FLUPIRTINE REDUCES FUNCTIONAL DEFICITS AND NEURONAL DAMAGE AFTER GLOBAL-ISCHEMIA IN RATS

Global cerebral ischemia leads to selective neuronal damage in the CA1 sector of the hippocampus and in the dorsolateral striatum. In additi on, it results in deficits in spatial learning and memory as shown by an increase in escape latency and swim distance during the escape tria ls and a reduction of time spent in the quadrant of the former platfor m position during the probe trial of the water maze. Flupirtine is a n on-opioid, centrally acting analgesic which has been shown to be neuro protective against N-methyl-D-aspartate (NMDA)-mediated toxicity in vi tro. The purpose of the present study was to investigate the potential protective effect of flupirtine in vivo with both behavioural and his tological measures of global cerebral ischemia. Global ischemia was in duced by four-vessel-occlusion (4VO) for 20 min in rats. Flupirtine wa s administered at a dose of 5 mg/kg i.p. either 20 min before and 50 m in after occlusion (pre-treatment) or directly and 70 min after occlus ion (post-treatment). 1 week after surgery, spatial learning and memor y was tested in the Morris water maze. Pre-treatment with flupirtine r educed the increase in escape latency and in swim distance induced by 4VO. It also diminished the deficit in spatial memory as revealed by a n increase in time spent in the quadrant of the former platform positi on during the probe trial which was reduced by 4VO. Post-treatment wit h flupirtine had no effect on the deficits in spatial learning and mem ory induced by 4VO. Neuronal damage in the CA1 sector of the hippocamp us and in the striatum produced by 4VO was significantly attenuated wi th pre-treatment of flupirtine whereas post-treatment did not affect t his neuronal damage. The present data demonstrate that pre-treatment w ith flupirtine exerts a protective effect on hippocampal and striatal neuronal damage and on deficits in spatial learning induced by 4VO. (C ) 1997 Elsevier Science B.V.