Abstracts

Free iron is an important catalyst for the initiation and propagation of free radical reactions and has been implicated in the pathogenesis of a variety of neuronal disorders. Studies in our laboratory have shown that status epilepticus (SE) results in increased mitochondrial superoxide production. The toxicity of superoxide radical is mediated in part via the release of redox-active iron from cellular iron stores including labile iron-sulfur centers. The role of intracellular iron in mediating seizure-induced brain damage is unknown.The goal of this study was to determine whether kainate-induced SE produces changes in mitochondrial iron levels, whether this correlates with mitochondrial and cellular oxidative stress and if SE-induced oxidative stress can be ameliorated with a cell-permeable iron chelator., Rats were injected with with 12 mg/kg kainic acid and hippocampal mitochondria were analyzed for chelatable (free) iron measured by the bleomycin method 24, 48 and 96 hr post-KA. N,N[prime]-bis (2-hydroxybenzyl) ethylenediamine-N,N[prime]-diacetic acid (HBED), a synthetic lipophilic cell-permeable chelator was used as an iron chelator. Brain HBED concentrations, reduced and oxidized glutathione levels and the oxidative DNA lesion 8-hydroxy-2[apos]-deoxyguanosine (8OHdG/2DG) were measured by an HPLC method coupled with electrochemical detection., Kainate-induced SE in rats resulted in a time-dependent increase in chelatable iron in mitochondrial fractions of the hippocampus. The time-course of the iron changes paralleled the inactivation of mitochondrial aconitase, DNA oxidation (8OHDdG/2DG) and glutathione depletion. Systemically administered HBED, a synthetic iron chelator ameliorated SE-induced changes in chelatable iron and oxidative stress. Furthermore, measurement of brain HBED levels confirmed its penetration in hippocampal tissue., These results suggest a role for mitochondrial iron in the pathogenesis of SE-induced brain damage and iron chelation as a novel therapeutic approach for the treatment of epileptic brain damage., (Supported by NIH R01NS039587.)