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首页> 外文期刊>Experimental Neurology >Electrophysiological actions of zonisamide on striatal neurons: Selective neuroprotection against complex I mitochondrial dysfunction.
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Electrophysiological actions of zonisamide on striatal neurons: Selective neuroprotection against complex I mitochondrial dysfunction.

机译：zonisamide对纹状体神经元的电生理作用：针对复杂I线粒体功能障碍的选择性神经保护。

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Since the anti-epileptic drug Zonisamide (ZNS) seems to exert beneficial effects in Parkinson's (PD) disease, we have investigated the electrophysiological effects of ZNS in a rat corticostriatal slice preparation. ZNS affected neither the resting membrane potential nor the input resistance of the putative striatal spiny neurons. In contrast, this drug depressed in a dose-dependent manner the current-evoked repetitive firing discharge with a EC(50) value of 16.38 microM. ZNS also reduced the amplitude of glutamatergic excitatory postsynaptic potentials (EPSPs) with a EC(50) value of 32.5 microM. Reduced activity of the mitochondrial respiratory chain, particularly complex I and II, is implicated in the pathophysiology of PD and Huntington's (HD) diseases, respectively. Thus, ZNS was also tested in two different in vitro neurotoxic models obtained by acutely exposing corticostriatal slices either to rotenone, a selective inhibitor of mitochondrial complex I, or to 3-nitropropionic acid (3-NP), an inhibitor of complex II. Additionally, we also investigated the effect of ZNS in an in vitro model of brain ischemia. Interestingly, low concentrations of ZNS (0.3, 1, 3 and 10 microM) significantly reduced the rotenone-induced toxicity protecting striatal slices from the irreversible loss of corticostriatal field potential (FP) amplitude via a GABA-mediated mechanism. Conversely, this drug showed no protection against 3-NP and ischemia-induced toxicity. Our data indicate that relatively high doses of ZNS are required to decrease striatal neuronal excitability while low concentrations of this drug are sufficient to protect striatum against mitochondrial impairment suggesting its possible use in the therapy of basal ganglia neurodegenerative diseases.
机译：由于抗癫痫药Zonisamide（ZNS）似乎在帕金森氏病（PD）中发挥了有益的作用，因此我们研究了ZNS在大鼠皮层皮质切片制剂中的电生理作用。 ZNS既不影响静息膜电位，也不影响假定的纹状体棘神经元的输入阻力。相反，该药物以剂量依赖性方式抑制了当前引起的重复放电，其EC（50）值为16.38 microM。 ZNS还以32.5 microM的EC（50）值降低了谷氨酸能兴奋性突触后电位（EPSPs）的幅度。线粒体呼吸链，特别是复合物I和II的活性降低，分别与PD和亨廷顿舞蹈病（HD）的病理生理有关。因此，还在两个不同的体外神经毒性模型中对ZNS进行了测试，这些模型通过将皮质类固醇片急性暴露于线粒体复合物I的选择性抑制剂鱼藤酮或复合物II的抑制剂3-硝基丙酸（3-NP）中获得。此外，我们还研究了ZNS在体外脑缺血模型中的作用。有趣的是，低浓度的ZNS（0.3、1、3和10 microM）通过GABA介导的机制显着降低了鱼藤酮诱导的毒性，保护了纹状体切片免受不可逆的皮质骨场电位（FP）振幅的损失。相反，该药物对3-NP和缺血诱导的毒性没有保护作用。我们的数据表明，需要较低剂量的ZNS来降低纹状体神经元的兴奋性，而低浓度的该药足以保护纹状体免受线粒体损害，表明其可能用于治疗基底节神经退行性疾病。

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