Effects of zonisamide on experimental tremors in rats

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Abstract

Objects

To study the effect of zonisamide on experimental tremors in rats.

Methods

Effect of zonisamide on harmaline- or oxotreorine-induced tremors, and tacrine-induced tremulous jaw movements (TJMs) was studied.

Results

Zonisamide significantly suppressed both harmaline- and oxotremorine-induced tremors dose-dependently. Zonisamide also significantly suppressed tacrine-induced TJMs, and this effect was not lost under conditions of monoamine-depletion or dopaminergic blockade.

Conclusion

The anti-tremor effects of zonisamide may be achieved by a non-dopaminergic mechanism. Since it effectively suppressed tremors that are based on different kinds of tremors, we propose a novel perspective of clinical potential of zonisamide as a non-specific, anti-tremor drug.

Introduction

Zonisamide is a widely used anti-epileptic drug. Recently, Murata et al. [1] reported a novel clinical efficacy of zonisamide, suggesting that it may improve motor functions in patients with Parkinson's disease (PD). Since then, attention has been paid to its therapeutic potential in treating PD, and its clinical efficacies in the treatment of PD symptoms are supported by a recent randomized, double-blind study [2]. However, the actual pathophysiological mechanism underlying the anti-parkinsonian effects of zonisamide remains uncertain. Based on preliminary clinical observations on the effects of zonisamide on both parkinsonian and essential tremors [3], [4], [5], [6], we have taken particular note of the possibility that zonisamide may have an anti-tremor effect. Thus, the present study aimed to study the effect of zonisamide on experimental tremors in rats. In the present study, three representative tremor models were used: harmaline- or oxotremorine-induced tremors, and cholinomimetic-induced tremulous jaw movements (TJMs), which have been proposed as a rodent model of pharmacologically induced parkinsonian tremor [7].

Section snippets

Animals

The subjects were adult male Sprague–Dawley rats (N=36), weighing 250–380 g at the time of experiments. The animals were housed in cages and kept in a temperature-controlled room (23±1 °C) under a 12 h/12 h light/dark cycle. Food and tap water were freely accessible. The experimental protocols were approved by Wakayama Medical University's Animal Care and Use Committee.

Assessment of tremors

First, the effect of zonisamide on harmaline- or oxotreorine-induced tremors was studied. Thirty minutes before the administration

Results

Zonisamide significantly suppressed both harmaline- and oxotremorine-induced tremors in rats, and the effects were found to be dose-dependent (Fig. 1A, B). Rats treated by a high dose of zonisamide (50 mg/kg) were under mild sedation.

Before examining the effects of zonisamde on tacrine-induced TJMs, to confirm that anti-parkinsonian drugs are effective at suppressing tacrine-induced TJMs, we studied the effect of levodopa on tacrine-induced TJMs. As demonstrated in Fig. 2a, a high dose (20 mg/kg)

Discussion

The present study revealed that zonisamide suppressed both harmaline- and oxotremorine-induced tremors in rats. In addition, zonisamide effectively suppressed tacrine-induced TJMs in rats, and this effect was not lost in rats with either monoamine-depletion induced by reserpine or complete blockade of dopaminergic neurotransmission by haloperidol. Thus, zonisamide may be capable of suppressing various types of tremor.

The anti-tremor effects of zonisamide appear likely not to be the result of

Acknowledgements

We gratefully acknowledge Ms. Tomomi Kubo and Mrs. Ai Suzuki for technical assistance. This study was partly supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (17590889, H.M.).

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