Abstracts

Rationale: Sudden Unexpected Death in Epilepsy (SUDEP) is where someone with epilepsy, who is otherwise healthy dies suddenly with no known cause.  Our lab recently discovered a COX-2 mediated period of severe hypoxia, which can cause cellular and behavioural dysfunction, during and following a seizure in the brain regions involved in the seizure. We hypothesize that SUDEP occurs when seizure activity propagates to brainstem breathing centers causing severe local hypoxia leading to dysfunction of brainstem breathing centers, breathing failure, and death. Further, that inhibition of COX-2 activity could prevent this severe hypoxia. Methods: Male C57 BL/6J mice were treated acutely with either (15, 50, & 100 mg/kg, n=5/group) ibuprofen or vehicle (n=5/group), intraperitoneally 30 minutes prior to intra-hippocampal kainic acid (KA) administration (1.4µg in 0.4µl). Brainstem and hippocampal EEG and tissue oxygen levels were recorded with chronically implanted probes. Breathing and heart rate were recorded through a chronic bipolar electrode in the diaphragm. Results: In both groups, epileptiform activity propagated to the brainstem from the hippocampus, leading to severe hypoxia in brainstem breathing centers. Vehicle-treated mice died during stage 5 seizures 45 minutes after KA administration, with terminal apnea occurring several minutes prior to cardiac arrest in all animals. Ibuprofen-pre-treatment prevented severe hypoxia and extend life in a dose dependent manner. Mice that received 15 mg/kg ibuprofen were indiscernible between controls, dying 45 minutes after KA. Mice that were treated with 50 mg/kg ibuprofen lived 5 hours after KA administration (p<0.0001), and mice that received 100 mg/kg ibuprofen lived 8 hours after KA administration (p<0.0001).  Conclusions: Our model is consistent with previous studies in persons with epilepsy: breathing failure is the precipitating cause of seizure-induced death. The severe local hypoxia observed in brainstem breathing centers immediately prior to apnea and death indicates seizure- induced brainstem hypoxia may be involved SUDEP. Moreover, severe hypoxia and death was prevented prior to the metabolism of the non-selective COX-2 inhibitor ibuprofen. Funding: CIHR, SUDEP Aware, Hotchkiss Brain Institute