The competitive NMDA antagonist CGP 40116 permanently reduces brain damage after middle cerebral artery occlusion in rats.

Abstract

In this study we evaluated the effect of the competitive N-methyl-D-aspartate (NMDA) antagonist D-(E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (CGP 40116) on both early (2 days) and late (28 days) ischemic brain damage in a rodent model of focal cerebral ischemia by means of magnetic resonance imaging (MRI) and conventional histology. Immediately after occlusion of the left middle cerebral artery (MCA), rats received either CGP 40116 (20 mg/kg i.p.) or isotonic saline. Two MRI scans were performed in each animal 2 and 28 days after MCA occlusion. After the second scan, rats were perfusion fixed for histological evaluation. The volume of lesioned brain tissue as determined by MRI or histology was calculated from the damaged area in single sections and the distance between them. CGP 40116 reduced acute infarct volume as measured by MRI 2 days after MCA occlusion by 44% (p < 0.05, analysis of variance). After 28 days the lesion detected by MRI was still significantly smaller in the drug-treated animals. This finding was confirmed by the histological analysis showing a 64% reduction in the volume of brain atrophy in the CGP 40116 group (p < 0.05, analysis of variance). There was a good correlation between the MRI data and the results of the histological evaluation (r = 0.9). Our results indicate that (a) the competitive NMDA antagonist CGP 40116 permanently protects brain tissue from the consequences of cerebral ischemia in a rat model for human stroke and (b) early and late pathological changes can be accurately measured by MRI.