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