Project description:Dyskinesias are characterized by abnormal repetitive involuntary movements due to dysfunctional neuronal activity. Although levodopa-induced dyskinesia, characterized by tic-like abnormal involuntary movements, has no clinical treatment for Parkinson’s disease patients, animal studies indicate that Riluzole, which interferes with glutamatergic neurotransmission, can improve the phenotype. The rat model of levodopa-induced dyskinesia is a unilateral lesion with 6-hydroxydopamine in the medial forebrain bundle, followed by the repeated administration of levodopa. The molecular pathomechanism of levodopa-induced dyskinesia is still not deciphered, however implication of epigenetic mechanisms was suggested. In this study, we investigated the striatum for DNA methylation alterations under chronic levodopa treatment with or without co-treatment with Riluzole. Our data show that the lesioned and contralateral striata have nearly identical DNA methylation profiles. Chronic levodopa and levodopa+Riluzole treatments led to DNA methylation loss, particularly outside of promoters, in gene bodies and CpG poor regions. We observed that several genes involved in the levodopa-induced dyskinesia underwent methylation changes. Furthermore, the Riluzole co-treatment, which improved the phenotype, pinpointed specific methylation targets, with more than 20% methylation difference relative to levodopa treatment alone. These findings indicate potential new druggable targets for levodopa-induced dyskinesia.
Project description:The anti-epileptic drug zonisamide is reported to exert beneficial effects in patients with Parkinson's disease. To elucidate the pathophysiological mechanisms underlying the anti-parkinsonism effects of zonisamide, we examined the effect of zonisamide co-administered with levodopa in the striata of rats with 6-hydoroxydopamine hemiparkinsonism by using a DNA microarray for genome-wide gene expression profiling. We found that the expression of some genes related to metabolism and nervous system development and function were upregulated by zonisamide; expression of these genes was downregulated by levodopa. Furthermore, many genes related to the immune system and inflammation were downregulated by zonisamide, and their expression was upregulated by levodopa. These results indicate that zonisamide has a protective effect when co-administered with levodopa.
Project description:The anti-epileptic drug zonisamide is reported to exert beneficial effects in patients with Parkinson's disease. To elucidate the pathophysiological mechanisms underlying the anti-parkinsonism effects of zonisamide, we examined the effect of zonisamide co-administered with levodopa in the striata of rats with 6-hydoroxydopamine hemiparkinsonism by using a DNA microarray for genome-wide gene expression profiling. We found that the expression of some genes related to metabolism and nervous system development and function were upregulated by zonisamide; expression of these genes was downregulated by levodopa. Furthermore, many genes related to the immune system and inflammation were downregulated by zonisamide, and their expression was upregulated by levodopa. These results indicate that zonisamide has a protective effect when co-administered with levodopa. Rats were anesthetized with pentobarbital 240 mg/kg, i.p. and unilateral lesions of the left medial forebrain bundle were made via injection of 8 mg 6-OHDA hydrobromide in 4 ml of sterile saline containing 0.01% ascorbic acid. Motor disturbance was assessed by counting the number of full rotations per min in a cylindrical container of M-OM-^F30 cm diameter at 10-min intervals for the first 60 min after METH (3 mg/kg, i.p.) administration [3]. Behavioral screening was carried out after 2-3 weeks of recovery and animals that performed at least 7 turns/min during METH challenge were certified as hemiparkinsonism rats and included in the study. Seven days after METH challenge, hemiparkinsonism rats were treated with saline, L-DOPA (100 mg/kg, i.p.), or L-DOPA (100 mg/kg, i.p.) and ZNS (50 mg/kg, i.p.) once per day for 7 days. L-DOPA was injected 30 min after benserazide hydrochloride (a peripheral decarboxylase inhibitor). ZNS was injected 30 min after L-DOPA injection. The 4 experimental groups were classified as follows: the non-lesioned side of saline-treated 6-OHDA-injected rats (NL), the lesioned side of saline-treated 6-OHDA-injected rats (SL), the lesioned side of L-DOPA-treated 6-OHDA-injected rats (DL), and the lesioned side of L-DOPA and ZNS-treated 6-OHDA-injected rats (ZDL). Three animals were assigned to each group.
Project description:Male Sprague-Dawley rats were used to establish exhausted-exercise model by motorized rodent treadmill. Yu-Ping-Feng-San at doses of 2.18 g/kg was administrated by gavage before exercise training for 10 consecutive days. Quantitative proteomics was performed for assessing the related mechanism of Yu-Ping-Feng-San.
Project description:We compared differential gene expression between Striatal tissue derived RNA isolated from Chronic Levodopa (L-DOPA) treated (L-Dopa methyl ester plus benserazide were given at 25 mg/kg and 6.25 mg/kg dose) - Parkinsonian and Dyskinetic Rats (LID Rats) for 8 days as compared to Parkinsonian Disease Control Rats (PD Control Rats). The hypothesis tested in the present study was that whether Inflammation has any role in Chronic Levodopa Induced Dyskinesia in Rats of Parkinson's disease model- as compared to Control Rats with Prakinson's disease by performing differential gene expression and pathway analyses.