Chelation of mitochondrial iron prevents seizure-induced mitochondrial dysfunction and neuronal injury.
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.
Liang
Li-Ping
LP
Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado 80045, USA.
Jarrett
Stuart G
SG
Patel
Manisha
M
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001761:Bleomycin; D002614:Chelating Agents / Q000008:administration & dosage*; D003124:Colorimetry / Q000379:methods; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004492:Edetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D005452:Fluoresceins; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology / Q000648:ultrastructure; D007501:Iron / Q000378:metabolism*; D007608:Kainic Acid; D008297:Male; D028361:Mitochondrial Diseases / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D009930:Organic Chemicals; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D013347:Subcellular Fractions / Q000187:drug effects / Q000473:pathology; D013997:Time Factors
D002614:Chelating Agents; D004272:DNA, Mitochondrial; D005452:Fluoresceins; D009930:Organic Chemicals; C435731:fluoro jade; D001761:Bleomycin; C037740:N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid; D004492:Edetic Acid; D007501:Iron; D005978:Glutathione; D007608:Kainic Acid; D019803:Glutathione Disulfide