison of bleeding scores was performed using ANOVA with the post hoc Tukey test. The bleeding scores with thrombin concentrations at 770 IU/mL were significantly lower than at 250 and 375 IU/mL at all four time points. The percentage of biopsies with a clinically acceptable bleeding score rose from 37.9, 46.6, and 71.2 % at 3 min to 55.2, 69.0, and 88.1 % at 12 min in the 250, 375, and 770 IU/mL thrombin groups, respectively. The study showed that the hemostatic response to thrombin was dose-related: using higher concentrations of thrombin with Gelfoam Powder yielded improved hemostasis, as determined by lower bleeding scores.

  18. Effects of Swimming Exercise on Learning and Memory in the Kainate-Lesion Model of Temporal Lobe Epilepsy

    PubMed Central

    Gorantla, Vasavi Rakesh; Pemminati, Sudhakar; Bond, Vernon; Meyers, Dewey G

    2016-01-01

    Introduction An aerobic exercise (Ex) augments neurogenesis and may ameliorate learning and memory deficits in the rat Kainic Acid (KA) model of temporal lobe epilepsy in the short-term but whether it reverses learning and memory deficits after a substantial period of delay remains unclear. Aim This study tests the hypothesis that aerobic Ex attenuates the learning and memory deficits associated with kainate seizures in the long-term. Materials and Methods A total of 60 rats were subjected to chemical lesioning using KA and to an Ex intervention consisting of a 30 days period of daily swimming for 15 min, immediately after KA lesioning (immediate exposure) or after a 60 days period of normal activity (delayed exposure). We evaluated spatial learning on a T-maze test, expressed as percentage of correct responses. We evaluated memory on a passive-avoidance test, expressed as time spent in a compartment in which the rats were previously exposed to an aversive stimulus. Results Ex increases the percentage of correct responses, percentage bias, and number of alternations, associated with the T-maze testing for the normal control, sham-operated control and kainate-lesioned animals after both immediate and delayed exposures to Ex. Ex decreased the time exposed to the aversive stimulus in the smaller compartment of the two-compartment passive-avoidance test, also for the normal control, sham-operated control and kainate-lesioned animals after both immediate and delayed exposures to Ex. Conclusion These findings suggest that, after temporal lobe epileptic seizures in rats, swimming exercise may attenuate the learning and memory deficits, even if the exercise treatment is delayed. PMID:28050361

  19. Neuroprotection of cerebrolysin in tissue culture models of brain ischemia: post lesion application indicates a wide therapeutic window.

    PubMed

    Schauer, E; Wronski, R; Patockova, J; Moessler, H; Doppler, E; Hutter-Paier, B; Windisch, M

    2006-07-01

    All attempts to reduce neuronal damage after acute brain ischemia by the use of neuroprotective compounds have failed to prove efficacy in clinical trials so far. One of the main reasons might be the relatively narrow time window for intervention. In this study 2 different tissue culture models of ischemia, excitotoxic lesion by the use of glutamate and oxygen-glucose deprivation (OGD), were used to investigate the effects of delayed application of Cerebrolysin (Cere) on neuronal survival. This drug consists of low molecular weight peptides with neuroprotective and neurotrophic properties similar to naturally occurring growth factors. After both types of lesion, acute as well as delayed treatment with Cere resulted in a dose dependent and significant rescue of neurons. In the model of excitotoxic cell death significant drug effects were found even when the treatment started with a delay of 96 hours after addition of glutamate. In the OGD model pronounced effects were found after 48 hours delay of treatment, and even after 72 hours a small but significant rescue of neurons was detected. The neuroprotective effects of a single addition of Cerebrolysin to the culture medium resulted in significant protection until end of the experiments which was up to 2 weeks after the initial lesion. A shift of the efficacious dosages from low to high concentrations indicates that most likely active compounds are used up, indicating that multiple dosing might even increase the effect size. In conclusion the results indicate that Cere displays a relatively wide therapeutic time window which might be explained by a combination of acute neuroprotective properties and neurotrophic efficacy.

  20. Antidyskinetic Effect of 7-Nitroindazole and Sodium Nitroprusside Associated with Amantadine in a Rat Model of Parkinson's Disease.

    PubMed

    Bortolanza, Mariza; Bariotto-Dos-Santos, Keila D; Dos-Santos-Pereira, Maurício; da-Silva, Célia Aparecida; Del-Bel, Elaine

    2016-07-01

    Amantadine is the noncompetitive antagonist of N-methyl-D-aspartate, receptor activated by the excitatory neurotransmitter glutamate. It is the only effective medication used to alleviate dyskinesia induced by L-3,4-dihydroxyphenylalanine (L-DOPA) in Parkinson's disease patients. Unfortunately, adverse effects as abnormal involuntary movements (AIMs) known as L-DOPA-induced dyskinesia limit its clinical utility. Combined effective symptomatic treatment modalities may lessen the liability to undesirable events. Likewise drugs known to interfere with nitrergic system reduce AIMs in animal models of Parkinson's disease. We aimed to analyze an interaction between amantadine, neuronal nitric oxide synthase inhibitor (7-nitroindazole, 7NI), and nitric oxide donor (sodium nitroprusside, SNP) in 6-hydroxydopamine-(6-OHDA)-lesioned rats (microinjection in the medial forebrain bundle) presenting L-DOPA-induced dyskinesia (20 mg/kg, gavage, during 21 days). We confirm that 7NI-30 mg/kg, SNP-2/4 mg/kg and amantadine-40 mg/kg, individually reduced AIMs. Our results revealed that co-administration of sub-effective dose of amantadine (10 mg/kg) plus sub-effective dose of 7NI (20 mg/kg) potentiates the effect of reducing AIMs scores when compared to the effect of the drugs individually. No superior benefit on L-DOPA-induced AIMs was observed with the combination of amantadine and SNP. The results revealed that combination of ineffective doses of amantadine and 7NI represents a new strategy to increase antidyskinetic effect in L-DOPA-induced AIMs. It may provide additional therapeutic benefits to Parkinson's disease patients from these disabling complications at lower and thus safer and more tolerable doses than required when either drug is used alone. To close, we discuss the paradox of both nitric oxide synthase inhibitor and/or donor produced AIMs reduction by targeting nitric oxide synthase.

  1. Histopathological characteristics of glutamine synthetase-positive hepatic tumor lesions in a mouse model of spontaneous metabolic syndrome (TSOD mouse)

    PubMed Central

    Takahashi, Tetsuyuki; Nishida, Takeshi; Baba, Hayato; Hatta, Hideki; Imura, Johji; Sutoh, Mitsuko; Toyohara, Syunji; Hokao, Ryoji; Watanabe, Syunsuke; Ogawa, Hirohisa; Uehara, Hisanori; Tsuneyama, Koichi

    2016-01-01

    We previously reported that Tsumura-Suzuki obese diabetic (TSOD) mice, a polygenic model of spontaneous type 2 diabetes, is a valuable model of hepatic carcinogenesis via non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). One of the characteristics of tumors in these mice is the diffuse expression of glutamine synthetase (GS), which is a diagnostic marker for hepatocellular carcinoma (HCC). In this study, we performed detailed histopathological examinations and found that GS expression was diffusely positive in >70% of the hepatic tumors from 15-month-old male TSOD mice. Translocation of β-catenin into nuclei with enhanced membranous expression also occurred in GS-positive tumors. Small lesions (<1 mm) in GS-positive cases exhibited dysplastic nodules, with severe nuclear atypia, whereas large lesions (>3 mm) bore the characteristics of human HCC, exhibiting nuclear and structural atypia with invasive growth. By contrast, the majority of GS-negative tumors were hepatocellular adenomas with advanced fatty change and low nuclear grade. In GS-negative tumors, loss of liver fatty acid-binding protein expression was observed. These results suggest that the histological characteristics of GS-positive hepatic tumors in TSOD mice resemble human HCC; thus, this model may be a useful tool in translational research targeting the NAFLD/NASH-HCC sequence. PMID:27446562

  2. Histopathological characteristics of glutamine synthetase-positive hepatic tumor lesions in a mouse model of spontaneous metabolic syndrome (TSOD mouse).

    PubMed

    Takahashi, Tetsuyuki; Nishida, Takeshi; Baba, Hayato; Hatta, Hideki; Imura, Johji; Sutoh, Mitsuko; Toyohara, Syunji; Hokao, Ryoji; Watanabe, Syunsuke; Ogawa, Hirohisa; Uehara, Hisanori; Tsuneyama, Koichi

    2016-08-01

    We previously reported that Tsumura-Suzuki obese diabetic (TSOD) mice, a polygenic model of spontaneous type 2 diabetes, is a valuable model of hepatic carcinogenesis via non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). One of the characteristics of tumors in these mice is the diffuse expression of glutamine synthetase (GS), which is a diagnostic marker for hepatocellular carcinoma (HCC). In this study, we performed detailed histopathological examinations and found that GS expression was diffusely positive in >70% of the hepatic tumors from 15-month-old male TSOD mice. Translocation of β-catenin into nuclei with enhanced membranous expression also occurred in GS-positive tumors. Small lesions (<1 mm) in GS-positive cases exhibited dysplastic nodules, with severe nuclear atypia, whereas large lesions (>3 mm) bore the characteristics of human HCC, exhibiting nuclear and structural atypia with invasive growth. By contrast, the majority of GS-negative tumors were hepatocellular adenomas with advanced fatty change and low nuclear grade. In GS-negative tumors, loss of liver fatty acid-binding protein expression was observed. These results suggest that the histological characteristics of GS-positive hepatic tumors in TSOD mice resemble human HCC; thus, this model may be a useful tool in translational research targeting the NAFLD/NASH-HCC sequence.

  3. Toward modeling of radio-frequency ablation lesions for image-guided left atrial fibrillation therapy: model formulation and preliminary evaluation.

    PubMed

    Linte, Cristian A; Camp, Jon J; Holmes, David R; Rettmann, Maryam E; Packer, Douglas L; Robb, Richard A

    2013-01-01

    In the context of image-guided left atrial fibrillation therapy, relatively very little work has been done to consider the changes that occur in the tissue during ablation in order to monitor therapy delivery. Here we describe a technique to predict the lesion progression and monitor the radio-frequency energy delivery via a thermal ablation model that uses heat transfer principles to estimate the tissue temperature distribution and resulting lesion. A preliminary evaluation of the model was conducted in ex vivo skeletal beef muscle tissue while emulating a clinically relevant tissue ablation protocol. The predicted temperature distribution within the tissue was assessed against that measured directly using fiberoptic temperature probes and showed agreement within 5°C between the model-predicted and experimentally measured tissue temperatures at prescribed locations. We believe this technique is capable of providing reasonably accurate representations of the tissue response to radio-frequency energy delivery.

  4. Vitamin D Repletion Reduces the Progression of Premalignant Squamous Lesions in the NTCU Lung Squamous Cell Carcinoma Mouse Model

    PubMed Central

    Mazzilli, Sarah A.; Hershberger, Pamela A.; Reid, Mary E.; Bogner, Paul N.; Atwood, Kristopher; Trump, Donald L.; Johnson, Candace S.

    2015-01-01

    The chemopreventive actions of vitamin D were examined in the N-nitroso-tris-chloroethylurea (NTCU) mouse model, a progressive model of lung squamous cell carcinoma (SCC). SWR/J mice were fed a deficient diet (D) containing no vitamin D3, a sufficient diet (S) containing 2000 IU/kg vitamin D3, or the same diets in combination with the active metabolite of vitamin D, calcitriol (C) (80 μg/kg, weekly). The percentage (%) of the mucosal surface of large airways occupied by dysplastic lesions was determined in mice after treatment with a total dose of 15 or 25 μmol NTCU (N). After treatment with 15 μmol NTCU, the % of the surface of large airways containing high-grade dysplastic (HGD) lesions were vitamin D-deficient +NTCU (DN), 22.7 % (p<0.05 compared to vitamin D-sufficient +NTCU (SN)); DN + C, 12.3%; SN, 8.7%; and SN + C, 6.6%. The extent of HGD increased with NTCU dose in the DN group. Proliferation, assessed by Ki-67 labeling, increased upon NTCU treatment. The highest Ki-67 labeling index was seen in the DN group. As compared to SN mice, DN mice exhibited a 3-fold increase (p <0.005) in circulating white blood cells (WBC), a 20% (p <0.05) increase in IL-6 levels, and a 4 -fold (p <0.005) increase in WBC in bronchial lavages. Thus, vitamin D repletion reduces the progression of premalignant lesions, proliferation, and inflammation, and may thereby suppress development of lung SCC. Further investigations of the chemopreventive effects of vitamin D in lung SCC are warranted. PMID:26276745

  5. Mechanistic modelling suggests that the size of preneoplastic lesions is limited by intercellular induction of apoptosis in oncogenically transformed cells

    PubMed Central

    Kundrát, Pavel; Bauer, Georg; Jacob, Peter; Friedland, Werner

    2012-01-01

    Selective removal of oncogenically transformed cells by apoptosis induced via signalling by surrounding cells has been suggested to represent a natural anticarcinogenic process. To investigate its potential effect in detail, a mechanistic model of this process is proposed. The model is calibrated against in vitro data on apoptosis triggered in transformed cells by defined external inducers as well as through signalling by normal cells under coculture conditions. The model predicts that intercellular induction of apoptosis is capable of balancing the proliferation of oncogenically transformed cells and limiting the size of their populations over long times, even if their proliferation per se were unlimited. Experimental research is desired to verify whether the predicted stable population of transformed cells corresponds to a kind of dormancy during early-stage carcinogenesis (dormant preneoplastic lesions), and how this process relates to other anticarcinogenic mechanisms taking place under in vivo conditions. PMID:22045028

  6. Hypericum Perforatum Hydroalcoholic Extract Mitigates Motor Dysfunction and is Neuroprotective in Intrastriatal 6-Hydroxydopamine Rat Model of Parkinson's Disease.

    PubMed

    Kiasalari, Zahra; Baluchnejadmojarad, Tourandokht; Roghani, Mehrdad

    2016-05-01

    Parkinson's disease is the second most common neurodegenerative disorder with selective and progressive decline of nigral dopaminergic neurons. Hypericum perforatum L. (H. perforatum, St. John's wort) has been traditionally used for management of different disorders, especially mild-to-moderate depression. This study was conducted to evaluate the effect of H. perforatum extract against unilateral striatal 6-hydroxydopamine (6-OHDA) toxicity and to unmask some involved mechanisms. Intrastriatal 6-OHDA-lesioned rats were treated with H. perforatum hydroalcoholic extract at a dose of 200 mg/kg/day started 1 week pre-surgery for 1 week post-surgery. The extract attenuated apomorphine-induced rotational behavior, decreased the latency to initiate and the total time on the narrow beam task, lowered striatal level of malondialdehyde and enhanced striatal catalase activity and reduced glutathione content, normalized striatal expression of glial fibrillary acidic protein, tumor necrosis factor α with no significant effect on mitogen-activated protein kinase, lowered nigral DNA fragmentation, and prevented damage of nigral dopaminergic neurons with a higher striatal tyrosine hydroxylase immunoreactivity. These findings reveal the beneficial effect of H. perforatum via attenuation of DNA fragmentation, astrogliosis, inflammation, and oxidative stress.

  7. Pink lesions.

    PubMed

    Giacomel, Jason; Zalaudek, Iris

    2013-10-01

    Dermoscopy (dermatoscopy or surface microscopy) is an ancillary dermatologic tool that in experienced hands can improve the accuracy of diagnosis of a variety of benign and malignant pigmented skin tumors. The early and more accurate diagnosis of nonpigmented, or pink, tumors can also be assisted by dermoscopy. This review focuses on the dermoscopic diagnosis of pink lesions, with emphasis on blood vessel morphology and pattern. A 3-step algorithm is presented, which facilitates the timely and more accurate diagnosis of pink tumors and subsequently guides the management for such lesions.

  8. Porcine skin visible lesion thresholds for near-infrared lasers including modeling at two pulse durations and spot sizes

    NASA Astrophysics Data System (ADS)

    Cain, Clarence P.; Polhamus, Garrett D.; Roach, William P.; Stolarski, David J.; Schuster, Kurt J.; Stockton, Kevin; Rockwell, Benjamin A.; Chen, Bo; Welch, Ashley J.

    2006-07-01

    With the advent of such systems as the airborne laser and advanced tactical laser, high-energy lasers that use 1315-nm wavelengths in the near-infrared band will soon present a new laser safety challenge to armed forces and civilian populations. Experiments in nonhuman primates using this wavelength have demonstrated a range of ocular injuries, including corneal, lenticular, and retinal lesions as a function of pulse duration. American National Standards Institute (ANSI) laser safety standards have traditionally been based on experimental data, and there is scant data for this wavelength. We are reporting minimum visible lesion (MVL) threshold measurements using a porcine skin model for two different pulse durations and spot sizes for this wavelength. We also compare our measurements to results from our model based on the heat transfer equation and rate process equation, together with actual temperature measurements on the skin surface using a high-speed infrared camera. Our MVL-ED50 thresholds for long pulses (350 µs) at 24-h postexposure are measured to be 99 and 83 Jcm-2 for spot sizes of 0.7 and 1.3 mm diam, respectively. Q-switched laser pulses of 50 ns have a lower threshold of 11 Jcm-2 for a 5-mm-diam top-hat laser pulse.

  9. Nodular lesions and mesangiolysis in diabetic nephropathy.

    PubMed

    Wada, Takashi; Shimizu, Miho; Yokoyama, Hitoshi; Iwata, Yasunori; Sakai, Yoshio; Kaneko, Shuichi; Furuichi, Kengo

    2013-02-01

    Diabetic nephropathy is a leading cause of end-stage renal failure all over the world. Advanced human diabetic nephropathy is characterized by the presence of specific lesions including nodular lesions, doughnut lesions, and exudative lesions. Thus far, animal models precisely mimicking advanced human diabetic nephropathy, especially nodular lesions, remain to be fully established. Animal models with spontaneous diabetic kidney diseases or with inducible kidney lesions may be useful for investigating the pathogenesis of diabetic nephropathy. Based on pathological features, we previously reported that diabetic glomerular nodular-like lesions were formed during the reconstruction process of mesangiolysis. Recently, we established nodular-like lesions resembling those seen in advanced human diabetic nephropathy through vascular endothelial injury and mesangiolysis by administration of monocrotaline. Here, in this review, we discuss diabetic nodular lesions and its animal models resembling human diabetic kidney lesions, with our hypothesis that endothelial cell injury and mesangiolysis might be required for nodular lesions.

  10. Influence of chronic L-DOPA treatment on immune response following allogeneic and xenogeneic graft in a rat model of Parkinson's disease.

    PubMed

    Breger, Ludivine S; Kienle, Korbinian; Smith, Gaynor A; Dunnett, Stephen B; Lane, Emma L

    2017-03-01

    Although intrastriatal transplantation of fetal cells for the treatment of Parkinson's disease had shown encouraging results in initial open-label clinical trials, subsequent double-blind studies reported more debatable outcomes. These studies highlighted the need for greater preclinical analysis of the parameters that may influence the success of cell therapy. While much of this has focused on the cells and location of the transplants, few have attempted to replicate potentially critical patient centered factors. Of particular relevance is that patients will be under continued L-DOPA treatment prior to and following transplantation, and that typically the grafts will not be immunologically compatible with the host. The aim of this study was therefore to determine the effect of chronic L-DOPA administered during different phases of the transplantation process on the survival and function of grafts with differing degrees of immunological compatibility. To that end, unilaterally 6-OHDA lesioned rats received sham surgery, allogeneic or xenogeneic transplants, while being treated with L-DOPA before and/or after transplantation. Irrespective of the L-DOPA treatment, dopaminergic grafts improved function and reduced the onset of L-DOPA induced dyskinesia. Importantly, although L-DOPA administered post transplantation was found to have no detrimental effect on graft survival, it did significantly promote the immune response around xenogeneic transplants, despite the administration of immunosuppressive treatment (cyclosporine). This study is the first to systematically examine the effect of L-DOPA on graft tolerance, which is dependent on the donor-host compatibility. These findings emphasize the importance of using animal models that adequately represent the patient paradigm.

  11. Oleoylethanolamide reduces L-DOPA-induced dyskinesia via TRPV1 receptor in a mouse model of Parkinson´s disease.

    PubMed

    González-Aparicio, Ramiro; Moratalla, Rosario

    2014-02-01

    The long-term use of levodopa (L-DOPA) in Parkinson's disease (PD) results in the development of abnormal involuntary movements called L-DOPA-induced dyskinesias. Increasing evidences suggest that the endocannabinoid system may play a role in the modulation of dyskinesias. In this work, we assessed the antidyskinetic effect of the endocannabinoid analog oleoylethanolamide (OEA), an agonist of PPARα and antagonist of TRPV1 receptors. We used a hemiparkinsonian model of PD in mice with 6-OHDA striatal lesion. The chronic L-DOPA treatment developed intense axial, forelimb and orolingual dyskinetic symptoms, as well as contralateral rotations. Treatment with OEA reduced all these symptoms without reducing motor activity or the therapeutic motor effects of L-DOPA. Moreover, the OEA-induced reduction in dyskinetic behavior correlated with a reduction in molecular correlates of dyskinesia. OEA reduced FosB striatal overexpression and phosphoacetylation of histone 3, both molecular markers of L-DOPA-induced dyskinesias. We found that OEA antidyskinetic properties were mediated by TRPV1 receptor, as pretreatment with capsaicin, a TRPV1 agonist, blocked OEA antidyskinetic actions, as well as the reduction in FosB- and pAcH3-overexpression induced by L-DOPA. This study supports the hypothesis that the endocannabinoid system plays an important role in the development and expression of dyskinesias and might be an effective target for the treatment of L-DOPA-induced dyskinesias. Importantly, there was no development of tolerance to OEA in any of the parameters we examined, which has important implications for the therapeutic potential of drugs targeting the endocannabinoid system.

  12. Mycobacterium-Host Cell Relationships in Granulomatous Lesions in a Mouse Model of Latent Tuberculous Infection.

    PubMed

    Ufimtseva, Elena

    2015-01-01

    Tuberculosis (TB) is a dangerous infectious disease characterized by a tight interplay between mycobacteria and host cells in granulomatous lesions (granulomas) during the latent, asymptomatic stage of infection. Mycobacterium-host cell relationships were analyzed in granulomas obtained from various organs of BALB/c mice with chronic TB infection caused by in vivo exposure to the Bacillus Calmette-Guérin (BCG) vaccine. Acid-fast BCG-mycobacteria were found to be morphologically and functionally heterogeneous (in size, shape, and replication rates in colonies) in granuloma macrophages, dendritic cells, and multinucleate Langhans giant cells. Cord formation by BCG-mycobacteria in granuloma cells has been observed. Granuloma macrophages retained their ability to ingest damaged lymphocytes and thrombocytes in the phagosomes; however, their ability to destroy BCG-mycobacteria contained in these cells was compromised. No colocalization of BCG-mycobacteria and the LysoTracker dye was observed in the mouse cells. Various relationships between granuloma cells and BCG-mycobacteria were observed in different mice belonging to the same line. Several mice totally eliminated mycobacterial infection. Granulomas in the other mice had mycobacteria actively replicating in cells of different types and forming cords, which is an indicator of mycobacterial virulence and, probably, a marker of the activation of tuberculous infection in animals.

  13. Direct measurement of the 3-dimensional DNA lesion distribution induced by energetic charged particles in a mouse model tissue

    PubMed Central

    Mirsch, Johanna; Tommasino, Francesco; Frohns, Antonia; Conrad, Sandro; Durante, Marco; Scholz, Michael; Friedrich, Thomas; Löbrich, Markus

    2015-01-01

    Charged particles are increasingly used in cancer radiotherapy and contribute significantly to the natural radiation risk. The difference in the biological effects of high-energy charged particles compared with X-rays or γ-rays is determined largely by the spatial distribution of their energy deposition events. Part of the energy is deposited in a densely ionizing manner in the inner part of the track, with the remainder spread out more sparsely over the outer track region. Our knowledge about the dose distribution is derived solely from modeling approaches and physical measurements in inorganic material. Here we exploited the exceptional sensitivity of γH2AX foci technology and quantified the spatial distribution of DNA lesions induced by charged particles in a mouse model tissue. We observed that charged particles damage tissue nonhomogenously, with single cells receiving high doses and many other cells exposed to isolated damage resulting from high-energy secondary electrons. Using calibration experiments, we transformed the 3D lesion distribution into a dose distribution and compared it with predictions from modeling approaches. We obtained a radial dose distribution with sub-micrometer resolution that decreased with increasing distance to the particle path following a 1/r2 dependency. The analysis further revealed the existence of a background dose at larger distances from the particle path arising from overlapping dose deposition events from independent particles. Our study provides, to our knowledge, the first quantification of the spatial dose distribution of charged particles in biologically relevant material, and will serve as a benchmark for biophysical models that predict the biological effects of these particles. PMID:26392532

  14. An improved model to investigate the efficacy of antidyskinetic agents in hemiparkinsonian rats.

    PubMed

    Spinnewyn, Brigitte; Charnet, Christelle; Cornet, Sylvie; Roubert, Véronique; Chabrier, Pierre-Etienne; Auguet, Michel

    2011-10-01

    A number of experimental models of L-DOPA-induced dyskinesia have been proposed, but these models result in a low to medium rate of dyskinetic animals with mild to severe symptoms. The objective of this study was to combine a model of 6-OHDA-induced parkinsonism and of L-DOPA-induced dyskinesia in rats to establish a reliable preclinical model. Two stereotaxic injections of 6-OHDA were administered in the left striatum. This model led to 90-100% of rats with a marked contralateral circling behaviour, significant limb use asymmetry (20%), a decrease in ipsilateral striatal dopamine content (70%) and degeneration of dopamine neurons in the substantia nigra (70%). Chronic treatment with L-DOPA was administered for 35 days and consisted of three phases with incremental daily doses. The third phase resulted in 83-90% of rats developing severe abnormal involuntary movements (AIMs) which included limb and locomotive dyskinesia, axial dystonia and orolingual dyskinesia. Reproducibility of the model, criteria of strict blinding, placebo-controlled design, randomization of study subjects and pretrial determination of sample size were used to measure efficacy of amantadine and istradefylline and to validate the protocol design. Acute or subchronic post-treatment with amantadine reduced the severity of dyskinesia while istradefylline punctually attenuated AIMs. Our experimental conditions using gradual development of dyskinesia induced by increasing doses of L-DOPA resulted in a reliable model of L-DOPA-induced dyskinesia with a high rate of dyskinetic rats.

  15. Gross Deletions Involving IGHM, BTK, or Artemis: A Model for Genomic Lesions Mediated by Transposable Elements

    PubMed Central

    van Zelm, Menno C.; Geertsema, Corinne; Nieuwenhuis, Nicole; de Ridder, Dick; Conley, Mary Ellen; Schiff, Claudine; Tezcan, Ilhan; Bernatowska, Ewa; Hartwig, Nico G.; Sanders, Elisabeth A.M.; Litzman, Jiri; Kondratenko, Irina; van Dongen, Jacques J.M.; van der Burg, Mirjam

    2008-01-01

    Most genetic disruptions underlying human disease are microlesions, whereas gross lesions are rare with gross deletions being most frequently found (6%). Similar observations have been made in primary immunodeficiency genes, such as BTK, but for unknown reasons the IGHM and DCLRE1C (Artemis) gene defects frequently represent gross deletions (∼60%). We characterized the gross deletion breakpoints in IGHM-, BTK-, and Artemis-deficient patients. The IGHM deletion breakpoints did not show involvement of recombination signal sequences or immunoglobulin switch regions. Instead, five IGHM, eight BTK, and five unique Artemis breakpoints were located in or near sequences derived from transposable elements (TE). The breakpoints of four out of five disrupted Artemis alleles were located in highly homologous regions, similar to Ig subclass deficiencies and Vh deletion polymorphisms. Nevertheless, these observations suggest a role for TEs in mediating gross deletions. The identified gross deletion breakpoints were mostly located in TE subclasses that were specifically overrepresented in the involved gene as compared to the average in the human genome. This concerned both long (LINE1) and short (Alu, MIR) interspersed elements, as well as LTR retrotransposons (ERV). Furthermore, a high total TE content (>40%) was associated with an increased frequency of gross deletions. Both findings were further investigated and confirmed in a total set of 20 genes disrupted in human disease. Thus, to our knowledge for the first time, we provide evidence that a high TE content, irrespective of the type of element, results in the increased incidence of gross deletions as gene disruption underlying human disease. PMID:18252213

  16. Impact of the Chronic Omega-3 Fatty Acids Supplementation in Hemiparkinsonism Model Induced by 6-Hydroxydopamine in Rats.

    PubMed

    Barros, Alexandre Sales; Crispim, Rafael Yuri Gouveia; Uchoa, Juliana Cavalcante; Souza, Ricardo Basto; Lemos, Jonatas Cavalcante; Filho, Gerardo Cristino; Bezerra, Mirna Marques; Pinheiro, Thales Fontenele Moraes; de Vasconcelos, Silvânia Maria Mendes; Macêdo, Danielle Silveira; de Barros Viana, Glauce Socorro; Aguiar, Lissiana Magna Vasconcelos

    2016-11-24

    Parkinson's disease (PD) is characterized by a progressive degeneration of dopaminergic neurons in the substantia nigra. The neuronal degeneration may result from the convergence of a number of different pathogenic factors, including apoptosis, excitotoxicity and oxidative stress. Many studies emphasize the importance of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in vital processes such as maintenance of the properties of cell membranes and the participation in signal transduction and biodynamic activity of neuronal membranes. In the present study, the protective effect of ω-3 PUFAs administration on the 6-hydroxydopamine (6-OHDA) model of PD in rats was investigated. ω-3 PUFAs (1.5 and 3.0 g/kg) was orally administered by gavage during 28 consecutive days to male Wistar rats. On the 4(th) day, hemiparkinsonism was induced through intrastriatal injection of 6-OHDA. On the 25(th) day, the animals were submitted to behavioural analysis. On the 28(th) day, after euthanasia, the brain areas were collected for neurochemical evaluation. ω-3 PUFAs (1.5 and 3.0 g/kg) restored monoamine and amino acids levels on the striatum from hemiparkinsonian rats, followed by reduction of the number of apomorphine-induced rotations and promotion of a partial locomotor recovery. In addition, ω-3 PUFAs (1.5 and 3.0 g/kg) decreased the lipid peroxidation levels and nitrite levels in the brain areas from hemiparkinsonian rats. Thus, the present study suggests that supplementation with ω-3 PUFAs prevents behavioural and neurochemical disturbances induced by 6-OHDA, presenting a potential neuroprotective action. This article is protected by copyright. All rights reserved.

  17. [Selective stimulations and lesions of the rat brain nuclei as the models for research of the human sleep pathology mechanisms].

    PubMed

    Šaponjić, Jasna

    2011-01-01

    Many complex behavioral phenomena such as sleep can not be explained without multidisciplinary experimental approach, and complementay approaches in the animal models "in vivo" and human studies. Electrophysiological, pharmacological, anatomical and immunohistochemical techniques, and particularly stereotaxically guided local nanovolume microinjection technique, enable us to selectively stimulate and lesion the brain nuclei or their specific neuronal subpopulation, and to reslove the mechanisms of certain brain structure regulatory role, and its afferent-efferent connectivity within the brain. Local stereotaxically guided nanovolume microinjection technique enable us to investigate in animals the brain nulcei functional topography with a resolution of < or = 10 microM, and at a level of 300 microM of effective radius within the brain tissue "in vivo". The advantage of local glutamate or DL- homocysteic acid microinjection stimulation or local excitotoxic (glutamate, ibotenic acid, IgG saporin) microinjection lesion over electrical stimulation/lesion of the same neuronal population are that they reduces the likelihood of activation/lesion of fibers of passage. Much of our knowledge of the sleep neuronal substrates is based on animal studies primarly in cat and rat. Selective pharmacological stimulation of the pedunculopontine tegmentum (PPT) in freely moving rat, using glutamate microinjection, proved that excitation of its cholinergic part is necessary for induction of wakefulness or REM (Datta S, 2001). Local nanovolume glutamate microinjection into PPT of anesthetized rats (Saponjić et al, 2003a) additionally evidenced P-wave and respiratory regulating neuronal subpopulation within the cholinergic compartment of PPT (apneogenic neuronal zone). Local microinjection of serotonin and noradrenaline into cholinergic PPT apneogenic zone evidenced their opposed impact through PPT on breathing, in contrast to their convergent regulatory role in behavioral state control

  18. Immunohistochemical cellular distribution of proteins related to M phase regulation in early proliferative lesions induced by tumor promotion in rat two-stage carcinogenesis models.

    PubMed

    Yafune, Atsunori; Taniai, Eriko; Morita, Reiko; Akane, Hirotoshi; Kimura, Masayuki; Mitsumori, Kunitoshi; Shibutani, Makoto

    2014-01-01

    We have previously reported that 28-day treatment with hepatocarcinogens increases liver cells expressing p21(Cip1), a G1/S checkpoint protein, and M phase proteins, i.e., nuclear Cdc2, Aurora B, phosphorylated-Histone H3 (p-Histone H3) and heterochromatin protein 1α (HP1α), in rats. To examine the roles of these markers in the early stages of carcinogenesis, we investigated their cellular distribution in several carcinogenic target organs using rat two-stage carcinogenesis models. Promoting agents targeting the liver (piperonyl butoxide and methapyrilene hydrochloride), thyroid (sulfadimethoxine), urinary bladder (phenylethyl isothiocyanate), and forestomach and glandular stomach (catechol) were administered to rats after initiation treatment for the liver with N-diethylnitrosamine, thyroid with N-bis(2-hydroxypropyl)nitrosamine, urinary bladder with N-butyl-N-(4-hydroxybutyl)nitrosamine, and forestomach and glandular stomach with N-methyl-N'-nitro-N-nitrosoguanidine. Numbers of cells positive for nuclear Cdc2, Aurora B, p-Histone H3 and HP1α increased within preneoplastic lesions as determined by glutathione S-transferase placental form in the liver or phosphorylated p44/42 mitogen-activated protein kinase in the thyroid, and hyperplastic lesions having no known preneoplastic markers in the urinary bladder, forestomach and glandular stomach. Immunoreactive cells for p21(Cip1) were decreased within thyroid preneoplastic lesions; however, they were increased within liver preneoplastic lesions and hyperplastic lesions in other organs. These results suggest that M phase disruption commonly occur during the formation of preneoplastic lesions and hyperplastic lesions. Differences in the expression patterns of p21(Cip1) between thyroid preneoplastic and proliferative lesions in other organs may reflect differences in cell cycle regulation involving G1/S checkpoint function between proliferative lesions in each organ.

  19. Empiric Antibiotic Treatment of Erythema Migrans-Like Skin Lesions As a Function of Geography: A Clinical and Cost Effectiveness Modeling Study

    PubMed Central

    Brinkerhoff, R. Jory; Wormser, Gary P.; Clemen, Robert

    2013-01-01

    Abstract The skin lesion of early Lyme disease, erythema migrans (EM), is so characteristic that routine practice is to treat all such patients with antibiotics. Because other skin lesions may resemble EM, it is not known whether presumptive treatment of EM is appropriate in regions where Lyme disease is rare. We constructed a decision model to compare the cost and clinical effectiveness of three strategies for the management of EM: Treat All, Observe, and Serology as a function of the probability that an EM-like lesion is Lyme disease. Treat All was found to be the preferred strategy in regions that are endemic for Lyme disease. Where Lyme disease is rare, Observe is the preferred strategy, as presumptive treatment would be expected to produce excessive harm and increased costs. Where Lyme disease is rare, clinicians and public health officials should consider observing patients with EM-like lesions who lack travel to Lyme disease-endemic areas. PMID:24107201

  20. Empiric antibiotic treatment of erythema migrans-like skin lesions as a function of geography: a clinical and cost effectiveness modeling study.

    PubMed

    Lantos, Paul M; Brinkerhoff, R Jory; Wormser, Gary P; Clemen, Robert

    2013-12-01

    The skin lesion of early Lyme disease, erythema migrans (EM), is so characteristic that routine practice is to treat all such patients with antibiotics. Because other skin lesions may resemble EM, it is not known whether presumptive treatment of EM is appropriate in regions where Lyme disease is rare. We constructed a decision model to compare the cost and clinical effectiveness of three strategies for the management of EM: Treat All, Observe, and Serology as a function of the probability that an EM-like lesion is Lyme disease. Treat All was found to be the preferred strategy in regions that are endemic for Lyme disease. Where Lyme disease is rare, Observe is the preferred strategy, as presumptive treatment would be expected to produce excessive harm and increased costs. Where Lyme disease is rare, clinicians and public health officials should consider observing patients with EM-like lesions who lack travel to Lyme disease-endemic areas.

  1. A blueprint for staging of murine melanocytic lesions based on the Cdk4 ( R24C/R24C ) ::Tyr- NRAS ( Q ) ( 61K ) model.

    PubMed

    Wurm, Elisabeth M T; Lin, Lynlee L; Ferguson, Blake; Lambie, Duncan; Prow, Tarl W; Walker, Graeme J; Soyer, H Peter

    2012-09-01

    It has been shown that gene mutations which drive the development of malignant melanoma (MM) in humans also lead to emergence of MM when engineered mice. However, little attention has been paid to the clinical and histopathological features of melanocytic lesions and their natural history in a given mouse model. This knowledge is crucial to enable us to understand how engineered mutations influence the initiation and evolution of melanocytic lesions, and/or for the use of mice as a preclinical model to test specific treatments. We recently reported the development of melanocytic proliferations along the spectrum of naevi to MM in a Cdk4 ( R24C/R24C ) ::Tyr- NRAS ( Q ) ( 61K ) mouse model. In this study, we followed the development of lesions over time using digital photography and dermoscopy with the aim to correlate the clinical and histopathological features of lesions developing in this model. We identified two types of lesions. The first are slow-growing dermal MMs that emanate from dermal naevi. The second did not emanate from naevi, grew rapidly, and appeared to be solely confined to the subcutaneous fat. We present a simple staging system for the MMs that progress from naevi, based on depth of extension into the dermis and subcutis. This represents a blueprint for documentation and follow-up of MMs in the live animal, which is critical for the proper use of murine melanoma models.

  2. Alcoholic extract of Bacopa monniera Linn. protects against 6-hydroxydopamine-induced changes in behavioral and biochemical aspects: a pilot study.

    PubMed

    Shobana, Chandrasekar; Kumar, Radhakrishnan Ramesh; Sumathi, Thangarajan

    2012-10-01

    Parkinson's disease is one of the commonest neurodegenerative diseases, and oxidative stress has been evidenced to play a vital role in its causation. In this study, we evaluated whether alcoholic extract of Bacopa monniera (AEBM), an antioxidant and memory enhancer can slow the neuronal injury in a 6-OHDA-rat model of Parkinson's. Rats were treated with 20 and 40 mg/kg bodyweight of AEBM for 3 weeks. On Day 21, 2 μl of 6-OHDA (12 μg in 0.01 % in ascorbic acid-saline) was infused into the right striatum, while the control group received 2 μl of vehicle. Three weeks after the 6-OHDA injection, the rats were tested for neurobehavioral activity (rotarod, locomotor activity, grip test, forced swim test, radial arm maze) and were killed after 6 weeks for the estimation of lipid peroxidation, reduced glutathione (GSH) content, activities of glutathione-S-transferase, glutathione reductase, glutathione peroxidase, superoxide dismutase (SOD), and catalase (CAT). The deficits in behavioral activity due to 6-OHDA lesioning were significantly and dose dependently restored by AEBM. Lesioning was followed by an increased lipid peroxidation and significant depletion of reduced GSH content in the substantia nigra, which was prevented with AEBM pretreatment. The activities of GSH-dependent enzymes, CAT and SOD in striatum were reduced significantly by lesioning, which were restored significantly and dose dependently by AEBM. This study indicates that the extract of B. monniera might be helpful in attenuating 6-OHDA-induced lesioning in rats.

  3. High-Frequency Stimulation of the Subthalamic Nucleus Restores Neural and Behavioral Functions During Reaction Time Task in a Rat Model of Parkinson’s Disease

    PubMed Central

    Li, Xiang-Hong; Wang, Jin-Yan; Gao, Ge; Chang, Jing-Yu; Woodward, Donald J.; Luo, Fei

    2015-01-01

    Deep brain stimulation (DBS) has been used in the clinic to treat Parkinson’s disease (PD) and other neuropsychiatric disorders. Our previous work has shown that DBS in the subthalamic nucleus (STN) can improve major motor deficits, and induce a variety of neural responses in rats with unilateral dopamine (DA) lesions. In the present study, we examined the effect of STN DBS on reaction time (RT) performance and parallel changes in neural activity in the cortico-basal ganglia regions of partially bilateral DA- lesioned rats. We recorded neural activity with a multiple-channel single-unit electrode system in the primary motor cortex (MI), the STN, and the substantia nigra pars reticulata (SNr) during RT test. RT performance was severely impaired following bilateral injection of 6-OHDA into the dorsolateral part of the striatum. In parallel with such behavioral impairments, the number of responsive neurons to different behavioral events was remarkably decreased after DA lesion. Bilateral STN DBS improved RT performance in 6-OHDA lesioned rats, and restored operational behavior-related neural responses in cortico-basal ganglia regions. These behavioral and electrophysiological effects of DBS lasted nearly an hour after DBS termination. These results demonstrate that a partial DA lesion-induced impairment of RT performance is associated with changes in neural activity in the cortico-basal ganglia circuit. Furthermore, STN DBS can reverse changes in behavior and neural activity caused by partial DA depletion. The observed long-lasting beneficial effect of STN DBS suggests the involvement of the mechanism of neural plasticity in modulating corticobasal ganglia circuits. PMID:20025062

  4. The 5-alpha reductase inhibitor finasteride reduces dyskinesia in a rat model of Parkinson's disease.

    PubMed

    Frau, Roberto; Savoia, Paola; Fanni, Silvia; Fiorentini, Chiara; Fidalgo, Camino; Tronci, Elisabetta; Stancampiano, Roberto; Meloni, Mario; Cannas, Antonino; Marrosu, Francesco; Bortolato, Marco; Devoto, Paola; Missale, Cristina; Carta, Manolo

    2017-05-01

    Levodopa-induced dyskinesia (LID) is a disabling motor complication occurring in Parkinson's disease patients (PD) after long-term l-DOPA treatment. Although its etiology remains unclear, there is accumulating evidence that LID relies on an excessive dopamine receptor transmission, particularly at the downstream signaling of D1 receptors. We previously reported that the pharmacological blockade of 5-alpha reductase (5AR), the rate limiting enzyme in neurosteroids synthesis, rescued a number of behavioral aberrations induced by D1 receptor-selective and non-selective agonists, without inducing extrapyramidal symptoms. Thus, the present study was designed to verify whether the 5AR inhibitor finasteride (FIN) may counteract the dyskinesias induced by dopaminergic agonists in 6-hydroxydopamine (6-OHDA)-lesioned rats. First, we assessed the acute and chronic effect of different doses of FIN (30-60mg/kg) on LID, in male 6-OHDA-lesioned dyskinetic rats. Thereafter, to fully characterize the therapeutic potential of FIN on LID and its impact on l-DOPA efficacy, we assessed abnormal involuntary movements and forelimb use in hemiparkinsonian male rats chronically injected with FIN (30-60mg/kg/24days) either prior to- or concomitant with l-DOPA administration. In addition, to investigate whether the impact of FIN on LID may be ascribed to a modulation of the D1- or D2/D3-receptor function, dyskinesias were assessed in l-DOPA-primed 6-OHDA-lesioned rats that received FIN in combination with selective direct dopaminergic agonists. Finally, we set to investigate whether FIN may produce similar effect in female hemiparkinsonian rats, as seen in males. The results indicated that FIN administrations significantly dampened LID in all tested treatment regimens, without interfering with the ability of l-DOPA to ameliorate forelimb use in the stepping test. The antidyskinetic effect appears to be due to modulation of both D1- and D2/D3-receptor function, as FIN also reduced abnormal

  5. Linking Cellular and Mechanical Processes in Articular Cartilage Lesion Formation: A Mathematical Model

    PubMed Central

    Kapitanov, Georgi I.; Wang, Xiayi; Ayati, Bruce P.; Brouillette, Marc J.; Martin, James A.

    2016-01-01

    Post-traumatic osteoarthritis affects almost 20% of the adult US population. An injurious impact applies a significant amount of physical stress on articular cartilage and can initiate a cascade of biochemical reactions that can lead to the development of osteoarthritis. In our effort to understand the underlying biochemical mechanisms of this debilitating disease, we have constructed a multiscale mathematical model of the process with three components: cellular, chemical, and mechanical. The cellular component describes the different chondrocyte states according to the chemicals these cells release. The chemical component models the change in concentrations of those chemicals. The mechanical component contains a simulation of a blunt impact applied onto a cartilage explant and the resulting strains that initiate the biochemical processes. The scales are modeled through a system of partial-differential equations and solved numerically. The results of the model qualitatively capture the results of laboratory experiments of drop-tower impacts on cartilage explants. The model creates a framework for incorporating explicit mechanics, simulated by finite element analysis, into a theoretical biology framework. The effort is a step toward a complete virtual platform for modeling the development of post-traumatic osteoarthritis, which will be used to inform biomedical researchers on possible non-invasive strategies for mitigating the disease. PMID:27843894

  6. A mouse model to study infection against porcine circovirus type 2: viral distribution and lesions in mouse

    PubMed Central

    2010-01-01

    Background Little information is known about viral distribution and transmission of porcine circovirus type 2 (PCV2) in species other than swine. It is still a debated topic whether the PCV2 could be infected and caused clinical lesions. Our study is aimed to estimate the susceptibility of Kunming mouse to PCV2. Forty-eight, 6-week-old Kunming mice were randomly divided into four groups. Group A (C1-C12) was inoculated with PK-15 cell culture as a control group. Group B (sPCV1-12) was inoculated orally and intramuscularly with PCV2 (106.2TCID50/ml). Group C (mPCV1-12) was inoculated orally and intramuscularly with PCV2 (106.2TCID50/ml) and a booster inoculation at days 14 and 28 after the first inoculation. Group D (MixPCV1-12) was unvaccinated but released into Group C. Each group was sacrificed at 7, 14, 28, and 42 days post-inoculation, respectively. Necropsy was checked on every mouse. Sera samples were collected for the test of PCV2 specific antibody. Tissues were collected for histopathology study and polymerase chain reaction (PCR). Results The results showed that viral replication, seroconversion, and microscopic lesions were found in inoculated mice. Continuous existence of PCV2 viruses in lymph nodes have been confirmed by PCR, which took at least seven days for the virus to be transferred into other organs from the primary interface, and the diffusion to thymus had been retarded for seven days. Special PCV2 antibody could be found in PCV2 inoculation mice and was significantly higher than that in the control. Further more, microscopic lesions and the main target of PCV2 focused in the lymph nodes with a characteristic depletion and occasional necrosis of lymphocytes in the cortex and paracortex were found in inoculated mice. Conclusions The Kunming mouse could be infected by PCV2 virus and used as a PCV2 infected experimental model. PMID:20630105

  7. A Uniform Approach to Modeling Risk Factor Relationships for Ischemic Lesion Prevalence and Extent: The Women's Health Initiative Magnetic Resonance Imaging Study

    PubMed Central

    Tooze, Janet A.; Gaussoin, Sarah A.; Resnick, Susan M.; Fischbein, Nancy J.; Robinson, Jennifer G.; Bryan, R. Nick; An, Yang; Espeland, Mark A.

    2010-01-01

    Background Both the prevalence and extent of brain magnetic resonance imaging (MRI) abnormalities are related to risk factors for dementia. Typically these associations have been explored separately, but an integrated modeling approach would allow the separate relationships to be consistently described and contrasted. Methods Region-specific measures of ischemic lesion volumes were obtained from standardized brain MRI from 1,403 women enrolled in the Women's Health Initiative hormone therapy trials. Mixed-effects mixed-distribution models were fitted to explore jointly the relationships that the region-specific prevalence of ischemic lesions and region-specific ischemic lesion volumes had with risk factors and scores from tests of cognitive function. Results Women with greater probabilities (prevalence) of having ischemic lesions in brain regions also tended to have larger volumes (extent) of ischemic lesions within the affected regions (p < 0.001). Across the 5 regions included in analyses (frontal, limbic, occipital, parietal and temporal), prevalence and extent varied (p < 0.001). Each was increased among women who were older, had hypertension or who had previously been classified as cognitively impaired (p < 0.01). Additionally, extent was significantly increased among women with a history of smoking (p = 0.02). Cognitive function tests were more strongly related to the extent than prevalence of ischemic lesions and relationships varied among cognitive domains (p < 0.001). Conclusions Mixed-effects mixed-distribution models provide a coherent basis for examining relationships involving the prevalence and extent of ischemic brain lesions. Across the cohort and regions we examined, relationships with risk factors and cognitive function appeared to be stronger for extent than for prevalence. PMID:19940514

  8. Modulation of Corpus Striatal Neurochemistry by Astrocytes and Vasoactive Intestinal Peptide (VIP) in Parkinsonian Rats.

    PubMed

    Yelkenli, İbrahim Halil; Ulupinar, Emel; Korkmaz, Orhan Tansel; Şener, Erol; Kuş, Gökhan; Filiz, Zeynep; Tunçel, Neşe

    2016-06-01

    The neurotoxin 6-hydroxydopamine (6-OHDA) is widely used in animal models of Parkinson's disease. In various neurodegenerative diseases, astrocytes play direct, active, and critical roles in mediating neuronal survival and functions. Vasoactive intestinal peptide (VIP) has neurotrophic actions and modulates a number of astrocytic activities. In this study, the effects of VIP on the striatal neurochemistry were investigated in parkinsonian rats. Adult Sprague-Dawley rats were divided into sham-operated, unilaterally 6-OHDA-lesioned, and lesioned + VIP-administered (25 ng/kg i.p.) groups. VIP was first injected 1 h after the intrastriatal 6-OHDA microinjection and then every 2 days throughout 15 days. Extracellular striatal concentration of glutathione (GSH), gamma-aminobutyric acid (GABA), glutamate (GLU), and lactate were measured in microdialysates by high-performance liquid chromatography (HPLC). Quantification of GABA and activity dependent neuroprotective protein (ADNP)-expressing cells were determined by glutamic acid decarboxylase (GAD)/ADNP + glial fibrillary acidic protein (GFAP) double immunohistochemistry. Our results demonstrated that a 6-OHDA lesion significantly increased the density of astrocytes in the striatum and VIP treatment slightly reduced the gliosis. Extracellular concentration of GABA, GLU, and lactate levels did not change, but GSH level significantly increased in the striatum of parkinsonian rats. VIP treatment reduced GSH level comparable to sham-operated groups, but enhanced GABA and GLU levels. Our double labeling results showed that VIP primarily acts on neurons to increase ADNP and GAD expression for protection. These results suggest that, in the 6-OHDA-induced neurodegeneration model, astrocytes were possibly activated for forefront defensiveness by modulating striatal neurochemistry.

  9. Neurotoxic lesions at the ventral mesopontine junction change sleep time and muscle activity during sleep: an animal model of motor disorders in sleep.

    PubMed

    Lai, Y-Y; Hsieh, K-C; Nguyen, D; Peever, J; Siegel, J M

    2008-06-23

    There is no adequate animal model of restless legs syndrome (RLS) and periodic leg movements disorder (PLMD), disorders affecting 10% of the population. Similarly, there is no model of rapid eye movement (REM) sleep behavior disorder (RBD) that explains its symptoms and its link to Parkinsonism. We previously reported that the motor inhibitory system in the brainstem extends from the medulla to the ventral mesopontine junction (VMPJ). We now examine the effects of damage to the VMPJ in the cat. Based on the lesion sites and the changes in sleep pattern and behavior, we saw three distinct syndromes resulting from such lesions; the rostrolateral, rostromedial and caudal VMPJ syndromes. The change in sleep pattern was dependent on the lesion site, but was not significantly correlated with the number of dopaminergic neurons lost. An increase in wakefulness and a decrease in slow wave sleep (SWS) and REM sleep were seen in the rostrolateral VMPJ-lesioned animals. In contrast, the sleep pattern was not significantly changed in the rostromedial and caudal VMPJ-lesioned animals. All three groups of animals showed a significant increase in periodic and isolated leg movements in SWS and increased tonic muscle activity in REM sleep. Beyond these common symptoms, an increase in phasic motor activity in REM sleep, resembling that seen in human RBD, was found in the caudal VMPJ-lesioned animals. In contrast, the increase in motor activity in SWS in rostral VMPJ-lesioned animals is similar to that seen in human RLS/PLMD patients. The proximity of the VMPJ region to the substantia nigra suggests that the link between RLS/PLMD and Parkinsonism, as well as the progression from RBD to Parkinsonism may be mediated by the spread of damage from the regions identified here into the substantia nigra.

  10. Predictive modeling of human perception subjectivity: feasibility study of mammographic lesion similarity

    NASA Astrophysics Data System (ADS)

    Xu, Songhua; Hudson, Kathleen; Bradley, Yong; Daley, Brian J.; Frederick-Dyer, Katherine; Tourassi, Georgia

    2012-02-01

    The majority of clinical content-based image retrieval (CBIR) studies disregard human perception subjectivity, aiming to duplicate the consensus expert assessment of the visual similarity on example cases. The purpose of our study is twofold: i) discern better the extent of human perception subjectivity when assessing the visual similarity of two images with similar semantic content, and (ii) explore the feasibility of personalized predictive modeling of visual similarity. We conducted a human observer study in which five observers of various expertise were shown ninety-nine triplets of mammographic masses with similar BI-RADS descriptors and were asked to select the two masses with the highest visual relevance. Pairwise agreement ranged between poor and fair among the five observers, as assessed by the kappa statistic. The observers' self-consistency rate was remarkably low, based on repeated questions where either the orientation or the presentation order of a mass was changed. Various machine learning algorithms were explored to determine whether they can predict each observer's personalized selection using textural features. Many algorithms performed with accuracy that exceeded each observer's self-consistency rate, as determined using a cross-validation scheme. This accuracy was statistically significantly higher than would be expected by chance alone (two-tailed p-value ranged between 0.001 and 0.01 for all five personalized models). The study confirmed that human perception subjectivity should be taken into account when developing CBIR-based medical applications.

  11. Predictive Modeling of Human Perception Subjectivity: Feasibility Study of Mammographic Lesion Similarity

    SciTech Connect

    Xu, Songhua; Tourassi, Georgia

    2012-01-01

    The majority of clinical content-based image retrieval (CBIR) studies disregard human perception subjectivity, aiming to duplicate the consensus expert assessment of the visual similarity on example cases. The purpose of our study is twofold: (i) discern better the extent of human perception subjectivity when assessing the visual similarity of two images with similar semantic content, and (ii) explore the feasibility of personalized predictive modeling of visual similarity. We conducted a human observer study in which five observers of various expertise were shown ninety-nine triplets of mammographic masses with similar BI-RADS descriptors and were asked to select the two masses with the highest visual relevance. Pairwise agreement ranged between poor and fair among the five observers, as assessed by the kappa statistic. The observers' self-consistency rate was remarkably low, based on repeated questions where either the orientation or the presentation order of a mass was changed. Various machine learning algorithms were explored to determine whether they can predict each observer's personalized selection using textural features. Many algorithms performed with accuracy that exceeded each observer's self-consistency rate, as determined using a cross-validation scheme. This accuracy was statistically significantly higher than would be expected by chance alone (two-tailed p-value ranged between 0.001 and 0.01 for all five personalized models). The study confirmed that human perception subjectivity should be taken into account when developing CBIR-based medical applications.

  12. Midbrain dopaminergic neurogenesis and behavioural recovery in a salamander lesion-induced regeneration model.

    PubMed

    Parish, Clare L; Beljajeva, Anna; Arenas, Ernest; Simon, András

    2007-08-01

    Death and lack of functional regeneration of midbrain dopaminergic (DA) neurons, decreased DA input in the target striatum and movement anomalies characterise Parkinson's disease (PD). There is currently no cure for PD. One way to promote recovery would be to induce or enhance DA neurogenesis. Whether DA neurogenesis occurs in the adult midbrain is a matter of debate. Here, we describe the creation of a salamander 6-hydroxydopamine model of PD to examine midbrain DA regeneration. We demonstrate a robust and complete regeneration of the mesencephalic and diencephalic DA system after elimination of DA neurons. Regeneration is contributed by DA neurogenesis, leads to histological restoration, and to full recovery of motor behaviour. Molecular analyses of the temporal expression pattern of DA determinants indicate that the regenerating DA neurons mature along a similar developmental program as their mammalian counterparts during embryogenesis. We also find that the adult salamander midbrain can reactivate radial glia-like ependymoglia cells that proliferate. The salamander model provides insights into the mechanisms of DA regeneration/neurogenesis and may contribute to the development of novel regenerative strategies for the mammalian brain.

  13. Photoacoustic imaging of an inflammatory lesion model in the neonatal rat brain

    NASA Astrophysics Data System (ADS)

    Guevara, Edgar; Berti, Romain; Londono, Irène; Xie, Ningshi; Bellec, Pierre; Lesage, Frédéric; Lodygensky, G. A.

    2014-09-01

    Periventricular leukomalacia (PVL) is a condition that may cause significant neurodevelopmental handicap in premature newborns. It is characterized by white matter injury, associated with inflammation. This work aimed to assess the impact of inflammation on cerebral oxygen saturation (sO2) using depth-sensitive photoacoustic tomography (PAT). The aspects of PVL were reproduced in a rodent model by injection of lipopolysaccharide (LPS) into the corpus callosum. The results of this exploratory work reveal lower sO2 values in LPS group, as compared to sham controls; showing decreased values in the corpus callosum and in the left cortex, ipsilateral to the injection site. Interhemispherical connectivity was not affected by LPS injection, as shown by functional connectivity analysis. This study supports the use of PAT as a non-invasive tool to assess oxygenation values in vivo in the newborn brain.

  14. A Noradrenergic Lesion Exacerbates Neurodegeneration in a Down Syndrome Mouse Model

    PubMed Central

    Lockrow, Jason; Boger, Heather; Gerhardt, Greg; Aston-Jones, Gary; Bachman, David; Granholm, Ann-Charlotte

    2012-01-01

    Individuals with Down syndrome (DS) acquire Alzheimer’s-like dementia (AD) and associated neuropathology earlier and at significantly greater rates than age-matched normosomic individuals. However, biological mechanisms have not been discovered and there is currently limited therapy for either DS- or AD-related dementia. Segmental trisomy 16 (Ts65Dn) mice provide a useful model for many of the degenerative changes which occur with age in DS including cognitive deficits, neuroinflammation, and degeneration of basal forebrain cholinergic neurons. Loss of noradrenergic locus coeruleus (LC) neurons is an early event in AD and in DS, and may contribute to the neuropathology. We report that Ts65Dn mice exhibit progressive loss of norepinephrine (NE) phenotype in LC neurons. In order to determine whether LC degeneration contributes to memory loss and neurodegeneration in Ts65Dn mice, we administered the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 2 doses of 50 mg/kg, i.p.) to Ts65Dn mice at four months of age, prior to working memory loss. At eight months of age, Ts65Dn mice treated with DSP-4 exhibited an 80% reduction in hippocampal NE, coupled with a marked increase in hippocampal neuroinflammation. Noradrenergic depletion also resulted in accelerated cholinergic neuron degeneration and a further impairment of memory function in Ts65Dn mice. In contrast, DSP-4 had minimal effects on normosomic littermates, suggesting a disease-modulated vulnerability to NE loss in the DS mouse model. These data suggest that noradrenergic degeneration may play a role in the progressive memory loss, neuroinflammation, and cholinergic loss occurring in DS individuals, providing a possible therapeutic avenue for future clinical studies. PMID:21098982

  15. Plastic changes at corticostriatal synapses predict improved motor function in a partial lesion model of Parkinson's disease.

    PubMed

    Bentea, Eduard; Moore, Cynthia; Deneyer, Lauren; Verbruggen, Lise; Churchill, Madeline J; Hood, Rebecca L; Meshul, Charles K; Massie, Ann

    2017-02-19

    In Parkinson's disease, striatal dopamine depletion leads to plastic changes at excitatory corticostriatal and thalamostriatal synapses. The functional consequences of these responses on the expression of behavioral deficits are incompletely understood. In addition, most of the information on striatal synaptic plasticity has been obtained in models with severe striatal dopamine depletion, and less is known regarding changes during early stages of striatal denervation. Using a partial model of nigral cell loss based on intranigral injection of the proteasome inhibitor lactacystin, we demonstrate ultrastructural changes at corticostriatal synapses with a 15% increase in the length and 30% increase in the area of the postsynaptic densities at corticostriatal synapses 1 week following toxin administration. This increase was positively correlated with the performance of lactacystin-lesioned mice on the rotarod task, such that mice with a greater increase in the size of the postsynaptic density performed better on the rotarod task. We therefore propose that lengthening of the postsynaptic density at corticostriatal synapses acts as a compensatory mechanism to maintain motor function under conditions of partial dopamine depletion. The ultrastructure of thalamostriatal synapses remained unchanged following lactacystin administration. Our findings provide novel insights into the mechanisms of synaptic plasticity and behavioral compensation following partial loss of substantia nigra pars compacta neurons, such as those occurring during the early stages of Parkinson's disease.

  16. Imperfect DNA lesion repair in the semiconservative quasispecies model: Derivation of the Hamming class equations and solution of the single-fitness peak landscape

    NASA Astrophysics Data System (ADS)

    Tannenbaum, Emmanuel; Sherley, James L.; Shakhnovich, Eugene I.

    2004-12-01

    This paper develops a Hamming class formalism for the semiconservative quasispecies equations with imperfect lesion repair, first presented and analytically solved in Y. Brumer and E.I. Shakhnovich (q-bio.GN/0403018, 2004). Starting from the quasispecies dynamics over the space of genomes, we derive an equivalent dynamics over the space of ordered sequence pairs. From this set of equations, we are able to derive the infinite sequence length form of the dynamics for a class of fitness landscapes defined by a master genome. We use these equations to solve for a generalized single-fitness-peak landscape, where the master genome can sustain a maximum number of lesions and remain viable. We determine the mean equilibrium fitness and error threshold for this class of landscapes, and show that when lesion repair is imperfect, semiconservative replication displays characteristics from both conservative replication and semiconservative replication with perfect lesion repair. The work presented here provides a formulation of the model which greatly facilitates the analysis of a relatively broad class of fitness landscapes, and thus serves as a convenient springboard into biological applications of imperfect lesion repair.

  17. Co-micronized Palmitoylethanolamide/Polydatin Treatment Causes Endometriotic Lesion Regression in a Rodent Model of Surgically Induced Endometriosis

    PubMed Central

    Di Paola, Rosanna; Fusco, Roberta; Gugliandolo, Enrico; Crupi, Rosalia; Evangelista, Maurizio; Granese, Roberta; Cuzzocrea, Salvatore

    2016-01-01

    Endometriosis is a chronic, painful disease characterized by the presence of endometrial glands and stroma outside the uterine cavity. Palmitoylethanolamide (PEA), an endogenous fatty acid amide, has anti-inflammatory and neuroprotective effects. PEA lacks free radical scavenging activity, unlike polydatin (PLD), a natural precursor of resveratrol. The aim of this study was to investigate the effect of orally administered co-micronized PEA/polydatin [m(PEA/PLD)] in an autologous rat model of surgically induced endometriosis. Endometriosis was induced in female Wistar albino rats by auto-transplantation of uterine squares (implants) into the intestinal mesentery and peritoneal cavity. Rats were distributed into one control group and one treatment group (10 animals each): m(PEA/PLD) 10 mg/kg/day. At 28 days after surgery the relative volume of the endometrioma was determined. Endometrial-like tissue was confirmed by histology: Masson trichrome and toluidine blue were used to detect fibrosis and mast cells, respectively. The treated group displayed a smaller cyst diameter, with improved fibrosis score and mast cell number decrease. m(PEA/PLD) administration decreased angiogenesis (vascular endothelial growth factor), nerve growth factor, intercellular adhesion molecule, matrix metalloproteinase 9 expression, and lymphocyte accumulation. m(PEA/PLD) treatment also reduced peroxynitrite formation, (poly-ADP)ribose polymerase activation, IkBα phosphorylation and nuclear facor-kB traslocation in the nucleus. Our results suggested that m(PEA/PLD) may be of use to inhibit development of endometriotic lesions in rats. PMID:27790149

  18. Co-micronized Palmitoylethanolamide/Polydatin Treatment Causes Endometriotic Lesion Regression in a Rodent Model of Surgically Induced Endometriosis.

    PubMed

    Di Paola, Rosanna; Fusco, Roberta; Gugliandolo, Enrico; Crupi, Rosalia; Evangelista, Maurizio; Granese, Roberta; Cuzzocrea, Salvatore

    2016-01-01

    Endometriosis is a chronic, painful disease characterized by the presence of endometrial glands and stroma outside the uterine cavity. Palmitoylethanolamide (PEA), an endogenous fatty acid amide, has anti-inflammatory and neuroprotective effects. PEA lacks free radical scavenging activity, unlike polydatin (PLD), a natural precursor of resveratrol. The aim of this study was to investigate the effect of orally administered co-micronized PEA/polydatin [m(PEA/PLD)] in an autologous rat model of surgically induced endometriosis. Endometriosis was induced in female Wistar albino rats by auto-transplantation of uterine squares (implants) into the intestinal mesentery and peritoneal cavity. Rats were distributed into one control group and one treatment group (10 animals each): m(PEA/PLD) 10 mg/kg/day. At 28 days after surgery the relative volume of the endometrioma was determined. Endometrial-like tissue was confirmed by histology: Masson trichrome and toluidine blue were used to detect fibrosis and mast cells, respectively. The treated group displayed a smaller cyst diameter, with improved fibrosis score and mast cell number decrease. m(PEA/PLD) administration decreased angiogenesis (vascular endothelial growth factor), nerve growth factor, intercellular adhesion molecule, matrix metalloproteinase 9 expression, and lymphocyte accumulation. m(PEA/PLD) treatment also reduced peroxynitrite formation, (poly-ADP)ribose polymerase activation, IkBα phosphorylation and nuclear facor-kB traslocation in the nucleus. Our results suggested that m(PEA/PLD) may be of use to inhibit development of endometriotic lesions in rats.

  19. Histological correlates of N40 auditory evoked potentials in adult rats after neonatal ventral hippocampal lesion: animal model of schizophrenia.

    PubMed

    Romero-Pimentel, A L; Vázquez-Roque, R A; Camacho-Abrego, I; Hoffman, K L; Linares, P; Flores, G; Manjarrez, E

    2014-11-01

    The neonatal ventral hippocampal lesion (NVHL) is an established neurodevelopmental rat model of schizophrenia. Rats with NVHL exhibit several behavioral, molecular and physiological abnormalities that are similar to those found in schizophrenics. Schizophrenia is a severe psychiatric illness characterized by profound disturbances of mental functions including neurophysiological deficits in brain information processing. These deficits can be assessed by auditory evoked potentials (AEPs), where schizophrenics exhibit abnormalities in amplitude, duration and latency of such AEPs. The aim of the present study was to compare the density of cells in the temporal cerebral cortex and the N40-AEP of adult NVHL rats versus adult sham rats. We found that rats with NVHL exhibit significant lower amplitude of the N40-AEP and a significant lower number of cells in bilateral regions of the temporal cerebral cortex compared to sham rats. Because the AEP recordings were obtained from anesthetized rats, we suggest that NVHL leads to inappropriate innervation in thalamic-cortical pathways in the adult rat, leading to altered function of cortical networks involved in processing of primary auditory information.

  20. Finite Element Modelling of the Femur Bone of a Subject Suffering from Motor Neuron Lesion Subjected to Electrical Stimulation.

    PubMed

    Gislason, Magnus K; Ingvarsson, Páll; Gargiulo, Paolo; Yngvason, Stefán; Guðmundsdóttir, Vilborg; Knútsdóttir, Sigrún; Helgason, Þórður

    2014-09-23

    Bone loss and a decrease in bone mineral density is frequently seen in patients with motor neuron lesion due to lack of mechanical stimulation. This causes weakening of the bones and a greater risk of fracture. By using functional electrical stimulation it is possible to activate muscles in the body to produce the necessary muscle force to stimulate muscle growth and potentially decrease the rate of bone loss. A longitudinal study was carried out on a single patient undergoing electrical stimulation over a 6 year period. The patient underwent a CT scan each year and a full three dimensional finite element model for each year was created using Mimics (Materialise) and Abaqus (Simulia) to calculate the risk of fracture under physiologically relevant loading conditions. Using empirical formulas connecting the bone mineral density to the stiffness and ultimate tensile stress of the bone, each element was assigned a unique material property, based on its density. The risk of fracture was estimated by calculating the ratio between the predicted stress and the ultimate tensile stress, should it exceed unity, failure was assumed. The results showed that the number of elements that were predicted to be at risk of failure varied between years.

  1. Induction of fatty streak-like lesions in vitro using a culture model system simulating arterial intima.

    PubMed Central

    Yamada, T.; Fan, J.; Shimokama, T.; Tokunaga, O.; Watanabe, T.

    1992-01-01

    In this study a two-compartment culture model of arterial intima was used for the in vitro induction of fatty streaklike lesions. The apparatus consisted of upper and lower compartments separated by a human amnion membrane stretched between them. Human umbilical vein endothelial cells (HUVECs) were cultured to confluence on the stromal surface of the amnion membrane. Maximal migration of blood mononuclear cells (MCs) through the HUVEC monolayer in response to a f-Met-Leu-Phe gradient was observed at 10(-8) mol/l; the migration was 3.29 times greater than that observed under the condition of random migration (control). In the study of MC transformation into lipid-laden cells in the amnion membrane (foam cell formation in 'arterial intima'), 10(6) MCs were incubated, in the presence of freshly prepared low-density lipoprotein (LDL; 100 microgram/ml). The lipid loading of MCs was time dependent. After 12 hours' incubation, 39% of the MCs that migrated into the amnion membrane contained a small number of lipid droplets, whereas the remaining 61% showed no lipid droplets. Only 1.7% of the cells contained a high number of lipid droplets in the cytoplasm and took on the appearance of foam cells. With time, the number of lipid-laden cells and the amounts of intracytoplasmic lipid droplets gradually increased. At 72 hours after incubation, 65.4% of the MCs were loaded with lipid droplets, and 20.9% of them, an eightfold increase over 12 hours of incubation, showed a foamy cell appearance. Because MCs consist of 70% monocytes and 30% lymphocytes, about 93% of the monocytes were filled with lipid after a 72-hour incubation. Ultrastructural examination showed that lipid-laden cells took on macrophage characteristics, such as wide and heterogeneous cytoplasm, indented nuclei, and abundant lysosomes. A minority of the MCs in the amnion were considered lymphocytes; they had scanty cytoplasm, round nuclei with abundant heterochromatin, no lysosomes, and no lipid vacuoles. In

  2. Restoring Spinal Noradrenergic Inhibitory Tone Attenuates Pain Hypersensitivity in a Rat Model of Parkinson's Disease

    PubMed Central

    Wang, Bing; Chen, Li-Hua

    2016-01-01

    In the present study, we investigated whether restoring descending noradrenergic inhibitory tone can attenuate pain in a PD rat model, which was established by stereotaxic infusion of 6-hydroxydopamine (6-OHDA) into the bilateral striatum (CPu). PD rats developed thermal and mechanical hypersensitivity at the 4th week after surgery. HPLC analysis showed that NE content, but not dopamine or 5-HT, significantly decreased in lumbar spinal cord in PD rats. Additional noradrenergic depletion by injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) aggravated pain hypersensitivity in PD rats. At the 5th week after injection of 6-OHDA, systemic treatment with pharmacological norepinephrine (NE) precursor droxidopa (L-DOPS) or α2 adrenoceptor agonist clonidine significantly attenuated thermal and mechanical pain hypersensitivity in PD rats. Furthermore, application of norepinephrine (NE) and 5-hydroxytryptamine (5-HT) reuptake inhibitors duloxetine, but not 5-HT selective reuptake inhibitors sertraline, significantly inhibited thermal and mechanical pain hypersensitivity in PD rats. Systemic administration of Madopar (L-DOPA) or the D2/D3 agonist pramipexole slightly inhibited the thermal, but not mechanical, hypersensitivity in PD rats. Thus, our study revealed that impairment of descending noradrenergic system may play a key role in PD-associated pain and restoring spinal noradrenergic inhibitory tone may serve as a novel strategy to manage PD-associated pain. PMID:27747105

  3. Fuzzy description of skin lesions

    NASA Astrophysics Data System (ADS)

    Laskaris, Nikolaos; Ballerini, Lucia; Fisher, Robert B.; Aldridge, Ben; Rees, Jonathan

    2010-02-01

    We propose a system for describing skin lesions images based on a human perception model. Pigmented skin lesions including melanoma and other types of skin cancer as well as non-malignant lesions are used. Works on classification of skin lesions already exist but they mainly concentrate on melanoma. The novelty of our work is that our system gives to skin lesion images a semantic label in a manner similar to humans. This work consists of two parts: first we capture they way users perceive each lesion, second we train a machine learning system that simulates how people describe images. For the first part, we choose 5 attributes: colour (light to dark), colour uniformity (uniform to non-uniform), symmetry (symmetric to non-symmetric), border (regular to irregular), texture (smooth to rough). Using a web based form we asked people to pick a value of each attribute for each lesion. In the second part, we extract 93 features from each lesions and we trained a machine learning algorithm using such features as input and the values of the human attributes as output. Results are quite promising, especially for the colour related attributes, where our system classifies over 80% of the lesions into the same semantic classes as humans.

  4. Nicotine is more addictive, not more cognitively therapeutic in a neurodevelopmental model of schizophrenia produced by neonatal ventral hippocampal lesions.

    PubMed

    Berg, Sarah A; Sentir, Alena M; Cooley, Benjamin S; Engleman, Eric A; Chambers, R Andrew

    2014-11-01

    Nicotine dependence is the leading cause of death in the United States. However, research on high rates of nicotine use in mental illness has primarily explained this co-morbidity as reflecting nicotine's therapeutic benefits, especially for cognitive symptoms, equating smoking with 'self-medication'. We used a leading neurodevelopmental model of mental illness in rats to prospectively test the alternative possibility that nicotine dependence pervades mental illness because nicotine is simply more addictive in mentally ill brains that involve developmental hippocampal dysfunction. Neonatal ventral hippocampal lesions (NVHL) have previously been demonstrated to produce post-adolescent-onset, pharmacological, neurobiological and cognitive-deficit features of schizophrenia. Here, we show that NVHLs increase adult nicotine self-administration, potentiating acquisition-intake, total nicotine consumed and drug seeking. Behavioral sensitization to nicotine in adolescence prior to self-administration is not accentuated by NVHLs in contrast to increased nicotine self-administration and behavioral sensitization documented in adult NVHL rats, suggesting periadolescent neurodevelopmental onset of nicotine addiction vulnerability in the NVHL model. Delivering a nicotine regimen approximating the exposure used in the sensitization and self-administration experiments (i.e. as a treatment) to adult rats did not specifically reverse NVHL-induced cortical-hippocampal-dependent cognitive deficits and actually worsened cognitive efficiency after nicotine treatment stopped, generating deficits that resemble those due to NVHLs. These findings represent the first prospective evidence demonstrating a causal link between disease processes in schizophrenia and nicotine addiction. Developmental cortical-temporal limbic dysfunction in mental illness may thus amplify nicotine's reinforcing effects and addiction risk and severity, even while producing cognitive deficits that are not

  5. HIV-1 promonocytic and lymphoid cell lines: an in vitro model of in vivo mitochondrial and apoptotic lesion.

    PubMed

    Morén, Constanza; González-Casacuberta, Ingrid; Álvarez-Fernández, Carmen; Bañó, Maria; Catalán-Garcia, Marc; Guitart-Mampel, Mariona; Juárez-Flores, Diana Luz; Tobías, Ester; Milisenda, José; Cardellach, Francesc; Gatell, Josep Maria; Sánchez-Palomino, Sonsoles; Garrabou, Glòria

    2017-02-01

    To characterize mitochondrial/apoptotic parameters in chronically human immunodeficiency virus (HIV-1)-infected promonocytic and lymphoid cells which could be further used as therapeutic targets to test pro-mitochondrial or anti-apoptotic strategies as in vitro cell platforms to deal with HIV-infection. Mitochondrial/apoptotic parameters of U1 promonocytic and ACH2 lymphoid cell lines were compared to those of their uninfected U937 and CEM counterparts. Mitochondrial DNA (mtDNA) was quantified by rt-PCR while mitochondrial complex IV (CIV) function was measured by spectrophotometry. Mitochondrial-nuclear encoded subunits II-IV of cytochrome-c-oxidase (COXII-COXIV), respectively, as well as mitochondrial apoptotic events [voltage-dependent-anion-channel-1(VDAC-1)-content and caspase-9 levels] were quantified by western blot, with mitochondrial mass being assessed by spectrophotometry (citrate synthase) and flow cytometry (mitotracker green assay). Mitochondrial membrane potential (JC1-assay) and advanced apoptotic/necrotic events (AnexinV/propidium iodide) were measured by flow cytometry. Significant mtDNA depletion spanning 57.67% (P < 0.01) was found in the U1 promonocytic cells further reflected by a significant 77.43% decrease of mitochondrial CIV activity (P < 0.01). These changes were not significant for the ACH2 lymphoid cell line. COXII and COXIV subunits as well as VDAC-1 and caspase-9 content were sharply decreased in both chronic HIV-1-infected promonocytic and lymphoid cell lines (<0.005 in most cases). In addition, U1 and ACH2 cells showed a trend (moderate in case of ACH2), albeit not significant, to lower levels of depolarized mitochondrial membranes. The present in vitro lymphoid and especially promonocytic HIV model show marked mitochondrial lesion but apoptotic resistance phenotype that has been only partially demonstrated in patients. This model may provide a platform for the characterization of HIV-chronicity, to test novel therapeutic options or

  6. Use of zoledronate to treat osteoblastic versus osteolytic lesions in a severe-combined-immunodeficient mouse model.

    PubMed

    Lee, Yu-Po; Schwarz, Edward M; Davies, Mark; Jo, Mark; Gates, Jeffrey; Zhang, Xuguang; Wu, Jing; Lieberman, Jay R

    2002-10-01

    Prostate adenocarcinoma is associated with the formation of osteoblastic metastases in bone. It has been hypothesized that osteoclastic bone resorption is a critical component before the development of these osteoblastic lesions in bone. This observation has led researchers to test agents that inhibit osteoclastic activity to prevent or halt the formation of metastatic prostate cancer lesions in bone. Bisphosphonates inhibit osteoclast activity, and previous studies showed that they have the ability to reduce the osteolytic bone resorption associated with multiple myeloma and breast cancer. The objective of this study was to evaluate the efficacy of zoledronate in limiting the formation and/or progression of osteoblastic lesions produced by the injection of known prostate cancer cells (LAPC-9 and PC-3 cells) into the tibia of SCID mice. The mice were treated with either 30- micro g or 150- micro g doses of zoledronate before tumor implantation (pretreatment group), or at weekly intervals after tumor implantation (weekly treatment group), or weekly starting one month after tumor implantation (delayed-treatment group). The zoledronate was very effective in limiting the formation of osteolytic lesions in PC-3 implanted tibias by inhibiting osteoclast activity. Radiographic and histological analysis at weekly intervals revealed that osteolytic lesions developed in the control tibias by 2 weeks, and there was complete destruction of the cortical bone in much of the proximal tibias by 4 weeks. In the treatment groups, there was minimal cortical destruction noted in the weekly treatment groups at both doses, whereas mild cortical erosion was evident in the pretreatment groups, with more cortical destruction noted in the 30- micro g group compared with the 150- micro g group. Tartrate-resistant acid phosphatase (TRAP) staining showed that zoledronate decreased osteoclastic numbers and that there was a dose-dependent response. In tibias implanted with the LAPC-9 cells, the

  7. Nogo-A Neutralization Improves Graft Function in a Rat Model of Parkinson’s Disease

    PubMed Central

    Seiler, Stefanie; Di Santo, Stefano; Widmer, Hans Rudolf

    2016-01-01

    Transplantation of fetal human ventral mesencephalic (VM) dopaminergic neurons into the striatum is a promising strategy to compensate for the characteristic dopamine deficit observed in Parkinson’s disease (PD). This therapeutic approach, however, is currently limited by the high number of fetuses needed for transplantation and the poor survival and functional integration of grafted dopaminergic neurons into the host brain. Accumulating evidence indicates that contrasting inhibitory signals endowed in the central nervous system (CNS) might support neuronal regeneration. Hence, in the present study we aimed at improving survival and integration of grafted cells in the host brain by neutralizing Nogo-A, one of the most potent neurite growth inhibitors in the CNS. For that purpose, VM tissue cultures were transplanted into rats with a partial 6-hydroxydopamine (6-OHDA) lesion causing a hemi-PD model and concomitantly treated for 2 weeks with intra-ventricular infusion of neutralizing anti-Nogo-A antibodies. Motor behavior using the cylinder test was assessed prior to and after transplantation as functional outcome. At the end of the experimental period the number of dopaminergic fibers growing into the host brain, the number of surviving dopaminergic neurons in the grafts as well as graft size was examined. We found that anti-Nogo-A antibody infusion significantly improved the asymmetrical forelimb use observed after lesions as compared to controls. Importantly, a significantly three-fold higher dopaminergic fiber outgrowth from the transplants was detected in the Nogo-A antibody treated group as compared to controls. Furthermore, Nogo-A neutralization showed a tendency for increased survival of dopaminergic neurons (by two-fold) in the grafts. No significant differences were observed for graft volume and the number of dopaminergic neurons co-expressing G-protein-coupled inward rectifier potassium channel subunit two between groups. In sum, our findings support the

  8. Predictive model for contrast-enhanced ultrasound of the breast: Is it feasible in malignant risk assessment of breast imaging reporting and data system 4 lesions?

    PubMed Central

    Luo, Jun; Chen, Ji-Dong; Chen, Qing; Yue, Lin-Xian; Zhou, Guo; Lan, Cheng; Li, Yi; Wu, Chi-Hua; Lu, Jing-Qiao

    2016-01-01

    AIM: To build and evaluate predictive models for contrast-enhanced ultrasound (CEUS) of the breast to distinguish between benign and malignant lesions. METHODS: A total of 235 breast imaging reporting and data system (BI-RADS) 4 solid breast lesions were imaged via CEUS before core needle biopsy or surgical resection. CEUS results were analyzed on 10 enhancing patterns to evaluate diagnostic performance of three benign and three malignant CEUS models, with pathological results used as the gold standard. A logistic regression model was developed basing on the CEUS results, and then evaluated with receiver operating curve (ROC). RESULTS: Except in cases of enhanced homogeneity, the rest of the 9 enhancement appearances were statistically significant (P < 0.05). These 9 enhancement patterns were selected in the final step of the logistic regression analysis, with diagnostic sensitivity and specificity of 84.4% and 82.7%, respectively, and the area under the ROC curve of 0.911. Diagnostic sensitivity, specificity, and accuracy of the malignant vs benign CEUS models were 84.38%, 87.77%, 86.38% and 86.46%, 81.29% and 83.40%, respectively. CONCLUSION: The breast CEUS models can predict risk of malignant breast lesions more accurately, decrease false-positive biopsy, and provide accurate BI-RADS classification. PMID:27358688

  9. Unilateral lesion of the nigrostriatal pathway decreases the response of fast-spiking interneurons in the medial prefrontal cortex to 5-HT1A receptor agonist and expression of the receptor in parvalbumin-positive neurons in the rat.

    PubMed

    Gui, Z H; Zhang, Q J; Liu, J; Zhang, L; Ali, U; Hou, C; Fan, L L; Sun, Y N; Wu, Z H; Hui, Y P

    2011-10-01

    5-Hydroxytryptamine(1A) (5-HT(1A)) receptors are expressed in the prefrontal cortical interneurons. Among these interneurons, calcium-binding protein parvalbumin (PV)-positive fast spiking (FS) interneurons play an important role in regulatory function of the prefrontal cortex. In the present study, the response of medial prefrontal cortex (mPFC) FS interneurons to the selective 5-HT(1A) receptor agonist 8-OH-DPAT and change in expression of 5-HT(1A) receptor on PV-positive neurons were examined in rats with 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) by using extracellular recording and double-labeling immunofluorescence histochemistry. Systemic administration of 8-OH-DPAT (1-243 μg/kg, i.v.) dose-dependently inhibited the mean firing rate of the FS interneurons in sham-operated and the lesioned rats, respectively. The cumulative doses producing inhibition in the lesioned rats (243 μg/kg) was significantly higher than that of sham-operated rats (27 μg/kg). Furthermore, the local application of 8-OH-DPAT (0.01 μg) in the mPFC inhibited the FS interneurons in sham-operated rats, while having no effect on firing rate of the FS interneurons in the lesioned rats. In contrast to sham-operated rats, the lesion of the SNc in rats did not cause the change of PV-positive neurons in the prelimbic prefrontal cortex, a subregion of the mPFC, whereas the lesion of the SNc markedly reduced in percentage of PV-positive neurons expressing 5-HT(1A) receptors. Our results indicate that degeneration of the nigrostriatal pathway results in the decreased response of FS interneurons in the mPFC to 5-HT(1A) receptor stimulation, which attributes to down-regulation of 5-HT(1A) receptor expression in these interneurons.

  10. Conjunctival instillation of plasminogen eliminates ocular lesion in B6.129P2-Plg(tm1Jld) transgenic mice, a model of ligneous conjunctivitis.

    PubMed

    Pignataro, G; Vinciguerra, A; Cuomo, O; Sirabella, R; Di Renzo, G F; Scorziello, A

    2013-08-01

    Ligneous conjunctivitis is a severe and rare chronic "idiopathic membraneous" conjunctivitis, characterized by the formation of pseudomembranes mostly on the palpebral surfaces that progressively replace the normal mucosa. Evidence has been provided that ligneous conjunctivitis is caused by a severe systemic plasminogen deficiency with decreased plasminogen antigen and decreased plasminogen functional activities. Objective of the present study is to verify the hypothesis that a topical eye application of plasminogen is able to ameliorate the consequences of this disease. Here we report the results of pre-clinical studies performed to investigate the therapeutic effectiveness of an eye-drop plasminogen preparation in B6.129P2-Plg(tm1Jld) transgenic mice, a model of ligneous conjunctivitis. The entity of protection mediated by plasminogen was evaluated by measuring the extent of the eye lesion by means of a computerized system and dedicated software. The results of the present study clearly showed that the administration for six times a day of plasminogen eye-drop solution in the lesioned eye of animals knock-out for plasminogen gene and developing ligneous conjunctivitis caused a dose and time related reduction of the extent of the ocular lesion. These findings may pave the road for the pharmacological treatment of the ocular lesion associated to the ligneous conjunctivitis that at the present is surgically treated by removing the pseudomembranes generated on the eye.

  11. Targeting Experimental Autoimmune Encephalomyelitis Lesions to a Predetermined Axonal Tract System Allows for Refined Behavioral Testing in an Animal Model of Multiple Sclerosis

    PubMed Central

    Kerschensteiner, Martin; Stadelmann, Christine; Buddeberg, Bigna S.; Merkler, Doron; Bareyre, Florence M.; Anthony, Daniel C.; Linington, Christopher; Brück, Wolfgang; Schwab, Martin E.

    2004-01-01

    In multiple sclerosis (MS) the structural damage to axons determines the persistent clinical deficit patients acquire during the course of the disease. It is therefore important to test therapeutic strategies that can prevent or reverse this structural damage. The conventional animal model of MS, experimental autoimmune encephalomyelitis (EAE), typically shows disseminated inflammation in the central nervous system, which leads to a clinical deficit that cannot be directly attributed to a defined tract system. For this reason we have developed a localized EAE model, in which large inflammatory lesions are targeted to the dorsal columns of the spinal cord, an area including the corticospinal tract. These lesions show the pathological hallmarks of MS plaques and lead to reproducible and pronounced deficits in hindlimb locomotion. Because of the anatomical specificity of this technique we can now use highly sensitive behavioral tests that assess the functional integrity of specific axonal tracts. We show that these tests are predictive of the site and extent of a given lesion and are more sensitive for assessing the clinical course than the scales commonly used for disseminated EAE models. We believe that this targeted EAE model will become a helpful new tool for the evaluation of therapeutic approaches for MS that attempt to protect axons or support their repair. PMID:15039233

  12. The efficacy of hydro alcoholic extract of Seidlitzia rosmarinus on experimental zoonotic cutaneous leishmaniasis lesions in murine model

    PubMed Central

    Ahmadi, Maryam; Fata, Abdolmajid; Khamesipour, Ali; Rakhshandeh, Hasan; Miramin Mohammadi, Akram; Salehi, Ghodratollah; Monavari, Hadi

    2014-01-01

    Objective: Leishmaniasis is one of the most important parasitic infectious diseases in the world. Since last century, many efforts have been made to control and treat the disease, but appropriate vaccines, pesticides and medicines are not available or even eligible. The purpose of this study was to evaluate the effect of hydro-alcoholic extract of Seidlitzia rosmarinus on the lesions of experimental Cutaneous Leishmaniasis (CL) in Balb/c mice. Materials and Methods: The population study was 60 Ballb/c mice which divided to 6 groups, all infected with Leishmania major [MRHO/75/IR]. Soon after the ulcer started to appear in the early stage, a dose of provided herbal extract with 5, 10 and 15% concentration applied on each lesion. The surface area of the lesions measured during an interval of 10 days. Direct Giemsa stained smears prepared two and four weeks after treatment. Results: Increasing the mean size of the lesions was statistically significant compared to those in control group (p>0.001). Visceral Leishmaniasis (VL) developed in all of the mice including the control group that received Eucerine alone. Survival rate in group receiving 15% S. rosmarinus extracts showed significantly higher compared to mice in control group (p<0.001). Conclusion: Hydro-alcoholic extracts of S.rosmarinus with concentrations below15% did not show a therapeutic effect on experimental CL ulcers of Balb/c mice. Further studies with higher concentrations or nano particles are recommended. PMID:25386402

  13. Simulation study of the effect of golden-angle KWIC with generalized kinetic model analysis on diagnostic accuracy for lesion discrimination

    PubMed Central

    Freed, Melanie; Kim, Sungheon G.

    2014-01-01

    Purpose To quantitatively evaluate temporal blurring of dynamic contrast-enhanced MRI data generated using a k-space weighted image contrast (KWIC) image reconstruction technique with golden-angle view-ordering. Methods K-space data were simulated using golden-angle view-ordering and reconstructed using a KWIC algorithm with a Fibonacci number of views enforced for each annulus in k-space. Temporal blurring was evaluated by comparing pharmacokinetic model parameters estimated from the simulated data with the true values. Diagnostic accuracy was quantified using receiver operator characteristic curves (ROC) and the area under the ROC curves (AUC). Results Estimation errors of pharmacokinetic model parameters were dependent on the true curve type and the lesion size. For 10 mm benign and malignant lesions, estimated AUC values using the true and estimate AIFs were consistent with the true AUC value. For 5 mm benign and 20 mm malignant lesions, estimated AUC values using the true and estimated AIFs were 0.906±0.020 and 0.905±0.021, respectively, as compared with the true AUC value of 0.896. Conclusions Although the investigated reconstruction algorithm does impose errors in pharmacokinetic model parameter estimation, they are not expected to significantly impact clinical studies of diagnostic accuracy. PMID:25267703

  14. The potential cost-effectiveness of the Diamondback 360® Coronary Orbital Atherectomy System for treating de novo, severely calcified coronary lesions: an economic modeling approach

    PubMed Central

    Chambers, Jeffrey; Généreux, Philippe; Lee, Arthur; Lewin, Jack; Young, Christopher; Crittendon, Janna; Mann, Marita; Garrison, Louis P.

    2015-01-01

    Background: Patients who undergo percutaneous coronary intervention (PCI) for severely calcified coronary lesions have long been known to have worse clinical and economic outcomes than patients with no or mildly calcified lesions. We sought to assess the likely cost-effectiveness of using the Diamondback 360® Orbital Atherectomy System (OAS) in the treatment of de novo, severely calcified lesions from a health-system perspective. Methods and results: In the absence of a head-to-head trial and long-term follow up, cost-effectiveness was based on a modeled synthesis of clinical and economic data. A cost-effectiveness model was used to project the likely economic impact. To estimate the net cost impact, the cost of using the OAS technology in elderly (⩾ 65 years) Medicare patients with de novo severely calcified lesions was compared with cost offsets. Elderly OAS patients from the ORBIT II trial (Evaluate the Safety and Efficacy of OAS in Treating Severely Calcified Coronary Lesions) [ClinicalTrials.gov identifier: NCT01092426] were indirectly compared with similar patients using observational data. For the index procedure, the comparison was with Medicare data, and for both revascularization and cardiac death in the following year, the comparison was with a pooled analysis of the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI)/Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trials. After adjusting for differences in age, gender, and comorbidities, the ORBIT II mean index procedure costs were 17% (p < 0.001) lower, approximately US$2700. Estimated mean revascularization costs were lower by US$1240 in the base case. These cost offsets in the first year, on average, fully cover the cost of the device with an additional 1.2% cost savings. Even in the low-value scenario, the use of the OAS is cost-effective with a cost per life-year gained of US$11,895. Conclusions: Based on economic modeling

  15. Antinociceptive effects of neurotropin in a rat model of central neuropathic pain: DSP-4 induced noradrenergic lesion.

    PubMed

    Kudo, Takashi; Kushikata, Tetsuya; Kudo, Mihoko; Kudo, Tsuyoshi; Hirota, Kazuyoshi

    2011-09-26

    Neurotropin is a nonprotein extract isolated from inflamed skin of rabbits inoculated with vaccinia virus, and used for treatment of neuropathic pain. In the present study, we have determined whether neurotropin could exert antinociceptive action using the central neuropathic pain model that we recently established. Rats were randomly allocated to 3 groups: Sham group (n=20), DSP-4 [N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine] group (50mg/kg ip, n=18), and DSP-4+5,7-DHT [5,7-dihydroxytryptamine] group (ip DSP-4 50mg/kg+icv 5,7-DHT 200μg, n=18). In Sham, DSP-4 and DSP-4+5,7-DHT groups, the effects of ip neurotropin (100NU/Kg) on hot-plate latency in rats with no lesion, noradrenergic neuron depletion and both noradrenergic and serotonergic neuronal depletion were studied, respectively. Rats in each group were subdivided equally to 2 subgroups: saline and neurotropin. After completion of the hot-plate tests, each rat was decapitated, the cerebral cortex was dissected from its internal structure for measurement of norepinephrine contents. Hot-plate latency significantly decreased by ∼40% 10 days after ip DSP-4 or after ip DSP-4 and 5,7-DHT. Norepinephrine contents in DSP-4 treated rats (55.6±6.3ng/ng tissue) and DSP-4+5,7-DHT treated rats (35.3±6.3ng/ng tissue) were significantly lower than those in intact rats (131.6±5.7ng/ng tissue, p<0.01). Neurotropin significantly increased the area under the curve (AUC) of the hot-plate latency in the DSP-4 and DSP-4+5,7-DHT groups but not in the Sham group. There was a significant correlation between AUC and norepinephrine contents in saline subgroup (p<0.01, r=0.597) but not in neurotropin subgroup in DSP-4 group. Neurotropin exerted an antinociceptive effect in DSP-4 induced central neuropathic pain. The present data suggest neuronal pathways other than descending inhibitory noradrenergic and serotonergic systems may be involved in neurotropin mediated antinociception.

  16. Major Alterations of Phosphatidylcholine and Lysophosphotidylcholine Lipids in the Substantia Nigra Using an Early Stage Model of Parkinson’s Disease

    PubMed Central

    Farmer, Kyle; Smith, Catherine A.; Hayley, Shawn; Smith, Jeffrey

    2015-01-01

    Parkinson’s disease (PD) is a progressive neurodegenerative disease affecting the nigrostriatal pathway, where patients do not manifest motor symptoms until >50% of neurons are lost. Thus, it is of great importance to determine early neuronal changes that may contribute to disease progression. Recent attention has focused on lipids and their role in pro- and anti-apoptotic processes. However, information regarding the lipid alterations in animal models of PD is lacking. In this study, we utilized high performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) and novel HPLC solvent methodology to profile phosphatidylcholines and sphingolipids within the substantia nigra. The ipsilateral substantia nigra pars compacta was collected from rats 21 days after an infusion of 6-hydroxydopamine (6-OHDA), or vehicle into the anterior dorsal striatum. We identified 115 lipid species from their mass/charge ratio using the LMAPS Lipid MS Predict Database. Of these, 19 lipid species (from phosphatidylcholine and lysophosphotidylcholine lipid classes) were significantly altered by 6-OHDA, with most being down-regulated. The two lipid species that were up-regulated were LPC (16:0) and LPC (18:1), which are important for neuroinflammatory signalling. These findings provide a first step in the characterization of lipid changes in early stages of PD-like pathology and could provide novel targets for early interventions in PD. PMID:26274953

  17. Osteolytica: An automated image analysis software package that rapidly measures cancer-induced osteolytic lesions in in vivo models with greater reproducibility compared to other commonly used methods☆

    PubMed Central

    Evans, H.R.; Karmakharm, T.; Lawson, M.A.; Walker, R.E.; Harris, W.; Fellows, C.; Huggins, I.D.; Richmond, P.; Chantry, A.D.

    2016-01-01

    Methods currently used to analyse osteolytic lesions caused by malignancies such as multiple myeloma and metastatic breast cancer vary from basic 2-D X-ray analysis to 2-D images of micro-CT datasets analysed with non-specialised image software such as ImageJ. However, these methods have significant limitations. They do not capture 3-D data, they are time-consuming and they often suffer from inter-user variability. We therefore sought to develop a rapid and reproducible method to analyse 3-D osteolytic lesions in mice with cancer-induced bone disease. To this end, we have developed Osteolytica, an image analysis software method featuring an easy to use, step-by-step interface to measure lytic bone lesions. Osteolytica utilises novel graphics card acceleration (parallel computing) and 3-D rendering to provide rapid reconstruction and analysis of osteolytic lesions. To evaluate the use of Osteolytica we analysed tibial micro-CT datasets from murine models of cancer-induced bone disease and compared the results to those obtained using a standard ImageJ analysis method. Firstly, to assess inter-user variability we deployed four independent researchers to analyse tibial datasets from the U266-NSG murine model of myeloma. Using ImageJ, inter-user variability between the bones was substantial (± 19.6%), in contrast to using Osteolytica, which demonstrated minimal variability (± 0.5%). Secondly, tibial datasets from U266-bearing NSG mice or BALB/c mice injected with the metastatic breast cancer cell line 4T1 were compared to tibial datasets from aged and sex-matched non-tumour control mice. Analyses by both Osteolytica and ImageJ showed significant increases in bone lesion area in tumour-bearing mice compared to control mice. These results confirm that Osteolytica performs as well as the current 2-D ImageJ osteolytic lesion analysis method. However, Osteolytica is advantageous in that it analyses over the entirety of the bone volume (as opposed to selected 2-D images

  18. Neuroprotective effects of herbal ethanol extracts from Gynostemma pentaphyllum in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease.

    PubMed

    Choi, Hyun Sook; Park, Mi Sook; Kim, Seung Hwan; Hwang, Bang Yeon; Lee, Chong Kil; Lee, Myung Koo

    2010-04-16

    6-Hydroxydopamine administration for 28 days (8 microg/2 microL) reduced the number of tyrosine hydroxylase (TH)-immunopositive neurons to 40.2% in the substantia nigra compared to the intact contralateral side. Dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid and norepinephrine levels were reduced to 19.1%, 52.3%, 47.1% and 67.4% in the striatum of 6-hydroxydopamine-lesioned rats compared to the control group, respectively. However, an oral administration of herbal ethanol extracts from Gynostemma pentaphyllum (GP-EX) (10 mg/kg and 30 mg/kg) starting on day 3 post-lesion for 28 days markedly ameliorated the reduction of TH-immunopositive neurons induced by 6-hydroxydopamine-lesioned rat brain from 40.2% to 67.4% and 75.8% in the substantia nigra. GP-EX administration (10 and 30 mg/kg) also recovered the levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid and norepinephrine in post-lesion striatum to 64.1% and 65.0%, 77.9% and 89.7%, 82.6% and 90.2%, and 88.1% and 89.2% of the control group. GP-EX at the given doses did not produce any sign of toxicity such as weight loss, diarrhea and vomiting in rats during the 28 day treatment period and four gypenoside derivatives, gynosaponin TN-1, gynosaponin TN-2, gypenoside XLV and gypenoside LXXIV were identified from GP-EX. These results suggest that GP-EX might be helpful in the prevention of Parkinson's disease.

  19. L-DOPA-induced dyregulation of extrastriatal dopamine and serotonin and affective symptoms in a bilateral rat model of Parkinson’s disease

    PubMed Central

    Jaunarajs, Karen L. Eskow; George, Jessica A.; Bishop, Christopher

    2012-01-01

    Convergent evidence indicates that raphestriatal serotonin (5-HT) neurons can convert and release dopamine (DA) derived from exogenous administration of the pharmacotherapeutic L-3,4-dihydroxyphenyl-L-alanine(L-DOPA) as a treatment for Parkinson’s disease (PD). While aspects of such neuroplasticity may be beneficial, chronic L-DOPA may also modify native 5-HT function, precipitating the appearance prevalent non-motor PD symptoms such as anxiety and depression. To examine this, male Sprague-Dawley rats were rendered parkinsonian with bilateral medial forebrain bundle 6-OHDA infusions and treated for at least 28 days with vehicle or L-DOPA. In the first experiment, striatal, hippocampal, amygdalar, and prefrontal cortex DA and 5-HT levels were examined at various post-treatment time-points. In experiment 2, L-DOPA’s effects on DA and 5-HT cell bodies in the substantia nigra pars compacta and dorsal raphe, respectively, were examined. Finally, the effects of L-DOPA on affective behaviors were assessed in locomotor chambers, social interaction, forced swim, and elevated plus maze behavioral tests. Bilateral 6-OHDA lesion induced approximately 80% DA and 30% 5-HT depletion in the striatum compared to sham-lesioned controls, while monoamine levels remained largely unchanged in extrastriatal regions. Tissue levels of DA were increased at the expense of 5-HT levels in parkinsonian rats subjected to chronic L-DOPA injections in all regions sampled, though DA or 5-HT cell bodies were unaffected. Behaviorally, rats could only be tested 24 hours after their last L-DOPA injection due to severe dyskinesia. Despite this, prior exposure to chronic L-DOPA treatment exerted a pronounced anxiogenic phenotype. Collectively, these results suggest that chronic L-DOPA treatment may interfere with the balance of DA and 5-HT function in affect-related brain regions and could induce and/or exacerbate non-motor symptoms in PD. PMID:22659568

  20. Effects of Swimming Exercise on Limbic and Motor Cortex Neurogenesis in the Kainate-Lesion Model of Temporal Lobe Epilepsy

    PubMed Central

    Gorantla, Vasavi R.; Sirigiri, Amulya; Volkova, Yulia A.; Millis, Richard M.

    2016-01-01

    Temporal lobe epilepsy (TLE) is a common neurological disease and antiseizure medication is often inadequate for preventing apoptotic cell death. Aerobic swimming exercise (EX) augments neurogenesis in rats when initiated immediately in the postictal period. This study tests the hypothesis that aerobic exercise also augments neurogenesis over the long term. Male Wistar rats (age of 4 months) were subjected to chemical lesioning using KA and to an EX intervention consisting of a 30 d period of daily swimming for 15 min, in one experiment immediately after KA lesioning (immediate exposure) and in a second experiment after a 60 d period of normal activity (delayed exposure). Morphometric counting of neuron numbers (NN) and dendritic branch points and intersections (DDBPI) was performed in the CA1, CA3, and dentate regions of hippocampus, in basolateral nucleus of amygdala, and in several areas of motor cortex. EX increased NN and DDBPI in the normal control and the KA-lesioned rats in all four limbic and motor cortex areas studied, after both immediate and 60 d delayed exposures to exercise. These findings suggest that, after temporal lobe epileptic seizures in rats, swimming exercise may improve neural plasticity in areas of the brain involved with emotional regulation and motor coordination, even if the exercise treatment is delayed. PMID:27313873

  1. Effects of Swimming Exercise on Limbic and Motor Cortex Neurogenesis in the Kainate-Lesion Model of Temporal Lobe Epilepsy.

    PubMed

    Gorantla, Vasavi R; Sirigiri, Amulya; Volkova, Yulia A; Millis, Richard M

    2016-01-01

    Temporal lobe epilepsy (TLE) is a common neurological disease and antiseizure medication is often inadequate for preventing apoptotic cell death. Aerobic swimming exercise (EX) augments neurogenesis in rats when initiated immediately in the postictal period. This study tests the hypothesis that aerobic exercise also augments neurogenesis over the long term. Male Wistar rats (age of 4 months) were subjected to chemical lesioning using KA and to an EX intervention consisting of a 30 d period of daily swimming for 15 min, in one experiment immediately after KA lesioning (immediate exposure) and in a second experiment after a 60 d period of normal activity (delayed exposure). Morphometric counting of neuron numbers (NN) and dendritic branch points and intersections (DDBPI) was performed in the CA1, CA3, and dentate regions of hippocampus, in basolateral nucleus of amygdala, and in several areas of motor cortex. EX increased NN and DDBPI in the normal control and the KA-lesioned rats in all four limbic and motor cortex areas studied, after both immediate and 60 d delayed exposures to exercise. These findings suggest that, after temporal lobe epileptic seizures in rats, swimming exercise may improve neural plasticity in areas of the brain involved with emotional regulation and motor coordination, even if the exercise treatment is delayed.

  2. Effects of (-)-sesamin on motor and memory deficits in an MPTP-lesioned mouse model of Parkinson's disease treated with l-DOPA.

    PubMed

    Zhao, T T; Shin, K S; Kim, K S; Park, H J; Kim, H J; Lee, K E; Lee, M K

    2016-12-17

    The present study investigated the effects of (-)-sesamin on motor and memory deficits in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model of Parkinson's disease (PD) with l-3,4-dihydroxyphenylalanine (l-DOPA). MPTP-lesioned (30mg/kg/day, 5days) mice showed deficits in memory including habit learning memory and spatial memory, which were further aggravated by daily treatment with 25mg/kg l-DOPA for 21days. However, daily treatment with (-)-sesamin (25 and 50mg/kg) for 21days ameliorated memory deficits in an MPTP-lesioned mouse model of PD treated with l-DOPA (25mg/kg). Both (-)-sesamin doses reduced decreases in the retention latency time in the passive avoidance test, latency to fall of rotarod test and distance traveled in the open field test, and attenuated decreases in tyrosine hydroxylase (TH)-immunopositive cells, dopamine, and its metabolites in the substantia nigra-striatum. (-)-Sesamin reduced increases in the retention transfer latency time in the elevated plus-maze test and N-methyl-d-aspartate receptor (NMDAR) expression and reduced decreases in the phosphorylation of extracellular signal-regulated kinase (ERK1/2) and cyclic AMP-response element binding protein (CREB) in the hippocampus. In contrast, daily treatment with 10mg/kg l-DOPA for 21days ameliorated memory deficits in MPTP-lesioned mice, and this effect was further improved by treatment with (-)-sesamin (25 and 50mg/kg). These results suggest that (-)-sesamin protects against habit learning memory deficits by activating the dopamine neuronal system, while spatial memory deficits are decreased by its modulatory effects on the NMDAR-ERK1/2-CREB system. Accordingly, (-)-sesamin may act as an adjuvant phytonutrient for motor and memory deficits in patients with PD receiving l-DOPA.

  3. Selective destruction of nigrostriatal dopaminergic neurons does not alter [3H]-ryanodine binding in rat striatum.

    PubMed

    Noël, F; Geurts, M; Maloteaux, J M

    2000-02-01

    Dopamine nigrostriatal neurons are important for motor control and may contain a particularly dense population of ryanodine receptors involved in the control of dopamine release. To test this hypothesis, we used a classical model of unilateral selective lesion of these neurons in rats based on 6-hydroxydopamine (6-OHDA) injection into the substantia nigra. Binding of [3H]-GBR 12935, used as a presynaptic marker since it labels specifically the dopamine uptake complex, was dramatically decreased by 83-100% in striatum homogenates after 6-OHDA lesion. On the contrary, no reduction of [3H]-ryanodine binding was observed. The present data indicate that [3H]-ryanodine binding sites present in rat striatum are not preferentially localized in dopaminergic terminals.

  4. High-Fat Diet Promotion of Endometriosis in an Immunocompetent Mouse Model is Associated With Altered Peripheral and Ectopic Lesion Redox and Inflammatory Status.

    PubMed

    Heard, Melissa E; Melnyk, Stepan B; Simmen, Frank A; Yang, Yanqing; Pabona, John Mark P; Simmen, Rosalia C M

    2016-07-01

    Endometriosis is a benign gynecological condition that causes considerable morbidity due to associated infertility, debilitating pelvic pain and inflammatory dysfunctions. Diet is a highly modifiable risk factor for many chronic diseases, but its contribution to endometriosis has not been extensively investigated, due partly to the paradoxical inverse association between obesity and disease incidence. Nevertheless, chronic exposure to dietary high-fat intake has been linked to greater systemic inflammation and oxidative stress, both features of women with endometriosis. Here, we evaluated the effects of a high-fat diet (HFD) (45% fat kcal) on endometriosis progression using an immunocompetent mouse model where ectopic lesion incidence was induced in wild-type recipients by ip administration of endometrial fragments from transcription factor Krüppel-like factor 9-null donor mice. We show that HFD significantly increased ectopic lesion numbers in recipient mice with no significant weight gain and modifications in systemic ovarian steroid hormone and insulin levels, relative to control diet-fed (17% fat kcal) mice. HFD promotion of lesion establishment was associated with reductions in stromal estrogen receptor 1 isoform and progesterone receptor expression, increased F4/80-positive macrophage infiltration, higher stromal but not glandular epithelial proliferation, and enhanced expression of proinflammatory and prooxidative stress pathway genes. Lesion-bearing HFD-fed mice also displayed higher peritoneal fluid TNFα and elevated local and systemic redox status than control diet-fed counterparts. Our results suggest that HFD intake exacerbates endometriosis outcome in the absence of ovarian dysfunction and insulin resistance in mice and warrants further consideration with respect to clinical management of endometriosis progression and recurrence in nonobese patients.

  5. Similar L-dopa-stimulated motor activity in mice with adult-onset 6-hydroxydopamine-induced symmetric dopamine denervation and in transcription factor Pitx3 null mice with perinatal-onset symmetric dopamine denervation.

    PubMed

    Li, Li; Sagot, Ben; Zhou, Fu-Ming

    2015-07-30

    The transcription factor Pitx3 null mutant (Pitx3Null) mice have a constitutive perinatal-onset and symmetric bilateral dopamine (DA) loss in the striatum. In these mice l-3,4-dihydroxyphenylalanine (l-dopa) induces apparently normal horizontal movements (walking) but also upward movements consisting of the vertical body trunk and waving paws that are absent in normal animals and in animals with the classic unilateral 6-hydroxydopamine (6-OHDA) lesion-induced DA denervation. Thus, a concern is that the perinatal timing of the DA loss and potential developmental abnormalities in Pitx3Null mice may underlie these upward movements, thus reducing the usefulness as a DA denervation model. Here we show that in normal wild-type (Pitx3WT) mice with adult-onset symmetric, bilateral 6-OHDA-induced DA lesion in the dorsal striatum, l-dopa induces normal horizontal movements and upward movements that are qualitatively identical to those in Pitx3Null mice. Furthermore, after unilateral 6-OHDA lesion of the residual DA innervation in the striatum in Pitx3Null mice, l-dopa induces contraversive rotation that is similar to that in Pitx3WT mice with the classic unilateral 6-OHDA lesion. These results indicate that in Pitx3Null mice, the bilateral symmetric DA denervation in the dorsal striatum is sufficient for expressing the l-dopa-induced motor phenotype and the perinatal timing of their DA loss is not a determining factor, providing further evidence that Pitx3Null mice are a convenient and suitable mouse model to study the consequences of DA loss and dopaminergic replacement therapy in Parkinson's disease.

  6. Protective effect of L-kynurenine and probenecid on 6-hydroxydopamine-induced striatal toxicity in rats: implications of modulating kynurenate as a protective strategy.

    PubMed

    Silva-Adaya, Daniela; Pérez-De La Cruz, Verónica; Villeda-Hernández, Juana; Carrillo-Mora, Paul; González-Herrera, Irma Gabriela; García, Esperanza; Colín-Barenque, Laura; Pedraza-Chaverrí, José; Santamaría, Abel

    2011-01-01

    The neuroactive metabolite at the kynunerine pathway, kynurenic acid (KYNA), is a well-known competitive antagonist at the co-agonist glycine site of the N-methyl-D-aspartate receptor (NMDAr), and also decreases the extracellular levels of glutamate by blocking α7-nicotinic acetylcholine receptor (α7-nAchr) located on glutamatergic terminals. KYNA has been often reported to be neuroprotective in different neurotoxic models. The systemic administration of L-kynurenine (L-KYN)--the precursor of KYNA--together with probenecid (PROB)--an inhibitor of organic acids transport--to rodents increases KYNA levels in the brain in a dose-dependent manner. The striatal infusion of the toxin 6-hydroxydopamine (6-OHDA) to rodents is one of the common models used to simulate Parkinson's disease (PD). Different studies have linked PD alterations with excessive glutamatergic transmission in the striatum since NMDAr antagonists exert beneficial effects in PD models. In this work we investigated the effect that a systemic administration of L-KYN+PROB exerted on the toxic model induced by 6-OHDA in rats. PROB (50 mg/kg, i.p.) + L-KYN (75 mg/kg, i.p.) were given to rats for seven consecutive days. On day two of treatment, the animals were infused with a single injection of 6-OHDA (20 μg/2 μl) into the right striatum. Fourteen days post-lesion, rotation behavior was assessed as a marker of motor impairment. The total levels of dopamine (DA) were also estimated in striatal tissue samples of 6-OHDA-treated animals as a neurochemical marker of damage. In addition, twenty eight days post-lesion, the striatal damage was assessed by hematoxylin/eosin staining and immunohistochemistry against glial fibrillary acidic protein (GFAP) in the same animals. Neurodegeneration was also assessed by Fluoro Jade staining. 6-OHDA infusion increased rotation behavior, striatal reactive gliosis and neurodegeneration, while DA levels were decreased. For all markers evaluated, we observed protective

  7. Simulation of spiculated breast lesions

    NASA Astrophysics Data System (ADS)

    Elangovan, Premkumar; Alrehily, Faisal; Pinto, R. Ferrari; Rashidnasab, Alaleh; Dance, David R.; Young, Kenneth C.; Wells, Kevin

    2016-03-01

    Virtual clinical trials are a promising new approach increasingly used for the evaluation and comparison of breast imaging modalities. A key component in such an assessment paradigm is the use of simulated pathology, in particular, simulation of lesions. Breast mass lesions can be generally classified into two categories based on their appearance; nonspiculated masses and spiculated masses. In our previous work, we have successfully simulated non-spiculated masses using a fractal growth process known as diffusion limited aggregation. In this new work, we have extended the DLA model to simulate spiculated lesions by using features extracted from patient DBT images containing spiculated lesions. The features extracted included spicule length, width, curvature and distribution. This information was used to simulate realistic looking spicules which were attached to the surface of a DLA mass to produce a spiculated mass. A batch of simulated spiculated masses was inserted into normal patient images and presented to an experienced radiologist for review. The study yielded promising results with the radiologist rating 60% of simulated lesions in 2D and 50% of simulated lesions in DBT as realistic.

  8. In vivo analysis of tissue by Raman microprobe: examination of human skin lesions and esophagus Barrett's mucosa on an animal model

    NASA Astrophysics Data System (ADS)

    Tfayli, Ali; Piot, Olivier; Derancourt, Sylvie; Cadiot, Guillaume; Diebold, Marie D.; Bernard, Philippe; Manfait, Michel

    2006-02-01

    In the last few years, Raman spectroscopy has been increasingly used for the characterization of normal and pathological tissues. A new Raman system, constituted of optic fibers bundle coupled to an axial Raman spectrometer (Horiba Jobin Yvon SAS), was developed for in vivo investigations. Here, we present in vivo analysis on two tissues: human skin and esophagus mucosa on a rat model. The skin is a directly accessible organ, representing a high diversity of lesions and cancers. Including malignant melanoma, basal cell carcinoma and the squamous cell carcinoma, skin cancer is the cancer with the highest incidence worldwide. Several Raman investigations were performed to discriminate and classify different types of skin lesions, on thin sections of biopsies. Here, we try to characterize in vivo the different types of skin cancers in order to be able to detect them in their early stages of development and to define precisely the exeresis limits. Barrett's mucosa was also studied by in vivo examination of rat's esophagus. Barrett's mucosa, induced by gastro-esophageal reflux, is a pretumoral state that has to be carefully monitored due to its high risk of evolution in adenocarcinoma. A better knowledge of the histological transformation of esophagus epithelium in a Barrett's type will lead to a more efficient detection of the pathology for its early diagnosis. To study these changes, an animal model (rats developing Barrett's mucosa after duodenum - esophagus anastomosis) was used. Potential of vibrational spectroscopy for Barrett's mucosa identification is assessed on this model.

  9. Time-course of SKF-81297-induced increase in glutamic acid decarboxylase 65 and 67 mRNA levels in striatonigral neurons and decrease in GABA(A) receptor alpha1 subunit mRNA levels in the substantia nigra, pars reticulata, in adult rats with a unilateral 6-hydroxydopamine lesion.

    PubMed

    Yamamoto, N; Soghomonian, J-J

    2008-06-26

    Striatal projection neurons use GABA as their neurotransmitter and express the rate-limiting synthesizing enzyme glutamic acid decarboxylase (GAD) and the vesicular GABA transporter vGAT. The chronic systemic administration of an agonist of dopamine D1/D5-preferring receptors is known to alter GAD mRNA levels in striatonigral neurons in intact and dopamine-depleted rats. In the present study, the effects of a single or subchronic systemic administration of the dopamine D1/D5-preferring receptor agonist SKF-81297 on GAD65, GAD67, PPD and vGAT mRNA levels in the striatum and GABA(A) receptor alpha1 subunit mRNA levels in the substantia nigra, pars reticulata, were measured in rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion. After a single injection of SKF-81297, striatal GAD65 mRNA levels were significantly increased at 3 but not 72 h. In contrast, striatal GAD67 mRNA levels were increased and nigral alpha1 mRNA levels were decreased at 72 but not 3 h. Single cell analysis on double-labeled sections indicated that increased GAD or vGAT mRNA levels after acute SKF-81297 occurred in striatonigral neurons identified by their lack of preproenkephalin expression. Subchronic SKF-81297 induced significant increases in striatal GAD67, GAD65, preprodynorphin and vGAT mRNA levels and decreases in nigral alpha1 mRNA levels. In the striatum contralateral to the 6-OHDA lesion, subchronic but not acute SKF-81297 induced a significant increase in GAD65 mRNA levels. The other mRNA levels were not significantly altered. Finally, striatal GAD67 mRNA levels were negatively correlated with nigral alpha1 mRNA levels in the dopamine-depleted but not dopamine-intact side. The results suggest that different signaling pathways are involved in the modulation by dopamine D1/D5 receptors of GAD65 and GAD67 mRNA levels in striatonigral neurons. They also suggest that the down-regulation of nigral GABA(A) receptors is linked to the increase in striatal GAD67 mRNA levels in the dopamine

  10. Impairments in set-shifting but not reversal learning in the neonatal ventral hippocampal lesion model of schizophrenia: further evidence for medial prefrontal deficits.

    PubMed

    Placek, Katerina; Dippel, William C; Jones, Shelby; Brady, Anne Marie

    2013-11-01

    The executive function processes of set-shifting and reversal learning in rodents are mediated by the medial prefrontal cortex and the orbitofrontal cortex, respectively. Here, we investigated both set-shifting and reversal learning in a developmental animal model of schizophrenia, the neonatal ventral hippocampal lesion (NVHL) model. The NVHL manipulation is known to disrupt development of the medial prefrontal cortex, and to impair behaviors dependent on this area, but potential orbitofrontal abnormalities and reversal learning deficits are less well studied. Animals received excitotoxic lesions of the ventral hippocampus (NVHL) or a sham treatment during the first postnatal week, and all animals were subsequently tested in adulthood on either an operant set-shifting or an operant reversal task. Results indicated that NVHL animals were able to acquire a simple discrimination rule and exhibited normal reversal learning, but were impaired on a prefrontal-dependent set-shifting task. Furthermore, this set-shifting deficit was due to an increase in perseverative errors, which indicate difficulty suppressing a previously learned strategy and result from medial prefrontal insult. Together, these results confirm and extend the idea that cognitive impairments in the NVHL animal are primarily driven by medial prefrontal abnormalities, while the orbitofrontal cortex may remain relatively unaffected.

  11. Novel Lesions of Bones and Joints Associated with Chikungunya Virus Infection in Two Mouse Models of Disease: New Insights into Disease Pathogenesis

    PubMed Central

    Goupil, Brad A.; McNulty, Margaret A.; Martin, Matthew J.; McCracken, Michael K.; Christofferson, Rebecca C.; Mores, Christopher N.

    2016-01-01

    Chikungunya virus is an arbovirus spread predominantly by Aedes aegypti and Ae. albopictus mosquitoes, and causes debilitating arthralgia and arthritis. While these are common manifestations during acute infection and it has been suggested they can recur in patients chronically, gaps in knowledge regarding the pathogenesis still exist. Two established mouse models were utilized (adult IRF 3/7 -/- -/- and wild-type C57BL/6J mice) to evaluate disease manifestations in bones and joints at various timepoints. Novel lesions in C57BL/6J mice consisted of periostitis (91%) and foci of cartilage of necrosis (50% of mice at 21 DPI). Additionally, at 21 DPI, 50% and 75% of mice exhibited periosteal bone proliferation affecting the metatarsal bones, apparent via histology and μCT, respectively. μCT analysis did not reveal any alterations in trabecular bone volume measurements in C57BL/6J mice. Novel lesions demonstrated in IRF 3/7 -/- -/- mice at 5 DPI included focal regions of cartilage necrosis (20%), periosteal necrosis (66%), and multifocal ischemic bone marrow necrosis (100%). Contralateral feet in 100% of mice of both strains had similar, though milder lesions. Additionally, comparison of control IRF 3/7 -/- -/- and wild-type C57BL/6J mice demonstrated differences in cortical bone. These experiments demonstrate novel manifestations of disease similar to those occurring in humans, adding insight into disease pathogenesis, and representing new potential targets for therapeutic interventions. Additionally, results demonstrate the utility of μCT in studies of bone and joint pathology and illustrate differences in bone dynamics between mouse strains. PMID:27182740

  12. Modelling the effects of blood component storage lesions on the quality of haemostatic resuscitation in massive transfusion for trauma

    PubMed Central

    Mays, James A.; Hess, John R.

    2017-01-01

    Background All blood components undergo loss of potency during storage. These loss-of-potency storage lesions are important in trauma resuscitation because they reduce the haemostatic capacity of mixtures of components that attempt to reconstitute whole blood. Even red cell storage-related loss of potency, which averages 17% with modern additive solutions, is important because 6 units of red cells must be given to achieve the effect of 5 fully potent units. Materials and methods Loss of potency of stored units of red blood cells, plasma, platelets, and cryoprecipitate were summed for dilutional, storage-related, pathogen reduction-related, and splenic sequestration-related causes and expressed as fractional plasma coagulation factor concentrations and platelet counts. Results Production of reconstituted whole blood from 1:1:1 unit ratios of red cells:plasma:platelets is associated with a 38% loss of plasma coagulation factor concentration and 56% loss of platelets. Storage losses of 17% for red cells, 10% for coagulation factors, and 30% for platelets are additive to pathogen reduction-related losses of 18% for coagulation factors and 30% for platelets. Discussion Component preparation and storage-related losses of potency for all blood components are serious problems for trauma resuscitation. Even red cell storage contributes to this problem and this can be made better in ways that can save many lives each year. PMID:28263173

  13. Intraarterial route increases the risk of cerebral lesions after mesenchymal cell administration in animal model of ischemia.

    PubMed

    Argibay, Bárbara; Trekker, Jesse; Himmelreich, Uwe; Beiras, Andrés; Topete, Antonio; Taboada, Pablo; Pérez-Mato, María; Vieites-Prado, Alba; Iglesias-Rey, Ramón; Rivas, José; Planas, Anna M; Sobrino, Tomás; Castillo, José; Campos, Francisco

    2017-01-16

    Mesenchymal stem cells (MSCs) are a promising clinical therapy for ischemic stroke. However, critical parameters, such as the most effective administration route, remain unclear. Intravenous (i.v.) and intraarterial (i.a.) delivery routes have yielded varied outcomes across studies, potentially due to the unknown MSCs distribution. We investigated whether MSCs reached the brain following i.a. or i.v. administration after transient cerebral ischemia in rats, and evaluated the therapeutic effects of both routes. MSCs were labeled with dextran-coated superparamagnetic nanoparticles for magnetic resonance imaging (MRI) cell tracking, transmission electron microscopy and immunohistological analysis. MSCs were found in the brain following i.a. but not i.v. administration. However, the i.a. route increased the risk of cerebral lesions and did not improve functional recovery. The i.v. delivery is safe but MCS do not reach the brain tissue, implying that treatment benefits observed for this route are not attributable to brain MCS engrafting after stroke.

  14. Intraarterial route increases the risk of cerebral lesions after mesenchymal cell administration in animal model of ischemia

    NASA Astrophysics Data System (ADS)

    Argibay, Bárbara; Trekker, Jesse; Himmelreich, Uwe; Beiras, Andrés; Topete, Antonio; Taboada, Pablo; Pérez-Mato, María; Vieites-Prado, Alba; Iglesias-Rey, Ramón; Rivas, José; Planas, Anna M.; Sobrino, Tomás; Castillo, José; Campos, Francisco

    2017-01-01

    Mesenchymal stem cells (MSCs) are a promising clinical therapy for ischemic stroke. However, critical parameters, such as the most effective administration route, remain unclear. Intravenous (i.v.) and intraarterial (i.a.) delivery routes have yielded varied outcomes across studies, potentially due to the unknown MSCs distribution. We investigated whether MSCs reached the brain following i.a. or i.v. administration after transient cerebral ischemia in rats, and evaluated the therapeutic effects of both routes. MSCs were labeled with dextran-coated superparamagnetic nanoparticles for magnetic resonance imaging (MRI) cell tracking, transmission electron microscopy and immunohistological analysis. MSCs were found in the brain following i.a. but not i.v. administration. However, the i.a. route increased the risk of cerebral lesions and did not improve functional recovery. The i.v. delivery is safe but MCS do not reach the brain tissue, implying that treatment benefits observed for this route are not attributable to brain MCS engrafting after stroke.

  15. Intraarterial route increases the risk of cerebral lesions after mesenchymal cell administration in animal model of ischemia

    PubMed Central

    Argibay, Bárbara; Trekker, Jesse; Himmelreich, Uwe; Beiras, Andrés; Topete, Antonio; Taboada, Pablo; Pérez-Mato, María; Vieites-Prado, Alba; Iglesias-Rey, Ramón; Rivas, José; Planas, Anna M.; Sobrino, Tomás; Castillo, José; Campos, Francisco

    2017-01-01

    Mesenchymal stem cells (MSCs) are a promising clinical therapy for ischemic stroke. However, critical parameters, such as the most effective administration route, remain unclear. Intravenous (i.v.) and intraarterial (i.a.) delivery routes have yielded varied outcomes across studies, potentially due to the unknown MSCs distribution. We investigated whether MSCs reached the brain following i.a. or i.v. administration after transient cerebral ischemia in rats, and evaluated the therapeutic effects of both routes. MSCs were labeled with dextran-coated superparamagnetic nanoparticles for magnetic resonance imaging (MRI) cell tracking, transmission electron microscopy and immunohistological analysis. MSCs were found in the brain following i.a. but not i.v. administration. However, the i.a. route increased the risk of cerebral lesions and did not improve functional recovery. The i.v. delivery is safe but MCS do not reach the brain tissue, implying that treatment benefits observed for this route are not attributable to brain MCS engrafting after stroke. PMID:28091591

  16. Classification of breast mass lesions using model-based analysis of the characteristic kinetic curve derived from fuzzy c-means clustering.

    PubMed

    Chang, Yeun-Chung; Huang, Yan-Hao; Huang, Chiun-Sheng; Chang, Pei-Kang; Chen, Jeon-Hor; Chang, Ruey-Feng

    2012-04-01

    The purpose of this study is to evaluate the diagnostic efficacy of the representative characteristic kinetic curve of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) extracted by fuzzy c-means (FCM) clustering for the discrimination of benign and malignant breast tumors using a novel computer-aided diagnosis (CAD) system. About the research data set, DCE-MRIs of 132 solid breast masses with definite histopathologic diagnosis (63 benign and 69 malignant) were used in this study. At first, the tumor region was automatically segmented using the region growing method based on the integrated color map formed by the combination of kinetic and area under curve color map. Then, the FCM clustering was used to identify the time-signal curve with the larger initial enhancement inside the segmented region as the representative kinetic curve, and then the parameters of the Tofts pharmacokinetic model for the representative kinetic curve were compared with conventional curve analysis (maximal enhancement, time to peak, uptake rate and washout rate) for each mass. The results were analyzed with a receiver operating characteristic curve and Student's t test to evaluate the classification performance. Accuracy, sensitivity, specificity, positive predictive value and negative predictive value of the combined model-based parameters of the extracted kinetic curve from FCM clustering were 86.36% (114/132), 85.51% (59/69), 87.30% (55/63), 88.06% (59/67) and 84.62% (55/65), better than those from a conventional curve analysis. The A(Z) value was 0.9154 for Tofts model-based parametric features, better than that for conventional curve analysis (0.8673), for discriminating malignant and benign lesions. In conclusion, model-based analysis of the characteristic kinetic curve of breast mass derived from FCM clustering provides effective lesion classification. This approach has potential in the development of a CAD system for DCE breast MRI.

  17. BRONCHIAL LESIONS OF MOUSE MODEL OF ASTHMA ARE PRECEDED BY IMMUNE COMPLEX VASCULITIS AND INDUCED BRONCHIAL ASSOCIATED LYMPHOID TISSUE (iBALT)

    PubMed Central

    Guest, Ian; Sell, Stewart

    2015-01-01

    We systematically examined by immune-histology the lungs of some widely used mouse models of asthma. These models include sensitization by multiple intraperitoneal injections of soluble ovalbumin (OVA) or of OVA with alum, followed by three intranasal or aerosol challenges 3 days apart. Within 24 hours after a single challenge there is fibrinoid necrosis of arterial walls with deposition of immunoglobulin and OVA and infiltration of eosinophilic polymorphonuclear cells that lasts for about 3 days followed by peribronchial B-cell infiltration and slight reversible goblet cell hypertrophy. After 2 challenges, severe eosinophilic vasculitis is present at 6 hours, increases by 72 hours and then declines; B-cell proliferation and significant goblet cell hypertrophy and hyperplasia (GCHTH) and bronchial smooth muscle hypertrophy recur more prominently. After 3 challenges, there is significantly increased induced bronchus associated lymphoid tissue (iBALT) formation, GCHTH and smooth muscle hypertrophy. Elevated levels of Th2 cytokines: IL-4, IL-5 and IL-13, are present in bronchial lavage fluids. Sensitized mice have precipitating antibody and positive Arthus skin reactions but also develop significant levels IgE antibody to OVA but only 1 week after challenge. We conclude that the asthma like lung lesions induced in these models is preceded by immune complex mediated eosinophilic vasculitis and iBALT formation. There are elevations of Th2 cytokines that most likely produce bronchial lesions that resemble human asthma. However, it is unlikely that mast cell activated atopic mechanisms are responsible as we found only a few presumed mast cells by toluidine blue and metachromatic staining limited to the most proximal part of the main stem bronchus, and none in the remaining main stem bronchus or in the lung periphery. PMID:26006019

  18. Krüppel-Like Factor 13 Deficiency in Uterine Endometrial Cells Contributes to Defective Steroid Hormone Receptor Signaling but Not Lesion Establishment in a Mouse Model of Endometriosis.

    PubMed

    Heard, Melissa E; Velarde, Michael C; Giudice, Linda C; Simmen, Frank A; Simmen, Rosalia C M

    2015-06-01

    Krüppel-like Factor (KLF) 13 and the closely related KLF9 are members of the Sp/KLF family of transcription factors that have collectively emerged as essential regulators of tissue development, differentiation, proliferation, and programmed cell death. Steroid hormone-responsive tissues express multiple KLFs that are linked to progesterone receptor (PGR) and estrogen receptor (ESR) actions either as integrators or as coregulators. Endometriosis is a chronic disease characterized by progesterone resistance and dysregulated estradiol signaling; nevertheless, distinct KLF members' contributions to endometriosis remain largely undefined. We previously demonstrated promotion of ectopic lesion establishment by Klf9 null endometrium in a mouse model of endometriosis. Here we evaluated whether KLF13 loss of expression in endometrial cells may equally contribute to lesion formation. KLF13 transcript levels were lower in the eutopic endometria of women with versus women without endometriosis at menstrual midsecretory phase. In wild-type (WT) mouse recipients intraperitoneally administered WT or Klf13 null endometrial fragments, lesion incidence did not differ with donor genotype. No differences were noted for lesion volume, number, proliferation status, and apoptotic index as well. Klf13 null lesions displayed reduced total PGR and ESR1 (RNA and immunoreactive protein) and altered expression of several PGR and ESR1 target genes, relative to WT lesions. Unlike for Klf9 null lesions, changes in transcript levels for PGR-A, ESR1, and Notch/Hedgehog-associated pathway components were not observed for Klf13 null lesions. Results demonstrate lack of a causative relationship between endometrial KLF13 deficiency and lesion establishment in mice, and they support the broader participation of multiple signaling pathways, besides those mediated by steroid receptors, in the pathology of endometriosis.

  19. Deep brain stimulation exacerbates hypokinetic dysarthria in a rat model of Parkinson's disease.

    PubMed

    King, Nathaniel O; Anderson, Collin J; Dorval, Alan D

    2016-02-01

    Motor symptoms of Parkinson's disease (PD) follow the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Deep brain stimulation (DBS) treats some parkinsonian symptoms, such as tremor, rigidity, and bradykinesia, but may worsen certain medial motor symptoms, including hypokinetic dysarthria. The mechanisms by which DBS exacerbates dysarthria while improving other symptoms are unclear and difficult to study in human patients. This study proposes an animal model of DBS-exacerbated dysarthria. We use the unilateral, 6-hydroxydopamine (6-OHDA) rat model of PD to test the hypothesis that DBS exacerbates quantifiable aspects of vocalization. Mating calls were recorded from sexually experienced male rats under healthy and parkinsonian conditions and during DBS of the subthalamic nucleus. Relative to healthy rats, parkinsonian animals made fewer calls with shorter and less complex vocalizations. In the parkinsonian rats, putatively therapeutic DBS further reduced call frequency, duration, and complexity. The individual utterances of parkinsonian rats spanned a greater bandwidth than those of healthy rats, potentially reducing the effectiveness of the vocal signal. This utterance bandwidth was further increased by DBS. We propose that the parkinsonism-associated changes in call frequency, duration, complexity, and dynamic range combine to constitute a rat analog of parkinsonian dysarthria. Because DBS exacerbates the parkinsonism-associated changes in each of these metrics, the subthalamic stimulated 6-OHDA rat is a good model of DBS-induced hypokinetic dysarthria in PD. This model will help researchers examine how DBS alleviates many motor symptoms of PD while exacerbating parkinsonian speech deficits that can greatly diminish patient quality of life.

  20. Aetiology of abfraction lesions.

    PubMed

    Lyons, K

    2001-09-01

    The aetiology of abfraction lesions is complex. Most evidence indicates that physical loading forces are a major contributing factor, although they are unlikely to be entirely responsible. Intraoral chemical influences and toothbrush abrasion, combined with the dynamics of inter-occlusal activity such as chewing, swallowing, and parafunction, lead to stress corrosion and may contribute to abfraction lesions. The multifactorial aetiology that operates in the initiation and progression of these lesions has made investigation difficult. Various theories have been proposed and numerous surveys and studies conducted, but the primary causal factor has yet to be definitively determined. This review concludes that occlusal loading is the initiating factor in the development of abfraction lesions.

  1. Neuroprotection by Exendin-4 Is GLP-1 Receptor Specific but DA D3 Receptor Dependent, Causing Altered BrdU Incorporation in Subventricular Zone and Substantia Nigra

    PubMed Central

    Harkavyi, A.; Rampersaud, N.; Whitton, P. S.

    2013-01-01

    Glucagon-like peptide-1 receptor (GLP-1R) activation by exendin-4 (EX-4) is effective in preclinical models of Parkinson's disease (PD) and appears to promote neurogenesis even in severely lesioned rats. In the present study, we determined the effects of EX-4 on cellular BrdU incorporation in the rat subventricular zone (SVZ) and substantia nigra (SN). We also determined the specificity of this effect with the GLP-1R antagonist EX-(9-39) as well as the potential role of dopamine (DA) D3 receptors. Rats were administered 6-OHDA and 1 week later given EX-4 alone, with EX-(9-39) or nafadotride (D3 antagonist) and BrdU. Seven days later, rats were challenged with apomorphine to evaluate circling. Extracellular DA was measured using striatal microdialysis and subsequently tissue DA measured. Tyrosine hydroxylase and BrdU were verified using immunohistochemistry. Apomorphine circling was reversed by EX-4 in lesioned rats, an effect reduced by EX-4, while both EX-(9-39) and NAF attenuated this. 6-OHDA decreased extracellular and tissue DA, both reversed by EX-4 but again attenuated by EX-(9-39) or NAF. Analysis of BrdU+ cells in the SVZ revealed increases in 6-OHDA-treated rats which were reversed by EX-4 and antagonised by either EX-(9-39) or NAF, while in the SN the opposite profile was seen. PMID:26316987

  2. Conditioned medium from mesenchymal stem cells induces cell death in organotypic cultures of rat hippocampus and aggravates lesion in a model of oxygen and glucose deprivation.

    PubMed

    Horn, Ana Paula; Frozza, Rudimar Luiz; Grudzinski, Patrícia Benke; Gerhardt, Daniéli; Hoppe, Juliana Bender; Bruno, Alessandra Nejar; Chagastelles, Pedro; Nardi, Nance Beyer; Lenz, Guido; Salbego, Christianne

    2009-01-01

    Cell therapy using bone marrow-derived mesenchymal stem cells (MSC) seems to be a new alternative for the treatment of neurological diseases, including stroke. In order to investigate the response of hippocampal tissue to factors secreted by MSC and if these factors are neuroprotective in a model of oxygen and glucose deprivation (OGD), we used organotypic hippocampal cultures exposed to conditioned medium from bone marrow-derived MSC. Our results suggest that the conditioned medium obtained from these cells aggravates lesion caused by OGD. In addition, the presence of the conditioned medium alone was toxic mainly to cells in the CA1, CA2 and CA3 areas of the hippocampal organotypic culture even in basal conditions. GABA stimulation and NMDA and AMPA receptors antagonists were able to reduce propidium iodide staining, suggesting that the cell death induced by the toxic factors secreted by MSC could involve these receptors.

  3. Muscle spindles exhibit core lesions and extensive degeneration of intrafusal fibers in the Ryr1(I4895T/wt) mouse model of core myopathy.

    PubMed

    Zvaritch, Elena; MacLennan, David H

    2015-04-24

    Muscle spindles from the hind limb muscles of adult Ryr1(I4895T/wt) (IT/+) mice exhibit severe structural abnormalities. Up to 85% of the spindles are separated from skeletal muscle fascicles by a thick layer of connective tissue. Many intrafusal fibers exhibit degeneration, with Z-line streaming, compaction and collapse of myofibrillar bundles, mitochondrial clumping, nuclear shrinkage and pyknosis. The lesions resemble cores observed in the extrafusal myofibers of this animal model and of core myopathy patients. Spindle abnormalities precede those in extrafusal fibers, indicating that they are a primary pathological feature in this murine Ryr1-related core myopathy. Muscle spindle involvement, if confirmed for human core myopathy patients, would provide an explanation for an array of devastating clinical features characteristic of these diseases and provide novel insights into the pathology of RYR1-related myopathies.

  4. The “Buruli Score”: Development of a Multivariable Prediction Model for Diagnosis of Mycobacterium ulcerans Infection in Individuals with Ulcerative Skin Lesions, Akonolinga, Cameroon

    PubMed Central

    Mueller, Yolanda K.; Bastard, Mathieu; Nkemenang, Patrick; Comte, Eric; Ehounou, Geneviève; Eyangoh, Sara; Rusch, Barbara; Tabah, Earnest Njih; Trellu, Laurence Toutous; Etard, Jean-Francois

    2016-01-01

    Background Access to laboratory diagnosis can be a challenge for individuals suspected of Buruli Ulcer (BU). Our objective was to develop a clinical score to assist clinicians working in resource-limited settings for BU diagnosis. Methododology/Principal Findings Between 2011 and 2013, individuals presenting at Akonolinga District Hospital, Cameroon, were enrolled consecutively. Clinical data were collected prospectively. Based on a latent class model using laboratory test results (ZN, PCR, culture), patients were categorized into high, or low BU likelihood. Variables associated with a high BU likelihood in a multivariate logistic model were included in the Buruli score. Score cut-offs were chosen based on calculated predictive values. Of 325 patients with an ulcerative lesion, 51 (15.7%) had a high BU likelihood. The variables identified for the Buruli score were: characteristic smell (+3 points), yellow color (+2), female gender (+2), undermining (+1), green color (+1), lesion hyposensitivity (+1), pain at rest (-1), size >5cm (-1), locoregional adenopathy (-2), age above 20 up to 40 years (-3), or above 40 (-5). This score had AUC of 0.86 (95%CI 0.82–0.89), indicating good discrimination between infected and non-infected individuals. The cut-off to reasonably exclude BU was set at scores <0 (NPV 96.5%; 95%CI 93.0–98.6). The treatment threshold was set at a cut-off ≥4 (PPV 69.0%; 95%CI 49.2–84.7). Patients with intermediate BU probability needed to be tested by PCR. Conclusions/Significance We developed a decisional algorithm based on a clinical score assessing BU probability. The Buruli score still requires further validation before it can be recommended for wide use. PMID:27045293

  5. Contralateral retinal dopamine decrease and melatonin increase in progression of hemiparkinsonium rat.

    PubMed

    Meng, Tao; Zheng, Zhi-Hong; Liu, Ting-Ting; Lin, Ling

    2012-05-01

    Both dopamine (DA) and melatonin (MLT) are abundant neuromodulators located in vertebrate retina. The retinal DA deficiency and variations in MLT levels have been linked to Parkinson's disease (PD). No studies have investigated the ipsilateral and contralateral DA and MLT in retina and their relationships in 6-hydroxydopamine (6-OHDA) induced hemiparkinsonian rats. We established PD rat model by unilateral injection of 6-OHDA into the right substantia nigra and the right medial forebrain bundle. Eye tissue was collected and the levels of MLT and DA were measured twice daily at 10:00 and 22:00. The concentrations of DA and its metabolites, 3,4-dihydroxyphenylacetic (DOPAC) and homovanillic acid (HVA), as well as MLT were determined by HPLC. The results show that DA levels in the eye contralateral to the side of a unilateral intracerebral 6-OHDA lesion significantly decreased (P < 0.001). Both the ratios of DOPAC/DA and HVA/DA were increased in comparison with the vehicle groups after 3 weeks post-lesion. The concentrations of MLT at 10:00 and 22:00 in both eyes were distinctly increased compared with the vehicle groups (P < 0.05). The change of DA and its metabolites, as well as MLT appeared to correlate well with the rotation behavior of rats. These findings suggest that rats receive a unilateral intracerebral injection of 6-OHDA that mainly causes the contralateral eye destruction of DA-containing neurons. Increased retinal MLT level probably is associated with the progression of PD.

  6. Effects of discontinuing a high-fat diet on mitochondrial proteins and 6-hydroxydopamine-induced dopamine depletion in rats.

    PubMed

    Ma, Delin; Shuler, Jeffrey M; Raider, Kayla D; Rogers, Robert S; Wheatley, Joshua L; Geiger, Paige C; Stanford, John A

    2015-07-10

    Diet-induced obesity can increase the risk for developing age-related neurodegenerative diseases including Parkinson's disease (PD). Increasing evidence suggests that mitochondrial and proteasomal mechanisms are involved in both insulin resistance and PD. The goal of this study was to determine whether diet intervention could influence mitochondrial or proteasomal protein expression and vulnerability to 6-Hydroxydopamine (6-OHDA)-induced nigrostriatal dopamine (DA) depletion in rats' nigrostriatal system. After a 3 month high-fat diet regimen, we switched one group of rats to a low-fat diet for 3 months (HF-LF group), while the other half continued with the high-fat diet (HF group). A chow group was included as a control. Three weeks after unilateral 6-OHDA lesions, HF rats had higher fasting insulin levels and higher Homeostasis model assessment of insulin resistance (HOMA-IR), indicating insulin resistance. HOMA-IR was significantly lower in HF-LF rats than HF rats, indicating that insulin resistance was reversed by switching to a low-fat diet. Compared to the Chow group, the HF group exhibited significantly greater DA depletion in the substantia nigra but not in the striatum. DA depletion did not differ between the HF-LF and HF group. Proteins related to mitochondrial function (such as AMPK, PGC-1α), and to proteasomal function (such as TCF11/Nrf1) were influenced by diet intervention, or by 6-OHDA lesion. Our findings suggest that switching to a low-fat diet reverses the effects of a high-fat diet on systemic insulin resistance, and mitochondrial and proteasomal function in the striatum. Conversely, they suggest that the effects of the high-fat diet on nigrostriatal vulnerability to 6-OHDA-induced DA depletion persist.

  7. Effects of discontinuing a high-fat diet on mitochondrial proteins and 6-hydroxydopamine-induced dopamine depletion in rats

    PubMed Central

    Ma, Delin; Shuler, Jeffrey M.; Raider, Kayla D.; Rogers, Robert S.; Wheatley, Joshua L.; Geiger, Paige C.; Stanford, John A.

    2015-01-01

    Diet-induced obesity can increase the risk for developing age-related neurodegenerative diseases including Parkinson’s disease (PD). Increasing evidence suggests that mitochondrial and proteasomal mechanisms are involved in both insulin resistance and PD. The goal of this study was to determine whether diet intervention could influence mitochondrial or proteasomal protein expression and vulnerability to 6-Hydroxydopamine (6-OHDA)-induced nigrostriatal dopamine (DA) depletion in rats’ nigrostriatal system. After a 3 month high-fat diet regimen, we switched one group of rats to a low-fat diet for 3 months (HF-LF group), while the other half continued with the high-fat diet (HF group). A chow group was included as a control. Three weeks after unilateral 6-OHDA lesions, HF rats had higher fasting insulin levels and higher Homeostasis model assessment of insulin resistance (HOMA-IR), indicating insulin resistance. HOMA-IR was significantly lower in HF-LF rats than HF rats, indicating that insulin resistance was reversed by switching to a low-fat diet. Compared to the Chow group, the HF group exhibited significantly greater DA depletion in the substantia nigra but not in the striatum. DA depletion did not differ between the HF-LF and HF group. Proteins related to mitochondrial function (such as AMPK, PGC-1α), and to proteasomal function (such as TCF11/Nrf1) were influenced by diet intervention, or by 6-OHDA lesion. Our findings suggest that switching to a low-fat diet reverses the effects of a high-fat diet on systemic insulin resistance, and mitochondrial and proteasomal function in the striatum. Conversely, they suggest that the effects of the high-fat diet on nigrostriatal vulnerability to 6-OHDA-induced DA depletion persist. PMID:25862572

  8. Finite Element Modeling of Balloon Angioplasty by Considering Overstretch of Remnant Non-diseased Tissues in Lesions

    NASA Astrophysics Data System (ADS)

    Gasser, T. Christian; Holzapfel, Gerhard A.

    2007-06-01

    The paper deals with the modeling of balloon angioplasty by considering the balloon-induced overstretch of remnant non-diseased tissues in atherosclerotic arteries. A stenotic artery is modeled as a heterogenous structure composed of adventitia, media and a model plaque, and residual stresses are considered. The constitutive models are able to capture the anisotropic elastic tissue response in addition to the inelastic phenomena associated with tissue stretches beyond the physiological domain. The inelastic model describes the experimentally-observed changes of the wall during balloon inflation, i.e. non-recoverable deformation, and tissue weakening. The contact of the artery with a balloon catheter is simulated by a point-to-surface strategy. The states of deformations and stresses within the artery before, during and after balloon inflation are computed, compared and discussed. The 3D stress states at physiological loading conditions before and after balloon inflation differ significantly, and even compressive normal stresses may occur in the media after dilation.

  9. Generation of mouse models of myeloid malignancy with combinatorial genetic lesions using CRISPR-Cas9 genome editing.

    PubMed

    Heckl, Dirk; Kowalczyk, Monika S; Yudovich, David; Belizaire, Roger; Puram, Rishi V; McConkey, Marie E; Thielke, Anne; Aster, Jon C; Regev, Aviv; Ebert, Benjamin L

    2014-09-01

    Genome sequencing studies have shown that human malignancies often bear mutations in four or more driver genes, but it is difficult to recapitulate this degree of genetic complexity in mouse models using conventional breeding. Here we use the CRISPR-Cas9 system of genome editing to overcome this limitation. By delivering combinations of small guide RNAs (sgRNAs) and Cas9 with a lentiviral vector, we modified up to five genes in a single mouse hematopoietic stem cell (HSC), leading to clonal outgrowth and myeloid malignancy. We thereby generated models of acute myeloid leukemia (AML) with cooperating mutations in genes encoding epigenetic modifiers, transcription factors and mediators of cytokine signaling, recapitulating the combinations of mutations observed in patients. Our results suggest that lentivirus-delivered sgRNA:Cas9 genome editing should be useful to engineer a broad array of in vivo cancer models that better reflect the complexity of human disease.

  10. Generation of mouse models of myeloid malignancy with combinatorial genetic lesions using CRISPR-Cas9 genome editing

    PubMed Central

    Heckl, Dirk; Kowalczyk, Monika S.; Yudovich, David; Belizaire, Roger; Puram, Rishi V.; McConkey, Marie E.; Thielke, Anne; Aster, Jon C.; Regev, Aviv; Ebert, Benjamin L.

    2014-01-01

    Genome sequencing studies have shown that human malignancies often bear mutations in four or more driver genes1, but it is difficult to recapitulate this degree of genetic complexity in mouse models using conventional breeding. Here we use the CRISPR-Cas9 system of genome editing2–4 to overcome this limitation. By delivering combinations of small guide RNAs (sgRNAs) and Cas9 with a lentiviral vector, we modified up to five genes in a single mouse hematopoietic stem cell (HSC), leading to clonal outgrowth and myeloid malignancy. We thereby generated models of acute myeloid leukemia (AML) with cooperating mutations in genes encoding epigenetic modifiers, transcription factors, and mediators of cytokine signaling, recapitulating the combinations of mutations observed in the human disease. Our results suggest that lentivirus-delivered sgRNA:Cas9 genome editing should be useful to engineer a broad array of in vivo cancer models that better reflect the complexity of human disease. PMID:24952903

  11. Imaging Pediatric Vascular Lesions

    PubMed Central

    Nguyen, Tuyet A.; Krakowski, Andrew C.; Naheedy, John H.; Kruk, Peter G.

    2015-01-01

    Vascular anomalies are commonly encountered in pediatric and dermatology practices. Most of these lesions are benign and easy to diagnose based on history and clinical exam alone. However, in some cases the diagnosis may not be clear. This may be of particular concern given that vascular anomalies may occasionally be associated with an underlying syndrome, congenital disease, or serious, life-threatening condition. Defining the type of vascular lesion early and correctly is particularly important to determine the optimal approach to management and treatment of each patient. The care of pediatric patients often requires collaboration from a multitude of specialties including pediatrics, dermatology, plastic surgery, radiology, ophthalmology, and neurology. Although early characterization of vascular lesions is important, consensus guidelines regarding the evaluation and imaging of vascular anomalies does not exist to date. Here, the authors provide an overview of pediatric vascular lesions, current classification systems for characterizing these lesions, the various imaging modalities available, and recommendations for appropriate imaging evaluation. PMID:26705446

  12. The Small Breathing Amplitude at the Upper Lobes Favors the Attraction of Polymorphonuclear Neutrophils to Mycobacterium tuberculosis Lesions and Helps to Understand the Evolution toward Active Disease in An Individual-Based Model

    PubMed Central

    Cardona, Pere-Joan; Prats, Clara

    2016-01-01

    Infection with Mycobacterium tuberculosis (Mtb) can induce two kinds of lesions, namely proliferative and exudative. The former are based on the presence of macrophages with controlled induction of intragranulomatous necrosis, and are even able to stop its physical progression, thus avoiding the induction of active tuberculosis (TB). In contrast, the most significant characteristic of exudative lesions is their massive infiltration with polymorphonuclear neutrophils (PMNs), which favor enlargement of the lesions and extracellular growth of the bacilli. We have built an individual-based model (IBM) (known as “TBPATCH”) using the NetLogo interface to better understand the progression from Mtb infection to TB. We have tested four main factors previously identified as being able to favor the infiltration of Mtb-infected lesions with PMNs, namely the tolerability of infected macrophages to the bacillary load; the capacity to modulate the Th17 response; the breathing amplitude (BAM) (large or small in the lower and upper lobes respectively), which influences bacillary drainage at the alveoli; and the encapsulation of Mtb-infected lesions by the interlobular septae that structure the pulmonary parenchyma into secondary lobes. Overall, although all the factors analyzed play some role, the small BAM is the major factor determining whether Mtb-infected lesions become exudative, and thus induce TB, thereby helping to understand why this usually takes place in the upper lobes. This information will be very useful for the design of future prophylactic and therapeutic approaches against TB. PMID:27065951

  13. Heavy ion-induced lesions in DNA: A theoretical model for the initial induction of DNA strand breaks and chromatin breaks

    SciTech Connect

    Schmidt, J.B.

    1993-01-01

    A theoretical model has been developed and used to calculate yields and spatial distributions of DNA strand breaks resulting from the interactions of heavy ions with chromatin in aqueous systems. The three dimensional spatial distribution of ionizing events has been modeled for charged particles as a function of charge and velocity. Chromatin has been modeled as a 30 nm diameter solenoid of nucleosomal DNA. The Monte Carlo methods used by Chatterjee et al. have been applied to DNA in a chromatin conformation. Refinements to their methods include: a combined treatment of primary and low energy (<2 keV) secondary electron interactions, an improved low energy delta ray model, and the combined simulation of direct energy deposition on the DNA and attack by diffusing hydroxyl radicals. Individual particle tracks are treated independently, which is assumed to be applicable to low fluence irradiations in which multiple particle effects are negligible. Single strand break cross section [open quotes]hooks[close quotes] seen