Murata M
Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Curr Pharm Des. 2004;10(6):687-93. doi: 10.2174/1381612043453180.
We found that zonisamide (ZNS) has beneficial effects on Parkinson's disease (PD). ZNS is originally synthesized in Japan and has been used for over 10 years to treat intractable epilepsy. We administered 300 mg of ZNS to a patient with PD who incidentally had convulsive attacks. The attacks disappeared and, surprisingly, the parkinsonian symptoms improved dramatically. An open trial of ZNS (given in addition to their anti-PD drugs) in advanced PD patients clearly showed the lessening of symptoms, especially wearing-off. Although the effects gradually decreased after 1.5 years, more than 30% improvement of UPDRS total score was maintained up to 3 years. Nation-wide double-blind controlled study confirmed that the small dose (50mg/day) of ZNS improved all the cardinal symptoms of PD. As for its mechanism, we showed that ZNS increases dopamine contents in the striatum by activating dopamine synthesis and the level of mRNA of tyrosine hydroxylase (TH) prior to that of TH protein. ZNS moderately inhibits monoamine oxydase (MAO) B. It has no effects on dopamine receptors, dopamine transporter or dopamine release. ZNS has no direct effects on glutamate receptors, adenosine receptors, or serotonergic system, which have been suggested to be effective points of anti-PD drug other than dopamine system. Therefore, it is suggested that the activation of dopamine synthesis and the moderate level of MAOB inhibition are main mechanisms of ZNS effects on PD. ZNS has significant effects on T-type Ca(++) channels and oxidative stress. They may also affect the beneficial action of ZNS on PD.
我们发现唑尼沙胺（ZNS）对帕金森病（PD）具有有益作用。ZNS最初在日本合成，已用于治疗难治性癫痫超过10年。我们给一名偶然患有惊厥发作的PD患者服用了300毫克ZNS。发作消失了，令人惊讶的是，帕金森症状也显著改善。对晚期PD患者进行的ZNS开放试验（除抗PD药物外给予）清楚地显示症状减轻，尤其是剂末现象。尽管1.5年后效果逐渐降低，但UPDRS总分仍保持超过30%的改善长达3年。全国性双盲对照研究证实，小剂量（50毫克/天）的ZNS改善了PD的所有主要症状。至于其作用机制，我们发现ZNS通过激活多巴胺合成以及在酪氨酸羟化酶（TH）蛋白水平之前提高TH的mRNA水平来增加纹状体中的多巴胺含量。ZNS适度抑制单胺氧化酶（MAO）B。它对多巴胺受体、多巴胺转运体或多巴胺释放没有影响。ZNS对谷氨酸受体、腺苷受体或血清素能系统没有直接影响，而这些系统已被认为是除多巴胺系统外抗PD药物的有效作用点。因此，提示多巴胺合成的激活和MAOB的适度抑制是ZNS对PD产生作用的主要机制。ZNS对T型钙通道和氧化应激有显著影响。它们也可能影响ZNS对PD的有益作用。
