Felbamate protects CA1 neurons from apoptosis in a gerbil model of global ischemia.
OBJECTIVE
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 death in hippocampal granule cells. The present study explores its neuroprotective potential in a gerbil model of global ischemia, in which good evidence exists that ischemia triggers apoptosis of CA1.


METHODS
Gerbils were subjected to bilateral carotid occlusion for 5 minutes and then 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 CA1 sector of the hippocampus were counted at sterotaxically defined levels.


RESULTS
Felbamate (200 mg/kg IV) administered after the release of carotid clamping did not change brain temperature but reduced neuronal death in CA1 from 332 +/- 60 cells per section of dorsal hippocampus 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 microg/mL and were above 100 microg/mL for at least 3 hours, and brain levels reached 150 microg/mL at 1 hour. In the 100-mg/kg group, blood serum levels were well below 100 microg/mL.


CONCLUSIONS
These results suggest that felbamate given post hoc is remarkably effective in preventing delayed apoptosis secondary to global ischemia but that effective neuroprotection requires doses higher than those used for anticonvulsant treatment.
Wasterlain
C G
CG
Department of Neurology, VA Medical Center at Sepulveda, California 91343-2099, USA.
Adams
L M
LM
Wichmann
J K
JK
Sofia
R D
RD
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002545:Brain Ischemia / Q000473:pathology / Q000517:prevention & control*; D016923:Cell Death; D002467:Cell Nucleus / Q000648:ultrastructure; D002470:Cell Survival; D003593:Cytoplasm / Q000648:ultrastructure; D004195:Disease Models, Animal; D000078328:Felbamate; D005849:Gerbillinae; D005998:Glycine / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects*; D007275:Injections, Intravenous; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D048448:Phenylcarbamates; D011409:Propylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
D000927:Anticonvulsants; D018696:Neuroprotective Agents; D048448:Phenylcarbamates; D011409:Propylene Glycols; D016194:Receptors, N-Methyl-D-Aspartate; D005998:Glycine; D000078328:Felbamate