CHARACTERIZATION OF THE CEREBROPROTECTIVE EFFICACY OF THE COMPETITIVENMDA RECEPTOR ANTAGONIST CGP40116 IN A RAT MODEL OF FOCAL CEREBRAL-ISCHEMIA - AN IN-VIVO MAGNETIC-RESONANCE-IMAGING STUDY

The cerebroprotective properties o the competitive NMDA antagonist D-( E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116) were eval uated in a rat model of focal cerebral ischemia. CGP 40116 (5-40 mg/kg i.v.) was injected immediately following permanent occlusion of the l eft middle cerebral artery (MCA). MK 801 (1 or 3 mg/kg i.V.), D-CPPene (20 mg/kg i.v.), and CGS 19755 (40 mg/kg i.v.) were used for comparis on. Lesion volume was assessed using in vivo magnetic resonance imagin g, which in initial experiments with parallel histological determinati ons proved to be an accurate method for the measurement of brain infar ction and the determination of a cerebroprotective drug effect. CGP 40 116 dose-dependently reduced the volume of cortical infarction, with a n ED50 of 11 mg/kg i.v. and a maximal effect equivalent to a 62% reduc tion in cortical edema volume. Its cerebroprotective efficacy was thus comparable to that of MK 801. The rank order of potency for the NMDA antagonists was MK 801 > CGP 40116 is similar to D-CPPene > CGS 19755. Neuroprotection by CGP 40116 was still apparent when treatment was st arted 30 min after MCA occlusion. It is concluded that CGP 40116 is an effective cerebroprotectant with potential clinical utility for ameli oration of focal cerebral ischemic damage.