Kudin Alexei P, Debska-Vielhaber Grazyna, Vielhaber Stefan, Elger Christian E, Kunz Wolfram S
Department of Epileptology, University of Bonn Medical Center, Bonn, Germany.
Epilepsia. 2004 Dec;45(12):1478-87. doi: 10.1111/j.0013-9580.2004.13504.x.
For the antiepileptic drug (AED) topiramate (TPM), neuroprotective effects have been reported in models of focal cerebral ischemia and experimental status epilepticus, but the putative mechanism of action has remained elusive.
We studied the effects of TPM on mitochondrial function in the pilocarpine rat model of chronic epilepsy and in isolated mitochondria from rat brain.
TPM treatment in status epilepticus at doses ranging from 20 to 100 mg/kg considerably improved the survival of rats and improved CA1 and CA3 pyramidal cell survival in a dose-dependent manner. This treatment increased the activity of mitochondrial respiratory chain complex I in the CA1 and CA3 pyramidal subfields and resulted in lower seizure frequencies in chronic epileptic rats. In vitro investigations of the action of TPM on isolated rat brain mitochondria ruled out any direct effects of the drug on mitochondrial oxidative phosphorylation but revealed a protective effect on hippocampal mitochondria against an external calcium challenge. This can explain its observed neuroprotective action in the concentration range tested. The in vitro effects of TPM on the calcium handling of isolated brain mitochondria was found to be comparable to the action of cyclosporin A.
The neuroprotective action of TPM seems to be directly related to its inhibitory effect on the mitochondrial permeability transition pore.
对于抗癫痫药物（AED）托吡酯（TPM），在局灶性脑缺血模型和实验性癫痫持续状态模型中已报道有神经保护作用，但其假定的作用机制仍不清楚。
我们在毛果芸香碱诱导的慢性癫痫大鼠模型以及大鼠脑分离线粒体中研究了TPM对线粒体功能的影响。
癫痫持续状态下，20至100mg/kg剂量的TPM治疗显著提高了大鼠的存活率，并以剂量依赖性方式改善了CA1和CA3锥体细胞的存活。该治疗增加了CA1和CA3锥体亚区线粒体呼吸链复合体I的活性，并降低了慢性癫痫大鼠的癫痫发作频率。对TPM作用于分离的大鼠脑线粒体的体外研究排除了该药物对线粒体氧化磷酸化的任何直接影响，但揭示了对海马线粒体抵抗外部钙挑战的保护作用。这可以解释在所测试的浓度范围内观察到的其神经保护作用。发现TPM对分离的脑线粒体钙处理的体外作用与环孢素A的作用相当。
TPM的神经保护作用似乎与其对线粒体通透性转换孔的抑制作用直接相关。
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