Delayed therapy of experimental ischemia with competitive n-methyl-d-aspartate antagonists in rabbits

Background and Purpose: N-methyl-D-aspartate antagonists are effective in limiting ischemic damage to the brain and spinal cord if treatment is begun at time of ischemic injury. More clinically relevant delayed therapy has not been adequately investigated. We report the temporal profile of efficacy for two competitive N-methyl-D-aspartate antagonists in therapy of central nervous system ischemia. Methods: CGS-19755 (30 mg/kg) or LY233053 (100 mg/kg) was administered 5, 30, or 60 minutes after reversible spinal cord ischemia in rabbits, induced by temporary occlusion of the infrarenal aorta. Duration of occlusion for individual animals was varied to provide a range of ischemia for each experimental group. The P₅₀ represents the duration (in minutes) associated with a 50% probability of resultant permanent paraplegia. Neuroprotection is demonstrated if a drug prolongs the P₅₀. Results: CGS-19755 significantly prolonged the P₅₀ (t test, P=.003) when given 5 minutes after ischemia, but not if delayed by 30 or 60 minutes (Pso: Control, 24.1; 5 minutes, 31.4; 30 minutes, 30.1; 60 minutes, 26.6). LY233053 was efficacious at 5 (P=.0008) and 30 (P=.002) minutes, but not at 60 minutes (P₅₀: Control, 26.8; 5 minutes, 39.4; 30 minutes, 36.0; 60 minutes, 25.6). Conclusions: These competitive N-methyl-D-aspartate antagonists are effective in limiting ischemic damage, but protection is lost if therapy is not initiated within 60 minutes of injury.