Abstracts

Rationale: Excessive NMDA receptor activation contributes to traumatic brain injury (TBI)-associated pathophysiology, including neuronal death, motor dysfunction, and posttraumatic epilepsy. The NMDAR is a multimeric ligand-gated cation channel composed of GluN1 and GluN2 (A-D) subunits. Our previous studies in a rat hippocampal slice culture model of posttraumatic epileptogenesis showed that chronic inhibition of GluN2B-containing NMDAR with Ro25, 6981 reduced posttraumatic synaptic reorganization and expression of seizure-like activity. In this study, we examined the ability of Ro25, 6981 to decrease posttraumatic seizure susceptibility in vivo, and improve posttraumatic motor function. Methods: Moderate TBI was induced in male Sprague-Dawley rats using the fluid percussion injury (FPI) model (~22ms, 1.5-2.0 atm). Ro25,6981 or saline was administered 1 hr after TBI i.p (6 mg/kg in saline), and thereafter i.c.v. (0.375 g/ l, 7 l/hr for 21 day followed by 20% reduction in dose/day for 5 day to minimize potential withdrawal effects). After drug delivery, EEG recording screws were implanted over the ipsi- and contralateral neocortex and a bipolar depth electrode placed in the ipsilateral ventral hippocampus. Rats were injected with low dose kainate (KA; 5mg/kg, i.p.) 6 weeks or 3 months after TBI to gauge seizure susceptibility. Video EEG was recorded 30 min prior and 90 min after KA injection. Behavioral tests were conducted 1 day prior, and 1, 3, and 8 days after TBI.Results: Preliminary analyses showed that chronic Ro25,6981 significantly reduced the number and duration of KA-induced electrographic seizures in the hippocampus at 3 months, but not 6 weeks following FPI. Ro25,6981 did not appear to reduce KA-induced seizure number or duration in ipsi- or contralateral neocortex. We are currently measuring behavioral seizure duration and severity. Behavioral analyses of Ro25,6981 effects showed no major change in rat weight (general health) or horizontal distance traveled in the open field test (motor function) in either TBI- or sham-treated rats, but did significantly improve TBI-induced forelimb flexion deficits when rats were tested during Ro25,6981 delivery.Conclusions: Our preliminary analyses suggest that chronic treatment with the GluN2B-selective NMDAR antagonist Ro25, 6981 significantly reduced hippocampal susceptibility to low dose KA-induced seizures and improves posttraumatic motor deficits. Effects of chronic treatment with Ro25, 6981 on KA-induced behavioral seizures remain to be analyzed. Funding supported by: USU Exploratory Research Grant R075PL