Abstracts

Rationale: Adult neurogenesis continues throughout life in the dentate gyrus of most mammalian species. The number of new neurons that are produced is regulated by many factors. Numerous studies have demonstrated that there is an increase in adult neurogenesis following seizure activity but the exact mechanism behind this is not clear. We have recently discovered in our lab that a severe hypoperfusion/hypoxic event occurs in the brain region involved with the seizure activity. This phenomenon is mediated by the cyclooxygenase-2 enzyme (COX-2) and can result in memory/learning and behavioural deficits. Because the neurogenic niche is highly dependent on vascularization, we hypothesized that the increase in neurogenesis observed following seizure is linked to the postictal hypoxic event. Inhibition of the COX-2 enzyme using ibuprofen can prevent postictal hypoxia and thus may attenuate the increase in neurogenesis. Methods: Male Long Evan rats were implanted with a bipolar electrode and optrode into the ventral and dorsal hippocampus, respectively. Seizures were electrically evoked through the bipolar electrodes while tissue oxygen levels were measured using the optrode. Animals were administered either DMSO as a vehicle or 20 mg/kg ibuprofen intraperioteneally 30 minutes prior to electrical stimulation once a day for a total of 30 sessions. Following the kindling protocol animals were perfused and brain sections were immunohistochemically labeled for doublecortin (DCX), a marker of immature neurons. Results: Vehicle treated animals showed a decrease in oxygen levels below the severe hypoxic threshold (<10 mmHg). This decrease in oxygen was attenuated in animals that were pre-treated with ibuprofen. Ibuprofen treatment had no significant effect on seizure duration.  As expected, DCX density was significantly increased in vehicle treated seizure animals in comparison to the vehicle treated control group (p<0.0432). However, no significant difference was observed between control DMSO and control ibuprofen animals or control DMSO and animals administered ibuprofen with elicited seizures. Conclusions: This data is consistent with our previous findings that seizures induce postictal hypoxia which is prevented with ibuprofen treatment.  We also confirm that that there is an increase in neurogenesis following seizures. Interestingly, our results demonstrate that pre-treatment with ibuprofen attenuates the increase in neurogenesis. This suggests that seizure-induced neurogenesis is most likely dependent on postictal hypoxia and not electrical seizure activity. Funding: CIHR, University of Calgary