AN INVESTIGATION OF THE POSSIBLE INTERACTION OF CLOMETHIAZOLE WITH GLUTAMATE AND ION-CHANNEL SITES AS AN EXPLANATION OF ITS NEUROPROTECTIVEACTIVITY

The activity of the neuroprotective agent clomethiazole at glutamate a nd ion channel sites has been investigated. Dizocilpine (3.25 mg/kg in traperitoneally) provided almost total protection against the damage p roduced by infusion of N-methyl-DL- aspartate (NMDLA; 75 mu g) into th e right hippocampus. In contrast, clomethiazole (96 mg/kg intraperiton eally) was without effect. Using ligand binding techniques, no evidenc e was found for clomethiazole interacting with NMDA, AMPA or sigma bin ding sites. Clomethiazole did inhibit the stimulatory effect of the me tabotropic glutamate receptor agonist 1S3R-aminocyclopentone-1,3-dicar boxylic acid (ACPD) on phosphoinositol hydrolysis, but only at a conce ntration of 10(-3)M, which is unlikely to have functional relevance. C lomethiazole was also without effect on ligand binding to Ca(2+)channe ls (N- or L- type), Na+ channels or ATP-sensitive K+ channels. Potenti ation of GABA function therefore remains the most plausible explanatio n for the neuroprotective activity of clomethiazole.