Posthypoxic treatment with felbamate is neuroprotective in a rat model of hypoxia‐ischemia

Abstract

Felbamate, a novel dicarbamate anticonvulsant that blocks the glycine site of the N-methyl-D-aspartate receptor and protects the hippocampal slice from hypoxic damage, shows remarkably low toxicity in animals and in humans. Since most treatment of human cerebral ischemia will have to be delivered after the insult, we investigated the neuroprotective potency of post hoc felbamate in rat pups with bilateral carotid ligations exposed to an atmosphere of 6.5% O2 for 1 hour. Brain temperature was unaffected by surgery, hypoxia, or felbamate. Neuroprotection was greatest at 300 mg/kg, less effective at 200 and 400 mg/kg, and ineffective at 100 mg/kg. Post hoc felbamate (300 mg/kg) reduced the volume of infarction from 67% +/- 7% of neocortex in unmedicated rats to 32% +/- 8%, 51% +/- 12%, 38% +/- 19%, and 53% +/- 10% when given 0, 1, 2, and 4 hours after hypoxic exposure, respectively. By 6 hours, post hoc protection was no longer significant. Delayed neuronal necrosis in hippocampal granule cells was reduced from 156 +/- 33 neurons to 12 +/- 7 (0 hours, p < 0.01) and 37 +/- 17 (1 hour, p < 0.05). These effects were obtained at plasma concentrations (60 to 120 mg/ml) that have occasionally been reached without serious toxicity in human anticonvulsant trials. These data suggest that, in this animal model, felbamate given after a hypoxic-ischemic insult is effective in reducing cerebral infarction and extremely effective in preventing delayed neuronal necrosis, but that the window of opportunity for post hoc treatment is only 1 to 4 hours.

NMDA/NR2B Selective Antagonists in the Treatment of Ischemic Brain Injury

“…The number of necrotic neurons in the dentate gyrus was reduced by 77% over the controls. Felbamate was also neuroprotective when it was administered after ischemia [54,56]. These data suggest that, in this animal model, felbamate is effective in reducing cerebral infarction and extremely effective in preventing delayed neuronal necrosis.…”

“…Wasterlain et al [54,55] tested the neuroprotective effects of felbamate in a model of incomplete cerebral ischemia and hypoxia in 7-day-old rats. Felbamate treatment before ischemia (300 mg/kg) reduced the surface of infarcted cortex by 42-49% compared to controls.…”

Apoptosis in a Neonatal Rat Model of Cerebral Hypoxia-Ischemia

“…Previous studies 22,30 have shown that granule cells of the dentate gyrus that undergo apoptosis 31,32 and in caspase-deficient mice. 33 Further investigation of excitotoxicity in cerebral ischemia may lead to a better understanding of modes of cell death such as apoptosis and necrosis and to more effective stroke treatments in the future.…”

“…20 A model of cerebral hypoxia-ischemia has been developed in the neonatal rat that reliably produces infarction primarily involving the cortex in the territory of the middle cerebral artery and selective neuronal death of the inner granule cell layers of the dentate gyrus. [21][22][23] The purpose of this study was to determine whether this model of ischemic damage in the cerebral cortex and inner granule cell layers of the dentate gyrus demonstrates evidence of apoptosis.…”

Prophylactic Neuroprotection to Improve Stroke Outcome

“…Unfortunately, most of these NMDA antagonists are only available as an intravenous formulation. Dextromethor phan, felbamate and remacemide are orally available NMDA antagonists [6,7], Another method to impede these channels is to inhibit presynaptic glutamate release by blocking sodium-conducting channels [8]. Sodium channel blockers, such as fos-phenytoin and BW1003C87, are effective in animal stroke models [9], Riluzole, an orally available modulator of glutamate re lease with a good safety profile, reduced mortality in amyotrophic lateral sclerosis [10].…”