Effect of zonisamide co-administration with levodopa on global gene expression in the striata of rats with Parkinson’s disease

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Abstract

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.

Highlights

► Long-term use of levodopa has been reported to have adverse effects. ► Zonisamide (ZNS) has beneficial effects for patients with Parkinson’s disease (PD). ► We aimed to elucidate the mechanism underlying ZNS’s protective effects against PD. ► Our results indicated neuroprotective effects of ZNS co-administered with levodopa.

Introduction

Parkinson’s disease (PD) is a chronic progressive neurological disorder with increasing incidence in the elderly population. Currently, the standard of care for PD patients is levodopa (l-DOPA), which only provides symptomatic relief early in the course of treatment, and whose long-term use is limited by side effects. The development of drugs that can overcome these shortcomings is required for the efficacious treatment of PD patients.

The anti-epileptic drug zonisamide (ZNS) has been reported to improve motor functions in patients [1]; its clinical efficacy in the treatment of PD symptoms is supported by the results of a randomized double-blind study [2]. However, the actual pathophysiological mechanism underlying the anti-parkinsonism effects of ZNS remains uncertain. The present study aimed to uncover the effect of ZNS co-administered with l-DOPA on gene expression in the striata of rats with 6-hydoroxydopamine (6-OHDA)-induced hemiparkinsonism using a DNA microarray for genome-wide gene expression profiling.

Section snippets

Materials

l-DOPA and benserazide hydrochloride were purchased from Roche, Japan. 6-OHDA hydrobromide were purchased from Sigma, USA, and methamphetamine (METH) and ZNS were obtained from Dainippon-Sumitomo Pharmaceutical, Japan. All other chemicals used were analytical grade.

Animals

Male Wistar rats were provided by Kyudo Inc. Ltd. and were kept at a controlled ambient temperature of 23 ± 1 °C and 50% ± 10% relative humidity. The Committee for Ethics in Animal Experiments, Faculty of Medicine, University of Miyazaki,

Analysis of the effect of 6-OHDA lesion on gene expression in the striatum

To identify the genes differentially expressed between the striata of the non-lesioned side and the lesioned side of saline-treated 6-OHDA injected animals, probes were selected for statistical analysis if they had flags “detected” in all samples of NL, SL, or both. A total of 20,366 out of 30,507 probes on the array were selected in this manner. These data were compared using t-tests, with a significance level set at p < 0.05.

The remaining probes were selected using the criterion of at least a

Discussion

In this study, we used 6-OHDA hemiparkinsonism rats to examine the effects of DA denervation and l-DOPA administration, and the effects of DA denervation and l-DOPA and ZNS co-administration on gene expression in the striatum using DNA microarray genome-wide gene expression profiling.

In the comparison between the DA-denervated side and the non-denervated side of the striata, we found significant upregulation of several PD-related genes including Fst, Nmu, and Tac3, and significant

Acknowledgments

ZNS was kindly provided by Dainippon-Sumitomo Pharmaceutical, Japan. This work was supported by internal funding from Hamamatsu University School of Medicine.

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