POSTISCHEMIC DIAZEPAM IS NEUROPROTECTIVE IN THE GERBIL HIPPOCAMPUS

In this study, we address the hypothesis that enhancement of gamma-ami nobutyric acid (GABA) neurotransmission following an ischemic episode is neuroprotective in the hippocampus. Mongolian gerbils were subjecte d to transient forebrain ischemia for 5 min by occlusion of the caroti d arteries and then administered diazepam (10 mg/kg i.p.) 30 min or 30 and 90 min following ischemia. Diazepam produced a significant decrea se in both rectal and brain temperature (4-6 degrees C) in the sham an d ischemic gerbils. 1 day following the onset of reperfusion, diazepam substantially reduced the hyperactivity normally induced by the ische mic episode. 7 days later, neuronal viability in the hippocampus was a ssessed. The single dose of diazepam completely protected the CA1 pyra midal cells of the hippocampus in 62% of the gerbils and the double do se of diazepam completely protected CA1 pyramidal neurons in 67% of th e gerbils. There was a significant correlation between the degree of p yramidal cell degeneration in the CA1 area of the hippocampus measured 7 days following ischemia and the degree of hyperactivity measured 1 day following ischemia. Diazepam also prevented the loss of [S-35]t-bu tylbicyclophosphorothionate ([S-35]TBPS) binding to GABA-gated chlorid e channels in the dendritic fields of the CA1 area of the hippocampus. Our findings support the hypothesis that enhancement of GABA neurotra nsmission following an ischemic event may offset neuronal excitability and prevent neuronal death in specific brain regions. We conclude tha t GABA-enhancing drugs, such as diazepam, are attractive candidates as neuroprotective agents following ischemic insults.