Neuroprotective effects of N-methyl-d-aspartate receptor antagonist on aspartate induced neurotoxicity in the spinal cord in vivo

Abstract

Much evidence has been gathered to show that neurotoxicity of excitatory amino acids is mainly activated through an N-methyl-D-aspartate (NMDA) receptor cascade. We evaluated the protective effects of NMDA receptor antagonists, MK-801 and CGS19755 on spinal cord neurons using the NMDA receptor mediated neurotoxicity model in vivo. New Zealand white rabbits underwent an infrarenal aortic isolation. Group A animals (n = 7) received segmental aspartate (50 mM) infusion for 10 minutes. Group B animals (n = 6) were pretreated with MK-801 (6mg/kg), a noncompetitive NMDA receptor antagonist, that was administrated intravenously for 3 hours beginning 1 hour before the segmental infusion of aspartate (50 mM) of 10 minutes. Group C animals (n = 6) received pretreatment with CGS19755 (30mg/kg), a competitive NMDA receptor antagonist, that was administrated in the same fashion as group B, followed by the segmental infusion of aspartate (50 mM). Neurologic status was scored at 12, 24, and 48 hours after operation using the Tarlov score. All the animals were sacrificed for histologic assessment at 48 hours. Group A animals exhibited paraplegia or paraparesis with marked neuronal necrosis. Group B and C animals showed significantly better neurologic function compared with group A (p = 0.0013, A vs. B) (p = 0.0011, A vs. C). Pathohistological change was not observed in group B and C animals. NMDA receptor antagonists can have protective effects on spinal cord neurons against aspartate induced neurotoxicity. This model may be useful in assaying protective agents in the spinal cord against neuronal injury mediated by NMDA receptors in vivo.