Abstracts

Rationale: Metabolic and redox mechanisms are emerging as an important area of investigation in the pathogenesis of temporal lobe epilepsy (TLE). TLE is the most common form of acquired epilepsy in which injury activates a series of cellular and molecular changes that ultimately lead to the development of a hyper-excitable state i.e. epileptogenesis. Whereas alterations in mitochondrial redox status and individual mitochondrial and/or glycolytic enzymes have been demonstrated in human and/or experimental TLE, demonstration of unequivocal deficits in authentic mitochondrial function i.e. oxygen consumption in a model of TLE is lacking. We asked if 1) alterations in mitochondrial oxidative phosphorylation and/or glycolytic rates occurred in experimental TLE and 2) whether reactive oxygen species (ROS) mediated these alterations. Methods: Real-time analysis of oxygen consumption rates (OCR) and glycolytic rates (ECAR) were assessed in isolated synaptosomes from the hippocampus of rats at various times (3h, 8h, 16h, 24h, 48h, 1wk, 3wk and 6wk) in the kainate or pilocarpine models of TLE using an extracellular flux analyzer (Seahorse Bioscience, North Billerica, MA, USA). Systemic administration of a metalloporphyrin catalytic antioxidant in conjunction with hippocampal oxidative stress markers was used to determine if oxidative stress drives metabolic changes.Results: In both kainate and pilocarpine models, decreases in mitochondrial OCR and ECAR were observed at time points coincident with increased oxidative stress i.e. decreased ratio of reduced to oxidized glutathione (GSH/GSSG) and increased levels of 3-nitrotyrosine. Systemic administration of the catalytic antioxidant attenuated deficits in mitochondrial OCR as well as alterations in redox status and 3-nitrotyrosine levels observed at an early time-point i.e. 24h post status epilepticus.Conclusions: These data demonstrate profound deficits in mitochondrial oxygen consumption i.e. evidence for mitochondrial dysfunction in experimental TLE. These changes are driven, at least during an early time point by increased oxidative stress. The data suggests that targeting mitochondrial and glycolytic dysfunction may represent important avenues for disease modification in TLE.