ATTENUATION BY CHLORMETHIAZOLE ADMINISTRATION OF THE RISE IN EXTRACELLULAR AMINO-ACIDS FOLLOWING FOCAL ISCHEMIA 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 4h. 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 4h 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.