Traumatic brain injuries (TBIs) are common amongst military personnel and in civilian populations, and there are currently no FDAapproved treatments. Over 6% of all epilepsies are due to TBIs. Throughout the CNS, voltage-gated "M-type" K+ ion channels play dominant roles in controlling neuronal firing and excitability; consequently, M-channel "openers" such as retigabine, have emerged as novel anti-convulsants. Astrocytes also play major roles in reducing abnormal neuronal electrical activity by activating energy-dependent transport mechanisms. TBI-induced seizures are accompanied by pronounced cytotoxic and vasogenic edema. Our research relies on identifying novel molecular targets to reduce acquired epilepsies and associated co-morbidities that develop after TBIs. Mice were subjected to controlled closed-cortical impacts (CCCI), with administration of retigabine (i.p. 1mg/kg), the P2Y1-receptor agonist (MRS2365, (i.p. .85mg/kg) both drugs or only vehicle, within 30 minutes of TBI, or a smaller cohort of sham TBI. After 24 hours, mice were implanted with EEG electrodes and seizure activity recorded the following day. Six days post-TBI, mice were given the chemoconvulstant, pilocarpine (i.p. 75mg/kg) at 30-minute intervals to induce subsequent seizures as a test for alterations in seizure susceptibility. Methylscopolamine (1mg/kg) was administered i.p. 30 minutes before application of pilocarpine to minimize peripheral cholinergic effects and mortality. Seizure susceptibility was assayed 24 hours after 3 injections of pilocarpine. Seizures were monitored by behavioral video and EEG recording. Our preliminary data show that administration of both retigabine and MRS2365 in combination to mice within 30min of TBI decreases subsequent post- TBI seizures as well as seizure susceptibility. Thus, no spontaneous post-TBI seizures were detected after TBI in retigabine treated animals and the percentage of mice displaying post-TBI seizures was decreased in both combinational and MRS2365 groups vs. vehicle controls. This approach has the potential to reduce the incidence of seizures after a TBI. We will present further preliminary data on mice undergoing CCCI-induced TBIs and likely also blast-TBIs, for this meeting. [ABSTRACT FROM AUTHOR]