Diazepam delays the death of hippocampal CA1 neurons following global ischemia.
Although diazepam provides limited long term neuroprotection, it may be useful for expanding the therapeutic time window after stroke by delaying neuronal death. However, it is not known to what extent diazepam maintains normal cellular structure and function in the first few days after ischemia. We used histological, immunohistochemical and electrophysiological endpoints to address this question. Gerbils underwent 5 min of global ischemia followed by 10 mg/kg diazepam (D) given 30 and 90 min later. Other animals were subjected to sham surgery, normothermic ischemia (I) or ischemia at 32 degrees C (Hypo). Postischemic brain temperature was regulated at approximately 37 degrees C for 24 h. Gerbils in the D and I groups were sacrificed 1, 2 and 3 days after ischemia. Sham and Hypo gerbils were sacrificed on day 3. CA1 cell counts, MAP2 staining and CA1 field potentials were performed at each survival time. Hypothermia prevented CA1 necrosis, preserved MAP2 integrity and maintained CA1 field potential amplitude. Ischemic gerbils showed a significant reduction in these 3 outcome measures by day 3. Diazepam-treated gerbils exhibited near normal levels of CA1 neurons and MAP2 staining. Most importantly, CA1 field potentials were similar to sham values and significantly preserved relative to non-treated ischemic gerbils. Diazepam maintains near normal structural and functional integrity up to 3 days after a global ischemic insult. As such, this drug may be useful for extending the therapeutic time window after cardiac arrest, stroke and related disorders.
Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada A1B 3V6. corbett@mun.ca
Dale
D
Corbett
Jennifer
J
Larsen
Kristopher D
KD
Langdon
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001831:Body Temperature; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D002452:Cell Count; D003975:Diazepam / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D005849:Gerbillinae; D006624:Hippocampus / Q000473:pathology* / Q000502:physiology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020521:Stroke / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology
D000927:Anticonvulsants; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D003975:Diazepam