Abstracts

Rationale: There is growing evidence that neuroinflammation represents both a hallmark and a mechanistic factor of chronic epilepsy. For example, both the activation of an inflammatory cytokine Interleukin-1? and its receptor and of Cycloogenase 2 (COX-2), the rate limiting enzyme in prostaglandin synthesis, have been implicated in epileptogenesis following status epilepticus (SE). Previous studies from our group showed acute neuroprotective effects of anti-inflammatory drugs in an animal model of SE. Here we examined whether treatment of SE with anti-inflammatory agents would modify the evolution of post-SE chronic epilepsy. Methods: SE was induced by LiCl and pilocarpine in male Wistar rats at postnatal day 21. One hour prior to SE induction, animals in the first group were injected with vehicle, while those in a second group received a single intraperitoneal injection of the combination of two anti-inflammatory drugs: CAY10404 (10 mg/kg; a COX-2 inhibitor) and human recombinant interleukin-1 receptor antagonist (hrIL-1ra; 100 mg/kg). Animals in a third group received injection of the same drug combination and treatment continued for 10 days. Four months after SE, animals were subjected to a continuous EEG and video monitoring for a period of 3 weeks for the purpose of acquisition and analysis of spontaneous recurrent seizures. At the end of monitoring, animals were euthanized and brains were processed for the analysis of mossy fiber sprouting using Timm staining, using a semi-quantitative scale (0-4 scale). Results: Four months after SE, the incidence of spontaneous seizures were observed in 5 of 7 vehicle-treated rats, 7 of 9 rats with single drug injection, and in 4 of 7 animals with 10-day treatment regimen (p>0.05 Across all groups). Protracted anti-inflammatory drug treatment reduced seizure frequency among animals with spontaneous seizures. Over three weeks of monitoring, vehicle-treated rats exhibited minimal-maximal-median seizures of 1-18-3; those which received a single injection - 2-13-3; and animals with repeated injections - 2-4-2 (p< 0.05 10 days of drug treatment vs. two other groups). The analysis of mossy fiber sprouting showed moderate synaptic reorganization in vehicle-treated rats as well as in animals treated with a single injection of anti-inflammatory drugs (Timm scores 1.35 0.17 and 1.48 0.08, respectively). There was a statistically significant decrease in mossy fiber sprouting in the animals treated with anti-inflammatory drugs for 10 days (Timm score 0.94 0.08; p<0.05 vs. each of two other groups). Conclusions: Protracted pharmacological blockade of interleukin-1? and COX-2 exerted disease-modifying effect in an animal model of post-SE epilepsy. These results support the notion that epilepsy patients may benefit from the introduction of anti-inflammatory agents in their treatment scheme. Acknowledgements. Supported by the Epilepsy Foundation Postdoctoral Training Fellowship (EP) and by the Epilepsy Foundation of America/Patricia L. Nangle Fund research grant (AM).