Post-ischemic diazepam does not reduce hippocampal CA1 injury and does not improve hypothermic neuroprotection after forebrain ischemia in gerbils.
The hippocampal CA1 sector is especially vulnerable to brief forebrain ischemia. Excitotoxicity is widely thought to contribute to this cell death. Accordingly, drugs that presumably counteract excitotoxicity, such as GABAergic agonists, have been repeatedly tested and found to reduce CA1 cell loss. Post-ischemic diazepam reduces CA1 injury. However, diazepam also causes hypothermia, which by itself is neuroprotective. Most studies fail to adequately control for this confound. In this study, we tested whether diazepam reduces injury in temperature controlled gerbils subjected to brief forebrain ischemia. Furthermore, we tested whether diazepam augments hypothermic neuroprotection. All gerbils were implanted with a core temperature telemetry probe and a cannula for the subsequent insertion of a thermocouple probe to measure ischemic brain temperature. Subsequently, they were given a 5-min normothermic ischemic insult. In Experiment 1, two groups of gerbils were given 10 mg/kg doses of diazepam (i.p.) at both 30 and 90 min post-ischemia. Temperature was maintained in one group by heating lamps. Another group was administered saline. Diazepam reduced cell death at 7 days post-ischemia when the drug-induced hypothermia was permitted, but not when it was prevented. In Experiment 2, four groups of ischemic gerbils were treated starting at 12 h post-ischemia with prolonged hypothermia, diazepam and the combination or saline treatment. Hypothermia, but not diazepam, provided partial neuroprotection and diazepam did not augment hypothermic neuroprotection. Thus, neuroprotection with diazepam is solely due to hypothermia. These data do not support the clinical use of diazepam as a neuroprotectant after global ischemia.
Davies
Laura M
LM
Centre for Neuroscience, University of Alberta, Edmonton, Alberta, Canada T6G 2E9.
MacLellan
Crystal L
CL
Corbett
Dale R
DR
Colbourne
Frederick
F
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001831:Body Temperature; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D003131:Combined Modality Therapy; D003975:Diazepam / Q000494:pharmacology*; D005260:Female; D005849:Gerbillinae; D006624:Hippocampus / Q000473:pathology*; D007036:Hypothermia, Induced; D018696:Neuroprotective Agents / Q000494:pharmacology
D000927:Anticonvulsants; D018696:Neuroprotective Agents; D003975:Diazepam