SOD2 Deficient Mice Exhibit Spontaneous Age-Related Seizures and Increased Susceptibility to Kainate-Induced Oxidative Damage and Apoptosis.
Abstract number :
3.027
Submission category :
Year :
2001
Submission ID :
226
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
M.N. Patel, Ph.D., Medicine, National Jewish Medical & Research Center, Denver, CO; B.J. Day, Ph.D., Medicine, National Jewish Medical & Research Center, Denver, CO; D.C. Wallace, Ph.D., Molecular Medicine, Emory University, Atlanta, GA; L-P. Liang, M.D.,
RATIONALE: We have previously demonstrated that systemic or local administration of kainate selectively inactivates mitochondrial aconitase, a superoxide-sensitive enzyme, at times preceding neuronal death (Neurosci. 101:563, 2000). The objective of this study was two-fold. The first was to determine if mice deficient in mitochondrial manganese superoxide dismutase (SOD2) have increased susceptibility to kainate-induced seizures and excitotoxicity. The second was to study age-related phenotypes resulting from mitochondrial oxidative stress.METHODS: Two strains of SOD2 heterozygous knockout (+/-) mice (C57B6 and CD-1) were administered kainate by systemic or intrahippocampal routes. Mitochondrial aconitase inactivation, an index of superoxide formation, behavioral seizures and cell loss were assessed. Cytochrome C release and TUNEL staining were used to assess apoptosis.RESULTS: Local administration of kainate resulted in mitochondrial aconitase inactivation (superoxide production) and hippocampal cell death, which were exacerbated in SOD2 +/- mice. Systemic administration of kainate resulted in exacerbation of behavioral seizures and hippocampal cell death in both strains of SOD2 +/- mice. Kainate-induced cytochrome C release and TUNEL staining were increased in SOD2 +/- mice. Interestingly, aged SOD2 +/- mice exhibited spontaneous behavioral seizures accompanied by mitochondrial superoxide production and oxidative DNA damage.CONCLUSIONS: These results support a role for mitochondrial superoxide production hippocampal pathology produced by kainate seizures. Furthermore, they suggest that mitochondrial superoxide radicals may play an important role in the pathogenesis of age-related seizure disorders.
Support: Supported by Parents Against Childhood Epilepsy (PACE) and NIH RO1NS39587 to M.N.P.