The ability of
diazepam, a
benzodiazepine full agonist, and
imidazenil, a
benzodiazepine partial agonist, to protect hippocampal area CA1 neurons from death for at least 35 days after
cerebral ischemia was investigated.
Diazepam (10 mg/kg) administered to gerbils 30 and 90 minutes after forebrain
ischemia produced significant protection of hippocampal 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 therapeutic window for
diazepam was short; there was no significant neuroprotection when the administration of
diazepam was delayed to 4 hours after
ischemia. The neuroprotective dose of
diazepam also produced
hypothermia (approximately 32 degrees C) for several hours after injection. To assess the role of
hypothermia in neuroprotection by
diazepam,
hypothermia depth and duration was simulated using a cold-water spray in separate gerbils. Seven days after
ischemia, neuroprotection by
hypothermia was similar to that produced by
diazepam. However, 35 days after
ischemia, there was no significant protection by
hypothermia, suggesting that
hypothermia does not play a significant role in long-term
diazepam 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, significant 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 administered as early
as 2 hours after
ischemia. The ability of
ischemia to produce deficits in working memory and of
benzodiazepines to prevent the deficits also was investigated. Gerbils trained on an eight-arm radial maze before
ischemia demonstrated a significant increase in the number of working errors 1 month after
ischemia. The
ischemia-induced deficits in working memory were completely prevented by
diazepam but not by
imidazenil. There was a significant, but weak, negative correlation between the degree of CA1 pyramidal cell survival and the number of working errors in both the
diazepam and
imidazenil groups. Thus, if given early enough during reperfusion, both
benzodiazepine full and partial agonists are neuroprotective for at least 35 days, but the lack of sedating side effects of
imidazenil must be weighed against its reduced efficacy.