A Novel Anti-Parkinsonian Agent, Zonisamide, Attenuates MPTP-Induced Neurotoxicity in Mice
A Novel Anti-Parkinsonian Agent, Zonisamide, Attenuates MPTP-Induced Neurotoxicity in Mice
复制标题
DOI：
10.1007/s12031-009-9181-z
复制
发表时间：
2009-09-01
影响因子：
3.1
通讯作者：
Araki, Tsutomu
中科院分区：
文献类型：
--
作者：
Yano, Ryohei;Yokoyama, Hironori;Araki, Tsutomu
唑尼沙胺，一种抗惊厥药物，最近已被证明对帕金森病（PD）发挥有益作用。然而，唑尼沙胺抗帕金森病作用的实际病理生理机制仍不清楚。在这里，我们确切地测试了唑尼沙胺对1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）神经毒性小鼠的神经保护作用。我们观察到，唑尼沙胺衰减MPTP诱导的多巴胺，3，4-二羟基苯乙酸（DOPAC），高香草酸（HVA）消耗在纹状体和减少酪氨酸羟化酶（TH）阳性神经元的损失和胶质细胞酸性蛋白（GFAP）阳性星形胶质细胞在纹状体和黑质5天后。我们的Western blot分析研究也表明唑尼沙胺可以防止MPTP处理后5天纹状体TH蛋白水平的下降和GFAP蛋白水平的升高。另一方面，在本研究中，与溶剂处理组相比，唑尼辛处理1天后正常小鼠纹状体中的纹状体多巴胺、DOPAC和HVA含量没有显著变化。此外，唑尼沙胺产生了显着增加的TH蛋白水平在纹状体1天后，与媒介物治疗组相比。相比之下，唑尼沙胺在1天后显示纹状体中的GFAP蛋白水平与媒介物处理组相比没有显著变化。这些结果表明，抗惊厥药物唑尼沙胺在小鼠PD MPTP模型中具有神经保护作用。我们的研究还表明，唑尼沙胺对多巴胺能细胞损伤的神经保护作用可能是通过提高MPTP处理后多巴胺能系统的TH活性介导的。我们的研究结果表明，唑尼沙胺可能为PD的治疗提供一种新的方法。
Zonisamide, an anti-convulsant drug, has recently been shown to exert beneficial effects in Parkinson's disease (PD). However, actual pathophysiological mechanism underlying the anti-parkinsonian effect of zonisamide remains uncertain. Here we tested exactly the neuroprotective effect of zonisamide against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice. We observed that zonisamide attenuated MPTP-induced dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) depletion in the striatum and reduced the loss of tyrosine hidroxylase (TH) positive neurons and the increase of glial fibrillary acidic protein (GFAP) positive astrocytes in the striatum and substantia nigra after 5 days. Our Western blot analysis study also showed that zonisamide can prevent the decrease of TH protein levels and increase of GFAP protein levels in the striatum 5 days after MPTP treatment. In the present study, on the other hand, zonisaimde treatment showed no significant changes of the striatal dopamine, DOPAC, and HVA content in the striatum of normal mice after 1 day, as compared to the vehicle-treated group. Furthermore, zonisamide produced a significant increase of the TH protein levels in the striatum after 1 day, as compared to vehicle-treated group. In contrast, zonisamide showed no significant changes of the GFAP protein levels in the striatum after 1 day, as compared to vehicle-treated group. These results show that anticonvulsant drug, zonisamide, has the neuroprotective effect in the MPTP model of PD in mice. Our study also demonstrates that the neuroprotective effect of zonisamide against dopaminergic cell damage may be mediated by the elevation of TH activity on dopaminergic system after MPTP treatment in mice. Our findings suggest that zonisamide may offer a new approach for the treatment of PD.