ABSTRACT
The effect of diazepam on NO-mediated cGMP synthesis was studied in rat brain slices. It was found that diazepam dose-dependently decreased cGMP synthesis in cerebellar slices, with an inhibition of 90% at 1 mM diazepam. cGMP levels in the presence of diazepam were not restored to control levels by the addition of 0.1 mM sodium nitroprusside, whereas the decrease in cerebellar cGMP levels induced by 0.1 mM L-NAME was restored by the simultaneous application of NO-donors. In addition to the decrease of cGMP levels in neuronal structures induced by 1 mM diazepam, we observed increased cGMP immunoreactivity in glial cells in the cerebellum, the hippocampus, and the cerebral cortex. The significance of this observation is discussed.
Subject(s)
Brain/metabolism , Cyclic GMP/metabolism , Diazepam/pharmacology , 1-Methyl-3-isobutylxanthine/pharmacology , Animals , Brain/drug effects , Cerebellum/drug effects , Cerebellum/metabolism , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , In Vitro Techniques , Kinetics , Male , Rats , Rats, Inbred LewABSTRACT
The neuroprotective effect of diazepam has been demonstrated in global ischemia models in vivo and in vitro [Neuroscience (2000) 471]. We studied the effect of diazepam on lesion volume in a photothrombotic model of focal brain ischemia in the rat, and the relation of such effect to time of drug administration. For this purpose we induced photochemically a focal brain lesion, and added diazepam 10 mg/kg intraperitoneally just before, at 1 and 4 h after lesion induction. After 24 h the rats were decapitated, and lesion volumes of 27 diazepam-treated rats were compared with that of 12 controls. Treated animals had a significant smaller lesion volume than controls, except those who received diazepam before induction of the lesion. We conclude that diazepam is neuroprotective in focal brain ischemia even when administered up to 4 h after ischemia onset.