Abstracts

Rationale: Reactive oxygen and nitrogen species (ROS/RNS) are mediators of oxidative stress but also function as second messengers in redox signaling. Mitochondrial dysfunction and oxidative stress are consequences of seizure activity but their contributing role to epileptogenesis is largely unknown. The goal of this study was to determine the extent of mitochondrial and tissue redox status and indices of oxidative and nitrosative stress during chemoconvulsant-induced epileptogenesis. Methods: Adult Sprague-Dawley rats were injected with vehicle, kainate or lithium and pilocarpine and chronically monitored with video and EEG for seizure activity for up to 12 weeks. Evidence of altered redox status and reactive species production and damage was measured at different time points during epileptogenesis i.e. shortly after induction of status epilepticus, prior to development of epilepsy (i.e. seizure-free latent period), and during the chronic stages of epilepsy. Results: In the lithium-pilocarpine model a time-dependent increase in hydrogen peroxide (H₂O₂) production that coincided with increased mitochondrial DNA (mtDNA) lesion frequency in the hippocampus was observed during epileptogenesis. In the kainate model a 20-25% increase in nitrite levels was observed shortly after treatment (8h-48h) and the 3-nitrotyrosine/tyrosine ratio increased 2-10-fold throughout all stages of epileptogenesis in the kainate and lithium-pilocarpine models. The mitochondrial redox status measured by reduced coenzyme A and its disulfide with glutathione (CoASH/CoASSG) was decreased 70-80% shortly after kainate and lithium-pilocarpine treatment and remained permanently decreased at all chronic time points. Hippocampal tissue redox status measured by glutathione (GSH) and its disulfide, GSSG, was decreased approximately 60% and remained permanently decreased throughout epileptogenesis in both the kainate and lithium-pilocarpine models. Conclusions: The production of ROS/RNS during the latent period and acute and chronic phases of epileptogenesis and a permanent alteration of mitochondrial and tissue redox status in two independent animal models of temporal lobe epilepsy suggest that redox-dependent processes may contribute to the progression of epileptogenesis.