FELBAMATE PROTECTS CA1 NEURONS FROM APOPTOSIS IN A GERBIL MODEL OF GLOBAL-ISCHEMIA

Background and Purpose Felbamate, a novel anticonvulsant that binds to the glycine site of the N-methyl-D-aspartate receptor, has been shown to have neuroprotective properties in vitro and in vivo. In a rat pup model of hypoxia-ischemia, felbamate selectively reduced delayed deat h in hippocampal granule cells. The present study explores its neuropr otective potential in a gerbil model of global ischemia, in which good evidence exists that ischemia triggers apoptosis of CA1. Methods Gerb ils were subjected to bilateral carotid occlusion for 5 minutes and th en treated with felbamate (100 or 200 mg/kg IV) or vehicle. They were killed 3 days later, and the numbers of live and dead neurons in the C AI sector of the hippocampus were counted at stereotaxically defined l evels. Results Felbamate (200 mg/kg IV) administered after the release of carotid clamping did not change brain temperature but reduced neur onal death in CA1 from 332+/-60 cells per section of dorsal hippocampu s in unmedicated gerbils to 62+/-12 cells in felbamate-treated animals (P<.001). A lower dose of felbamate (100 mg/kg post hoc) showed only a nonsignificant reduction of neuronal death. In the 200-mg/kg group, felbamate serum concentrations peaked at 162 mu g/mL and were above 10 0 mu g/mL for at least 3 hours, and brain levels reached 150 mu g/mL a t 1 hour. In the 100-mg/kg group, blood serum levels were well below 1 00 mu g/mL. Conclusions These results suggest that felbamate given pos t hoc is remarkably effective in preventing delayed apoptosis secondar y to global ischemia but that effective neuroprotection requires doses higher than those used for anticonvulsant treatment.