Phenytoin protects against ischemia-produced neuronal cell death.

Brief bilateral carotid occlusion in the gerbil produces forebrain ischemia that results in almost complete neuronal destruction in the CA1 sector of the hippocampus. Treatment with phenytoin (200 mg/kg) blocked the ischemia-induced neuronal death. The average density of CA1 pyramidal neurons (cells/mm CA1) was 253.6 +/- 4.4 in the sham surgery group, 12.3 +/- 3.4 in the ischemia group, and 119.5 +/- 16.6 in the group treated with phenytoin before ischemia. Thus, phenytoin reduced ischemia-produced neuronal loss in hippocampal CA1 by 44.4% (P less than 0.001). The plasma levels of phenytoin that produced this effect ranged from 28.1 to 45.0 mg per liter, with a mean phenytoin level of 34.7 +/- 1.7 mg/l (n = 10). The results suggest that phenytoin may be a clinically useful cerebroprotective agent.