Postischemic diazepam is neuroprotective in the gerbil hippocampus.
In this study, we address the hypothesis that enhancement of gamma-aminobutyric acid (GABA) neurotransmission following an ischemic episode is neuroprotective in the hippocampus. Mongolian gerbils were subjected to transient forebrain ischemia for 5 min by occlusion of the carotid arteries and then administered diazepam (10 mg/kg i.p.) 30 min or 30 and 90 min following ischemia. Diazepam produced a significant decrease in both rectal and brain temperature (4-6 degrees C) in the sham and ischemic gerbils. 1 day following the onset of reperfusion, diazepam substantially reduced the hyperactivity normally induced by the ischemic episode. 7 days later, neuronal viability in the hippocampus was assessed. The single dose of diazepam completely protected the CA1 pyramidal cells of the hippocampus in 62% of the gerbils and the double dose of diazepam completely protected CA1 pyramidal neurons in 67% of the gerbils. There was a significant correlation between the degree of pyramidal cell degeneration in the CA1 area of the hippocampus measured 7 days following ischemia and the degree of hyperactivity measured 1 day following ischemia. Diazepam also prevented the loss of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding to GABA-gated chloride channels in the dendritic fields of the CA1 area of the hippocampus. Our findings support the hypothesis that enhancement of GABA neurotransmission following an ischemic event may offset neuronal excitability and prevent neuronal death in specific brain regions. We conclude that GABA-enhancing drugs, such as diazepam, are attractive candidates as neuroprotective agents following ischemic insults.
Schwartz
R D
RD
Department of Pharmacology, Duke University Medical Center, Durham, NC 27710.
Huff
R A
RA
Yu
X
X
Carter
M L
ML
Bishop
M
M
D000818:Animals; D001831:Body Temperature; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002470:Cell Survival / Q000187:drug effects; D003975:Diazepam / Q000494:pharmacology*; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D012007:Rectum
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; C037476:tert-butylbicyclophosphorothionate; D003975:Diazepam