Mitochondria as potential trigger for neuronal cell death observed in epilepsy

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Prolonged seizures (status epilepticus) induced in experimental models by kainic acid or pilocarpine are known to activate programmed cell death mechanisms. This cell death observed also in human epilepsy is one of the most important aspects of epileptogenesis. In the hippocampus the loss of CA1, CA3 and CA4 pyramidal neurons, with relative sparing of the granular neurons of the dentate gyrus and some types of interneurones, is the histopathological hallmark of Ammon’s horn sclerosis. The mechanism that underlies this regional selectivity remains to be elucidated, some data point to differential expression of proaportotic and antiapoptotic genes. The probably most important factor preceding neuronal cell death after status epilepticus is the increased level of reactive oxygen species observed in various models of experimental epilepsy – kainate-induced hippocampal damage, pilocarpine treatment and low Mg²⁺-induced epileptiform activity in brain slices and slice cultures. Mitochondria are known to be the most important source of production of reactive oxygen species. Moreover, increased production of reactive oxygen species is a feature of partially respiratory chain-inhibited mitochondria and it is noteworthy to mention in this context that a severe impairment of respiratory chain complex I activity is present in the areas of epileptogenesis - in CA3 neurons of the hippocampus from patients with Ammon’s horn sclerosis and in the parahippocampal gyrus of patients with parahippocampal lesions. Similar observations we made recently in the vulnerable CA1 and CA3 hippocampal subfields of pilocarpine-treated chronic epileptic rats. As potential cause of the detected respiratory chain impairment we could delineate a decrease of the mtDNA copy number. This finding indicates a possible substantial role of oxygen radicals in causing neuronal mtDNA damage occurring selectively in the areas of epileptogenesis.