THE PROTECTIVE ACTION OF CHLORMETHIAZOLE AGAINST ISCHEMIA-INDUCED NEURODEGENERATION IN GERBILS WHEN INFUSED AT DOSES HAVING LITTLE SEDATIVEOR ANTICONVULSANT ACTIVITY

1 The effect of chlormethiazole administration on delayed neuronal dea th in gerbil hippocampus following transient global ischaemia has been examined. Chlormethiazole was administered either intraperitoneally o r by intravenous infusion with either the dose or the time of infusion varied. 2 Chlormethiazole (600 mu mol kg(-1), i.p.) given 60 min afte r ischaemia produced substantial (>60%) neuroprotection when damage wa s assessed 5, 14 or 21 days later, indicating the drug does not merely delay cell death. 3 Infusion protocols were developed which would res ult in sustained and defined plasma concentrations. Chlormethiazole (9 30 mu mol kg(-1)) was then infused intravenously for 30 min, 76.5 min or 110 min in ways resulting in sustained plasma concentrations of 200 , 100 and 50 nmol ml(-1) respectively. When treatment was initiated 30 min after the ischaemic episode all protocols provided effective neur oprotection. There was a dose-dependent decline in protection when pla sma chlormethiazole concentrations of 50, 30 and 10 nmol ml(-1) were s ustained for 110 min with no protection observed at 10 nmol ml(-1). 4 In contrast, when a plasma concentration of 10 nmol ml(-1) was sustain ed by infusion for 24 h, almost total neuroprotection against the isch aemic damage was achieved. This plasma concentration produced no sedat ive or anticonvulsant activity. 5 These data suggest that neuroprotect ion depends on both dose and duration of chlormethiazole administratio n and that excellent neuroprotection is possible in the absence of the sedative and anticonvulsant effects of the drug.