Attenuation by chlormethiazole administration of the rise in extracellular amino acids following focal ischaemia in the cerebral cortex of the rat.

1. In vivo microdialysis has been used to investigate the concentration of various amino acids and lactate in the extracellular fluid of the rat cortex following focal ischaemia, the probe being placed in the core of the infarct area. 2. An ischaemic infarct was produced in the cortex by use of a photochemical dye (Rose Bengal) and light irradiation. There was a marked increase in lactate concentration (300%) over the next 4 h. Substantial increases were also seen in the concentration of the excitatory (glutamate and aspartate), inhibitory (GABA and taurine) and other amino acids (serine, alanine, asparagine). 3. Administration of chlormethiazole (200 mg kg-1, i.p.) 5 min after the onset of ischaemia reduced the ischaemia-induced neurodegeneration by approximately 30%, measured histologically 24 h later. 4. Chlormethiazole (200 mg kg-1, i.p.) administration also reduced the rise in the concentration of lactate and all the amino acids by between 30-60% during the first 4 h after the onset of ischaemia. 5. Analysis of the time course of the amino acid changes suggested that chlormethiazole is not neuroprotective because of the inhibition of excitatory amino acid release but rather that the attenuated rise in the concentration of all the amino acids is reflective of neuroprotection and therefore decreased cell death. 6. This conclusion was supported by the observation that the enhanced efflux of glutamate from slices of cerebral cortex which had been induced by incubation of the slices in an hypoxic medium was unaltered by the presence of a high concentration of chlormethiazole (1 mM) in the medium. 7. Overall the data strengthen the evidence for the neuroprotective effect of chlormethiazole in this model of focal ischaemia.

The protective action of chlormethiazole against ischaemia-induced neurodegeneration in gerbils when infused at doses having little sedative or anticonvulsant activity.

1. The effect of chlormethiazole administration on delayed neuronal death in gerbil hippocampus following transient global ischaemia has been examined. Chlormethiazole was administered either intraperitoneally or by intravenous infusion with either the dose or the time of infusion varied. 2. Chlormethiazole (600 mumol kg-1, i.p.) given 60 min after ischaemia produced substantial (> 60%) neuroprotection when damage was assessed 5, 14 or 21 days later, indicating the drug does not merely delay cell death. 3. Infusion protocols were developed which would result in sustained and defined plasma concentrations. Chlormethiazole (930 mumol 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 neuroprotection. There was a dose-dependent decline in protection when plasma chlormethiazole concentrations of 50, 30 and 10 nmol ml-1 were sustained 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 sustained by infusion for 24 h, almost total neuroprotection against the ischaemic damage was achieved. This plasma concentration produced no sedative or anticonvulsant activity. 5. These data suggest that neuroprotection depends on both dose and duration of chlormethiazole administration and that excellent neuroprotection is possible in the absence of the sedative and anticonvulsant effects of the drug.