Diazepam-induced neuroprotection: dissociating the effects of hypothermia following global ischemia

Abstract

Global cerebral ischemia produces hippocampal CA1 neuronal loss which in turn leads to deficits in memory related tasks. Previous studies have shown that the benzodiazepine diazepam is effective at attenuating this cell death and the related behavioural impairments. However these studies have been confounded by diazepam-induced hypothermia. In this study we sought to determine the neuroprotective efficacy of diazepam in the absence of hypothermia. Diazepam (10 mg/kg) was administered to two groups of gerbils at 30 and 90 min following a 5-min ischemic insult. In one group the brain temperature was monitored for 24 h post-ischemically but not regulated. In the second group, post-ischemic brain temperature was maintained at 36.5°C to counteract the hypothermia produced by diazepam. Both behaviour (open field performance) and CA1 cell counts from these groups were compared to those from sham/normal, no drug ischemic and vehicle ischemic groups at 10 days survival. In animals treated with diazepam without temperature regulation, there was significant histological and behavioural protection at 10 days compared to untreated ischemic animals. Preventing hypothermia in diazepam-treated animals resulted in a decrease in the number of cells surviving (from 41.2 to 31.6% of sham) and abolished behavioural protection. Diazepam appears to have limited ability to attenuate neuronal loss and its neuroprotective efficacy is augmented by the concurrent hypothermic actions of the drug itself.