Abstracts

Rationale: We previously determined that following the cessation of brief focal seizures, a long-lasting severe hypoperfusion/hypoxic event occurs in the brain regions involved in the seizure. We reasoned that there may also be changes in local oxygen levels during and following focal status epilepticus (SE). An epileptic state can be induced in rodents either by the infusion of a chemoconvulsant or prolonged electrical stimulation of the perforant pathways. We aimed to compare both models with the goal to prevent generalized SE, limit lethality, and ultimately produce self-generating seizures whilst recording oxygen levels in the hippocampus. We hypothesized that; 1) during SE there would be drastic increases in hippocampal oxygen levels and 2) following the termination of SE spontaneous hippocampal seizures would produce episodes of postictal hypoxia. Methods: A dose of urethane (0.833mg/kg) was administered subcutaneously to induce sedation before the induction of SE to sequester electrical activity and prevent generalized SE. In the intrahippocampal kainic acid model, kainic acid (3.5mg/mL) was infused directly into the rat ventral hippocampus over a period of 4 minutes. In the electrical stimulation model, a 24-hour bilateral stimulation protocol of the perforant pathways was used (2Hz continuous paired-pulse with a 10-second 20Hz train once per minute). In both groups oxygen levels and EEG were recorded in the dorsal hippocampus throughout the first 24 hours. Immediately after the 24-hour induction period, rats were transferred to a 24/7 video-EEG monitoring unit. Hippocampal EEG was monitored continuously for 4 to 6 weeks. Results: We observed that the infusion of kainic acid (n=4) resulted in a rapid-onset status epilepticus which usually lasted for 2 to 4 hours. Oxygen levels in the hippocampus remained in the normoxic range (18-35 mm Hg) during this period, except for during bouts of seizure activity which would result in mild hyperoxia (>40 mm Hg). Twenty-four hours of stimulation to the perforant pathway (n=8) resulted in continuous severe hyperoxia (>50 mm Hg) in the hippocampus for the duration of stimulation. Following epilepsy induction, both groups displayed epileptiform or “seizure-like” activity within 5 days. Over time, the epileptiform activity developed into self-generating behavioural seizures. We also observed that self-generating seizures resulted in severe postictal hypoxia (<10 mm Hg) in the hippocampus. Conclusions: This study advances our current understanding of epilepsy models in relation to local oxygen levels and may lead to the development of new treatments or preventative strategies for people with epilepsy. Funding: CIHR, AIHS