[The discovery of an antiparkinsonian drug, zonisamide]

We serendipitously found that zonisamide (ZNS), an antiepileptic agent, has beneficial effects on Parkinson disease. A 25 mg once a day of ZNS (200-600 mg/day for epilepsy), significantly improves motor function of advanced patients with Parkinson disease. Its effects maintained at least one year even in patients with advanced stage. It was finally approved as an anti parkinsonian agent in Japan on January 2009. As the mechanism of antiparkinsonian effects of ZNS, we showed that ZNS increases dopamine contents in the striatum by activating dopamine synthesis through increasing the levels of tyrosine hydroxylase (TH) mRNA and TH protein. It moderately inhibits monoamine oxydase (MAO) activity. ZNS shows significant inhibition on T-type Ca++ channel. It may also affect the beneficial effects of ZNS on Parkinson disease. ZNS also showed neuroprotective effects on several parkinsonian models. It markedly inhibited quinoprotein formation and increased the level of glutathione by enhancing the astroglial cystine transport system and/or astroglial proliferation through S100beta. We will verify the neuroprotective effects of ZNS on patients with Parkinson disease and study the factors responsible for the individual difference of the effects of ZNS by using genome wide association study (GWAS) in the near feature.