Abstracts

Rationale: Neuroprotectin D1 (NPD1), a derivative of docosahexaenoic acid (DHA), is responsible for omega-3 fatty acid-mediated neuroprotection. We found that DHA and NPD1 limit kindling epileptogenesis in rodents. Since the dentate gyrus (DG) region play a critical role during epileptogenesis, we determined the effect of NPD1 on DG hyperexcitabiltiy in vivo related with seizure susceptibility as a consequence of status epilepitcus (SE) in adult male rats. Methods: One week prior to SE induction, bipolar electrode units and a micro-cannula connected with Alzet minipumps loaded with artificial cerebral spinal fluid were implanted in the dorsal right hippocampus and in the third ventricle, respectively. SE was induced by pilocarpine (350 mg/kg, intraperitoneal,ip), and diazepam (10mg/kg, ip) was injected 90 minutes after SE. Then rats were randomly selected for NPD1 (2?l/day) or vehicle delivery into the third ventricle immediately after SE; NPD1 or vehicle was continuously infused for two weeks. Behavioral and hippocampal electrical activities were monitored daily. Hippocampal hyperexcitabitlity was assessed by either DG stimulation with 12 consecutive electrical stimulations or subconvulsive doses of pilocarpine (ip). Evoked behavioral responses and afterdischarges (AD), duration and spikes from DG electrical recordings were quantified in both treated groups. In addition, in other groups of treated rats, a silicon probe (16 channels) was inserted in the DG-CA1 axis one week after SE. Spontaneous epileptiform activity and location, number and duration of burst of high frequency oscillations (HFOs; 200-300 Hz) were analyzed by combined process automation for larger scale LFP analysis. At the end of the experiments, animals were sacrificed and histological procedures were conducted to verify electrode position in the brains. Student s-t test was used for statistical analysis. Results: We observed that post-SE animals displayed limbic seizures with increase in seizure severity during DG stimulations. NPD1-treated rats showed a reduced AD duration and number of evoked spikes, compared with vehicle-treated rats. HFOs were detected in the hippocampus in both treated animals; however, NPD1 significantly reduced HFOs in the DG-CA3 region, compared with vehicle-treated rats. NPD1 increased the latency for evoked seizure onset, compared with vehicle.Conclusions: These results suggest that NPD1 attenuates seizure susceptibility, modulating the DG-CA3 circuitry after SE. DHA-NPD1 lipid signaling is proposed as a target for limiting epileptogenesis