Abstracts

RATIONALE: Epileptic seizures are a prominent clinical feature of mitochondrial diseases. Mitochondria have vital functions such as energy generation, control of cell death and free radical production. Which of these critical mitochondrial functions contributes to the seizures associated with mitochondrial diseases is unknown. Understanding the role of mitochondrial dysfunction in seizure susceptibility can provide insight into the mechanisms by which seizures are triggered in rare mitochondrial diseases as well as by common metabolic insults such as hypoxia or trauma. Manganese superoxide dismutase (MnSOD) heterozygous knockout (+/-) mice with chronically increased mitochondrial superoxide were used as a model to determine if mitochondrial oxidative stress and resultant dysfunction renders the brain vulnerable to increased seizure activity.
METHODS: Two strains of MnSOD (+/-) mice and their wild type littermates were analyzed for spontaneous, handling-induced and kainate-induced seizures. Spontaneous and handling-induced seizures were analyzed in three age groups of mice (4-5, 9-12 and [gt]18 month old). Seizure severity and incidence was correlated with mitochondrial aconitase inactivation, an index of mitochondrial superoxide production and cell death.
RESULTS: MnSOD (+/-) mice had 50% brain MnSOD activity and 25-30% inactivation mitochondrial aconitase, an index of steady-state superoxide production. Spontaneous and handling-induced seizures were observed in a subset of 9-18 month old MnSOD (+/-) mice. The subset of aged MnSOD (+/-) mice that developed spontaneous seizures also showed increased mitochondrial superoxide production and cell death compared to age-matched MnSOD (+/-) mice that did not develop seizures. Kainate-induced seizures, mitochondrial superoxide production and apoptosis were exacerbated in young MnSOD (+/-) mice.
CONCLUSIONS: These results suggest that mitochondrial oxidative stress may be an important biochemical mechanism that renders the brain vulnerable to epileptic seizures. Furthermore, mitochondrial dysfunction arising from oxidative stress may play a mechanistic role in seizure disorders associated with rare mitochondrial diseases as well as common age-related disorders, that are known to increase mitochondrial oxidative stress.
[Supported by: NIH RO1NS39587 and Parents Against Childhood Epilepsy (P.A.C.E.)]