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Ralf Gold - One of the best experts on this subject based on the ideXlab platform.
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l7 laquinimod in the r6 2 mouse model of huntington s disease
Journal of Neurology Neurosurgery and Psychiatry, 2016Co-Authors: Gisa Ellrichmann, Kalliopi Pitarokoili, Liat Hayardeny, Alina Blusch, Oluwaseun Fatoba, Janine Brunner, Carsten Saft, Ralf GoldAbstract:Introduction The transgenic mouse model R6/2 (141–157 CAG repeats) of Huntington’s disease (HD) recapitulates basic pathophysiological similarities of HD and some of its clinical symptoms. Laquinimod as an immunomodulatory orally substance has shown to downregulate astrocytic and microglial activation which are common pathways in neurodegenerative diseases. Methods We investigated the therapeutic efficacy of laquinimod in the R6/2 mouse model treating the animals with different concentrations of laquinimod (0.5/1.5/5/25 mg/kg body weight (bw)) by oral gavage. We explore the neuroprotective potential of laquinimod analysing behaviour (rotarod), weight, survival and histopathological changes after treatment. Results Oral treatment with laquinimod (especially 0.5 mg/kg bw) not only improved motor impairment but also weight course and extended survival in R6/2 mice. R6/2 mice that were treated with 0.5 mg laquinimod showed longer life spans, as determined by Kaplan Meier analysis (p-value = 0.1). Upon analysis of motor performance, Latency-to-Fall values during rotarod testing in R6/2 mice were significantly different at the age of 12 weeks in the 0.5 and 25 mg/kg bw treated group (p* In the histological analysis, laquinimod treatment resulted in preservation of morphologically intact neurons in the motor cortex and striatum as revealed by neuronal marker NeuN and medium spiny neuron’s (MSN’s) marker DARPP-32. Biochemical analysis also showed significant increase in brain derived neurotrophic factor (BDNF) level in the cortical (*p Conclusion together, these findings suggest that treatment with laquinimod could provide a potential therapy for the up-regulation or modulation of neuroprotective pathways in HD.
Himangsu K. Bora - One of the best experts on this subject based on the ideXlab platform.
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Movement Disorder in Copper toxicity Rat Model: Role of Inflammation and Apoptosis in the Corpus Striatum
Neurotoxicity research, 2019Co-Authors: Jayantee Kalita, Vijay Kumar, Usha K. Misra, Himangsu K. BoraAbstract:The pattern of copper (Cu) toxicity in humans is similar to Wilson disease, and they have movement disorders and frequent involvement of corpus striatum. The extent of cell deaths in corpus striatum may be the basis of movement disorder and may be confirmed in the experimental study. to evaluate the extent of apoptosis and glial activation in corpus striatum following Cu toxicity in a rat model, and correlate these with spontaneous locomotor activity (SLA), six male Wistar rats were fed normal saline (group I) and another six were fed copper sulfate 100 mg/kgBWt/daily orally (group II). At 1 month, neurobehavioral studies including SLA, rotarod, and grip strength were done. Corpus striatum was removed and was subjected to glial fibrillary acidic protein (GFAP) and caspase-3 immunohistochemistry. The concentration of tissue Cu, total antioxidant capacity (TAC), glutathione (GSH), malondialdehyde (MDA), and glutamate were measured. Group II rats had higher expression of caspase-3 (Mean ± SEM 32.67 ± 1.46 vs 4.47 ± 1.08; p < 0.01) and GFAP (41.81 ± 1.68 vs 31.82 ± 1.27; p < 0.01) compared with group I. Neurobehavioral studies revealed reduced total distance traveled, time moving, the number of rearing, Latency to Fall on the rotarod, grip strength, and increased resting time compared with group I. The expression of GFAP and caspase-3 correlated with SLA parameters, tissue Cu, GSH, MDA, TAC, and glutamate levels. The impaired locomotor activity in Cu toxicity rats is due to apoptotic and inflammatory-mediated cell death in the corpus striatum because of Cu-mediated oxidative stress and excitotoxicity.
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a study of dose response and organ susceptibility of copper toxicity in a rat model
Journal of Trace Elements in Medicine and Biology, 2015Co-Authors: Vijay Kumar, Jayantee Kalita, U K Misra, Himangsu K. BoraAbstract:Copper (Cu) in higher concentration is toxic and results in various organ dysfunction. We report Cu concentration in liver, brain and kidney in the rat model following chronic exposure of oral copper sulphate at different subtoxic doses and correlate the tissue Cu concentrations with respective organ dysfunction. Fifty-four male wistar rats divided in 3 groups, the control group received saline water and the experimental group (Group-IIA and IIB) received oral copper sulphate in dose of 100 and 200mg/kg Body Weight. At the end of 30 days, 60 days and 90 days of exposure, six rats were sacrificed from each group. The maximum peak force in grip strength, Latency to Fall in rotarod and percentage attention score in Y-maze were significantly reduced in the copper sulphate exposed rats compared to the controls at all time points and these were more marked in Group-IIB compared to Group-IIA. Cu concentration was significantly higher in liver, kidney and brain in the Group-II compared to the Group-I. The Cu concentration was highest in the liver (29 folds) followed by kidney (3 folds) and brain (1.5 folds). Serum ALT, AST and bilirubin correlated with liver Cu, BUN with kidney Cu, and grip strength, rotarod and Y-maze findings correlated with brain Cu level. In rats, chronic oral copper sulphate exposure at subtoxic level results in neurobehavioral abnormality and liver and kidney dysfunctions due to increased Cu concentration in the respective organs. Liver is the most vulnerable organ and copper toxicity increases with increasing dose and duration of exposure.
Jorge M A Oliveira - One of the best experts on this subject based on the ideXlab platform.
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i10 effects of mitoq on behavioural and biochemical phenotypes of a huntington s disease mouse model
Journal of Neurology Neurosurgery and Psychiatry, 2018Co-Authors: Brigida R Pinho, Liliana M Almeida, Michael P. Murphy, Ana I Duarte, Paula M Canas, Paula I Moreira, Jorge M A OliveiraAbstract:Background Huntington’s disease (HD) is caused by mutant huntingtin (mHtt) and presents increased oxidative stress biomarkers, suggesting that aberrant redox signaling is associated with HD pathogenesis. Treatment with MitoQ, a mitochondria-targeted antioxidant, was neuroprotective in other models of neurodegenerative disorders, including ALS, Parkinson’s and Alzheimer’s diseases. Aims Evaluate the efficacy of MitoQ in rescuing HD phenotypes in vivo. Methods MitoQ (500 µM) or vehicle were administered in drinking water to wild-type and R6/2 HD mice (that expresses mHtt exon 1) from 5 weeks. Animal welfare and weight were monitored 2x/week and behaviour assessed at 5–6 and 10–11 weeks. Animals were euthanized at 11 weeks and tissues collected for MitoQ quantification by LC-MS/MS and protein analysis by Western-Blot. Results MitoQ was detected in brain, heart, liver and muscle. R6/2 mice differed from wild-type by presenting paw clasping, reduced body weight gain, decreased grasping strength, open-field rearings, and Latency to Fall from an accelerating rotarod. In the pole test, R6/2 mice required more time to descend a vertical pole than controls, and MitoQ rescued this phenotype. The R6/2 mouse cortex presented increased levels of NMDAR1 and inducible Hsp70, and decreased levels of TFAM, mGLUR2, Hsp40 and mitochondrial Hsp70. The R6/2 mouse liver presented decreased NRF2 and increased SOD2 and protein carbonyls. Treatment with MitoQ reduced NMDAR1 levels in the R6/2 mouse cortex. Conclusions: These results in the accelerated HD R6/2 mouse model suggest that MitoQ has some protective potential (fine motor tasks – pole test), possibly by attenuating excitotoxicity (NMDAR1). Further studies with a slower, more progressive HD model, expressing full-length mHtt, should help clarify the protective potential of MitoQ. Acknowledgements: FCT: P2020-PTDC/NEU-NMC/0412/2014; POCI-01-0145-FEDER-016577; 3599-PPCDT; UID/QUI/50006/2013; SFRH/BPD/102259/2014.
Gisa Ellrichmann - One of the best experts on this subject based on the ideXlab platform.
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l7 laquinimod in the r6 2 mouse model of huntington s disease
Journal of Neurology Neurosurgery and Psychiatry, 2016Co-Authors: Gisa Ellrichmann, Kalliopi Pitarokoili, Liat Hayardeny, Alina Blusch, Oluwaseun Fatoba, Janine Brunner, Carsten Saft, Ralf GoldAbstract:Introduction The transgenic mouse model R6/2 (141–157 CAG repeats) of Huntington’s disease (HD) recapitulates basic pathophysiological similarities of HD and some of its clinical symptoms. Laquinimod as an immunomodulatory orally substance has shown to downregulate astrocytic and microglial activation which are common pathways in neurodegenerative diseases. Methods We investigated the therapeutic efficacy of laquinimod in the R6/2 mouse model treating the animals with different concentrations of laquinimod (0.5/1.5/5/25 mg/kg body weight (bw)) by oral gavage. We explore the neuroprotective potential of laquinimod analysing behaviour (rotarod), weight, survival and histopathological changes after treatment. Results Oral treatment with laquinimod (especially 0.5 mg/kg bw) not only improved motor impairment but also weight course and extended survival in R6/2 mice. R6/2 mice that were treated with 0.5 mg laquinimod showed longer life spans, as determined by Kaplan Meier analysis (p-value = 0.1). Upon analysis of motor performance, Latency-to-Fall values during rotarod testing in R6/2 mice were significantly different at the age of 12 weeks in the 0.5 and 25 mg/kg bw treated group (p* In the histological analysis, laquinimod treatment resulted in preservation of morphologically intact neurons in the motor cortex and striatum as revealed by neuronal marker NeuN and medium spiny neuron’s (MSN’s) marker DARPP-32. Biochemical analysis also showed significant increase in brain derived neurotrophic factor (BDNF) level in the cortical (*p Conclusion together, these findings suggest that treatment with laquinimod could provide a potential therapy for the up-regulation or modulation of neuroprotective pathways in HD.
Meizhu Zheng - One of the best experts on this subject based on the ideXlab platform.
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alkaloids extracted from uncaria rhynchophylla demonstrate neuroprotective effects in mptp induced experimental parkinsonism by regulating the pi3k akt mtor signaling pathway
Journal of Ethnopharmacology, 2021Co-Authors: Meizhu Zheng, Minghui Chen, Chunming Liu, Yajun Fan, Dongfang ShiAbstract:Abstract Ethnopharmacological relevance Alkaloids isolated from Uncaria rhynchophylla (Miq.) Miq. ex Havil. (Rubiaceae), alkaloids (URA) have been used to treat diseases related to the central nervous system, such as Parkinson's disease. Nevertheless, the potential mechanisms underlying their neuroprotective effects are not well-understood. Aim of the study We investigated the neuroprotective effects of URAs in a mouse model of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) and the possible involvement of a molecular signaling pathway. Materials and methods Two typical experiments for animal behavior despair, the spontaneous motor activity and the rotarod experiments, were employed to evaluate the efficacy of URAs in mice with PD symptoms. Dopamine (DA) neurons and their metabolism were evaluated using high-performance liquid chromatography-tandem mass spectrometry. The mechanism of action of the alkaloids was investigated by analyzing their effects on the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mtoR) signaling pathway using western blotting. Results URA treatment effectively improved the behaviors of the mice during the “spontaneous motor activity and Latency to Fall off the rotarod test”. Moreover, URAs demonstrated a protective role in dopaminergic neurons by increasing the expression of the dopamine transporter and tyrosine hydroxylase, which were supposed to be reduced by MPTP, inhibiting dopamine turnover, and changing dopamine and relevant metabolites. In addition to its association with the increase in the Bcl-2/Bad ratio, URA treatment also attenuated the cleaved caspase-3 level and enhanced the phosphorylation of Akt and mtoR. Conclusion These findings provide evidence that URA can effectively protect neurons from the neurotoxicity caused by MPTP in mouse models of PD by up-regulating the PI3K/Akt/mtoR signaling pathway.
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neuroprotection by paeoniflorin in the mptp mouse model of parkinson s disease
Neuropharmacology, 2017Co-Authors: Meizhu Zheng, Yuchi ZhangAbstract:Abstract Paeoniflorin (PF) is a major bioactive ingredient in Radix Paeonia alba roots that has low toxicity and has been shown to have neuroprotective effects. Our in vitro experiments suggested that PF affords a significant neuroprotective effect against MPP+-induced damage and apoptosis in PC12 cells through Bcl-2/Bax/caspase-3 pathway. The objectives of the present study were to explore the potential neuroprotective effect of PF in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-treated mouse model of Parkinson's disease (PD). Our results demonstrated that PF treatment ameliorated the behavioral deficits of “in spontaneous motor activity and Latency to Fall of the rotarod test”, and reduced dopaminergic cell loss that were induced by MPTP in a dose-dependent manner in an in vivo model of PD. In addition, we found that treatment of PF protected dopaminergic neurons by preventing MPTP-induced decreases in striatal and substantia nigra dopaminergic transporter (DAT) and tyrosine hydroxylase (TH) protein levels, and by changing dopamine catabolism and inhibiting dopamine turnover. Furthermore, it was also associated with up-regulation of the Bcl-2/BAD ratio, and inhibition of the activation of caspase-9 and caspase-3. These results showed that PF promoted dopamine neuron survival in vivo due to the MAO-B inhibition, and the PI3K/Akt signaling pathway may have mediated the protection of PF against MPTP, suggesting that PF treatment might represent a neuroprotective treatment for PD.
