IN-VIVO MODELS OF CEREBRAL-ISCHEMIA - EFFECTS OF PARENTERALLY ADMINISTERED NMDA RECEPTOR GLYCINE SITE ANTAGONISTS

Both in vitro and in vivo experiments have implicated extracellular gl ycine in the pathogenesis of ischemic brain damage. Recently, halogena ted derivatives of quinoxaline-2,3-dione have been synthesized that po ssess bioavailability when parenterally administered and minimal psych otomimetic properties. Such compounds have allowed investigation into the efficacy of glycine receptor antagonism as a strategy for protecti on against cerebral ischemic insults. Rats underwent either 90 min of middle cerebral artery filament occlusion or 10 min of forebrain ische mia with recovery while receiving intraperitoneal injections of either a glycine receptor antagonist (ACEA-1021, ACEA-1031, or ACEA-1011) or vehicle (dimethyl sulfoxide). Both ACEA-1021 and ACEA-1031 reduced ce rebral infarct volumes and were associated with a reduced incidence of hemiparesis resulting from MCA occlusion. ACEA-1011, administered in a smaller dose had no effect. In the forebrain ischemia model, glycine receptor antagonism had no effect on delayed neuronal necrosis in the hippocampal CA1 sector, neocortex, or caudoputamen. We conclude that pharmacologic antagonism of glycine at the strychnine-insensitive glyc ine receptor presents a neuroprotective profile similar to that previo usly observed for antagonists of glutamate at the N-methyl-D-aspartate complex with a potential for fewer side effects.