Abstracts

Rationale: Recently our lab discovered a local hypoxic event that occurs post seizure, an event that we call postictal hypoxia (PIH). In hippocampal tissue, the local vasoconstriction causes oxygen levels to drop below the critical threshold (<10 mm Hg) for approximately one hour, a level associated with poor outcomes. Our lab theorizes that PIH contributes to the development of seizure-induced brain abnormalities and behavioral dysfunction associated with epilepsy. Interestingly, while pharmacological agents can block or attenuate PIH, such as acetaminophen or nifedipine, it is yet to be treated in a clinical setting. This study seeks to investigate the effects of four commonly consumed drugs: nicotine, ethanol, tetrahydrocannabinol (THC), and caffeine, on the onset and recovery of PIH. As persons with epilepsy are likely to have these drugs on board their system during seizures, it’s important to establish the effects of these drugs on PIH. Methods: To test the hypothesis that acute administration of nicotine, ethanol, THC, or caffeine will cause changes in PIH profiles, we utilized the electrical kindling model and a rat animal model. An electrode was placed into the rat ventral hippocampus (CA3), with an oxygen measuring fiber-optic optrode (CA1). Rats were administered vehicle (saline) or low, medium, high doses of nicotine (0.25mg/kg, 0.50mg/kg or 1.00mg/kg), ethanol (0.50g/kg, 1.00g/kg. 2.00g/kg), THC (0.20mg/kg, 1.0mg/kg, or 2.50mg/kg), or caffeine (1.0mg/kg, 5.0mg/kg, 10.0mg/kg, or 15.0mg/kg) via an IP injection, 10 or 30 minutes pre-seizure. The rats’ baseline hippocampal oxygen was measured to determine effects of drugs and establish a clear relationship to the onset of PIH. Following seizure elicitation, rats had their hippocampal oxygen levels continually measured until they returned to their pre-injection baseline. Results: Acute administration (n=5) of nicotine, ethanol, and THC in animals naïve to the drugs caused no significant effect on hippocampal baseline oxygen, PIH onset or recovery, or seizure duration. The three drugs appear to have no effect on PIH, at high, medium, or low doses. However, caffeine administration (n=5) at a high (15.0mg/kg) and medium (10.0mg/kg) dose cause a significant drop in baseline hippocampal pO2, 10.00mg/kg (*p<0.0001), 15.00mg/kg (*p<0.0001), reaching the critical threshold of hypoxia even before the seizure onset. Caffeine also caused a prolongation of PIH, significantly delaying recovery. Conclusions: Our data suggests that acute administration of nicotine, ethanol, and THC had no effect on PIH. However, caffeine appears to be engaging mechanisms that worsen the expression of PIH. The study warrants a future investigation of caffeine’s molecular targets to elucidate the mechanisms involved in PIH. The study highlights the need for a chronic study with caffeine, to determine its effects. Ultimately, these studies should help determine if people with self-generated seizures should avoid consuming caffeine. Funding: CIHR