LONG-TERM NEUROPROTECTION BY BENZODIAZEPINE - FULL VERSUS PARTIAL AGONISTS AFTER TRANSIENT CEREBRAL-ISCHEMIA IN THE GERBIL

The ability of diazepam, a benzodiazepine full agonist, and imidazenil , a benzodiazepine partial agonist, to protect hippocampal area CA1 ne urons from death for at least 35 days after cerebral ischemia was inve stigated. Diazepam (10 mg/kg) administered to gerbils 30 and 90 minute s after forebrain ischemia produced significant protection of hippocam pal area CA1 pyramidal neurons 7 days later. In gerbils surviving for 35 days, diazepam produced the same degree of neuroprotection (70% +/- 30%) in the hippocampus compared with 7 days after ischemia. The ther apeutic window for diazepam was short; there was no significant neurop rotection when the administration of diazepam was delayed to 4 hours a fter ischemia. The neuroprotective dose of diazepam also produced hypo thermia (similar to 32 degrees C) for several hours after injection. T o assess the role of hypothermia in neuroprotection by diazepam, hypot hermia depth and duration was simulated using a cold-water spray in se parate gerbils. Seven days after ischemia, neuroprotection by hypother mia was similar to that produced by diazepam. However, 35 days after i schemia, there was no significant protection by hypothermia, suggestin g that hypothermia does not play a significant role in long-term diaze pam neuroprotection. Imidazenil (3 mg/kg), which produced only minimal hypothermia, protected area CA1 of hippocampus to the same degree as that by diazepam 7 days after ischemia. At 35 days after ischemia, sig nificant protection remained, but it was considerably reduced compared with 7 days. Like diazepam, the therapeutic window for imidazenil was short. Imidazenil neuroprotection was lost when the drug was administ ered as early as 2 hours after ischemia. The ability of ischemia to pr oduce deficits in working memory and of benzodiazepines to prevent the deficits also was investigated. Gerbils trained on an eight-arm radia l maze before ischemia demonstrated a significant increase in the numb er of working errors 1 month after ischemia. The ischemia-induced defi cits in working memory were completely prevented by diazepam but not b y imidazenil. There was a significant, but weak, negative correlation between the degree of CA1 pyramidal cell survival and the number of wo rking errors in both the diazepam and imidazenil groups. Thus, if give n early enough during reperfusion, both benzodiazepine full and partia l agonists are neuroprotective for at least 35 days, but the lack of s edating side effects of imidazenil must be weighed against its reduced efficacy.