Abstracts

RATIONALE: The anticonvulsant felbamate exhibits strong neuroprotective properties, but hematotoxicity, possibly attributable to oxidative metabolities, has limited its use. Therefore, we examined the neuroprotective efficacy of its close relative fluoro-felbamate,which is less likely to produce such metabolites, and is quite effective as an anticonvulsant. METHODS: Using in vitro rat hippocampal slices, we monitored the CA1 orthodromic and antidromic population spike (PS) amplitude during hypoxia with and without fluoro-felbamate treatment. We also assessed the effect of fluoro-felbamate on hypoxic death of hippocampal granule cells in culture, and in vivo against histological damage produced by transient bilateral carotid occlusion for 10 min. in gerbils, or by hypoxia-ischemia following bilateral carotid occlusions and hypoxia in rat pups. RESULTS: Fluoro-felbamate provided dose-dependent neuroprotection of CA1 PS amplitude in hippocampal slices at concentrations of 256 mg/l and greater (p<0.05). At a fluoro-felbamate concentration of 100 mg/l CA1 orthodromic and antidromic PS amplitude recovered to 96.0% ? 2.0 and 96.3% ? 1.9, compared to unmedicated slices which recovered to 2.6% ? 2.6 and 12.4% ? 1.0, respectively. The EC50 for fluoro-felbamate was 51.3 mg/l and 49.8 mg/l for neuroprotection against in vitro hypoxia, compared to an EC50 for orthodromic hypoxic neuroprotection of 198.7 mg/l for felbamate. Fluoro-felbamate (300 mg/l) reduced hypoxid death of cultured hippocampal granule cells (p<0.01) and (300 mg/kg) provided in vivo neuroprotection against subicular/CA1 damage in dorsal hippocampus in the gerbil model of transient global ischemia. It reduced the volume of infarcted cortex in our rat pup model by 39-47% (p<0.01). CONCLUSIONS: These studies demonstrate that the anti-convulsant fluoro-felbamate provide neuroprotection in two different models of hypoxia in vitro and in two separate models of ischemia or of hypoxia-ischemia in vivo.