Neuroprotective efficacy of AR-A008055, a clomethiazole analogue, in a global model of acute ischaemic stroke and its effect on ischaemia-induced glutamate and GABA efflux in vitro

We have investigated the neuroprotective properties of AR-A008055 [(+/-)-1- (4-methyl-5-thiazolyl-1-phenyl-methylamine], a novel compound structurally related to clomethiazole. Administration (i.p.) of (+/-)-AR-A008055 60 min after 5 min of global cerebral ischaemia in gerbils produced a dose-depende nt protection of the hippocampus from damage. Both enantiomers [(R)-(+)-AR- A008055 and (S)-(-)-AR-A008055] at 600 gmol/kg produced similar protection to that following clomethiazole (600 mu mol/kg) and both produced similar a nd sustained neuroprotection, at 4, 7 and 21 days post-insult. When infused intravenously over a 2-h period, both enantiomers produced concentration-d ependent neuroprotection, with the enantiomers providing similar protection at every plasma concentration (50-200 nmol/ml). The efficacy of (S)-(-)-AR -A008055 was similar to clomethiazole, but it was slightly less potent. Isc haemia-induced glutamate efflux from rat brain cortical prisms in vitro was inhibited by both isomers (100 muM). The inhibitory effect of (R)-(+)-AR-A 008055 was blocked by bicuculline (10 muM) and picrotoxin (100 muM), while the effect of (S)-(-)-AR-A008055 was only antagonised by picrotoxin. This i ndicated that (S)-(-)-AR-A008055, like clomethiazole, is able to open the G ABAA-chloride channel in the absence of endogenous GABA. (R)-(+)-AR-A008055 was more potent than (S)-(-)-ARA008055 in enhancing the concentration of G ABA in the medium following 30 min exposure of tissue to the ischaemic cond itions., suggesting that it is an effective GABA uptake inhibitor. This act ion may explain both its effect on glutamate efflux in vitro and its neurop rotective effect in vivo. (C) 2001 Published by Elsevier Science Ltd.