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The Journal of Neuroscience, November 5, 2008, 28(45):11550-11556; doi:10.1523/JNEUROSCI.3016-08.2008

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Neurobiology of Disease
Chelation of Mitochondrial Iron Prevents Seizure-Induced Mitochondrial Dysfunction and Neuronal Injury

Li-Ping Liang, Stuart G. Jarrett, and Manisha Patel

Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado 80045

Correspondence should be addressed to Dr. Manisha Patel, Department of Pharmaceutical Sciences, Research Building 2, 12700 East 19th Avenue, Aurora, CO 80045. Email: manisha.patel{at}uchsc.edu

Chelatable iron is an important catalyst for the initiation and propagation of free radical reactions and implicated in the pathogenesis of diverse neuronal disorders. Studies in our laboratory have shown that mitochondria are the principal source of reactive oxygen species production after status epilepticus (SE). We asked whether SE modulates mitochondrial iron levels by two independent methods and whether consequent mitochondrial dysfunction and neuronal injury could be ameliorated with a cell-permeable iron chelator. Kainate-induced SE resulted in a time-dependent increase in chelatable iron in mitochondrial but not cytosolic fractions of the rat hippocampus. Systemically administered N,N'-bis (2-hydroxybenzyl) ethylenediamine-N,N'-diacetic acid (HBED), a synthetic iron chelator, ameliorated SE-induced changes in chelatable iron, mitochondrial oxidative stress (8-hydroxy-2' deoxyguanosine and glutathione depletion), mitochondrial DNA integrity and hippocampal cell loss. Measurement of brain HBED levels after systemic administration confirmed its penetration in hippocampal mitochondria. These results suggest a role for mitochondrial iron in the pathogenesis of SE-induced brain damage and subcellular iron chelation as a novel therapeutic approach for its management.

Key words: kainic acid; epilepsy; oxidative stress; iron chelator; glutathione; mtDNA damage

Received June 30, 2008; revised Aug. 7, 2008; accepted Sept. 23, 2008.

Correspondence should be addressed to Dr. Manisha Patel, Department of Pharmaceutical Sciences, Research Building 2, 12700 East 19th Avenue, Aurora, CO 80045. Email: manisha.patel{at}uchsc.edu






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