Protective use of N-methyl-D-aspartate receptor antagonists as a spinoplegia against excitatory amino acid neurotoxicity

Abstract

Objective: Paraplegia remains a serious complication of thoracic and thoracoabdominal aortic operations. To avoid this dreadful complication, N-methyl-D-aspartate (NMDA) receptor antagonists have been examined in the ischemic or excitotoxic neuronal injury model. In the present study, we evaluated the protective efficacy of NMDA receptor antagonists that were infused segmentally after aortic clamping, as a spinoplegia, to reduce aspartate neurotoxicity in the spinal cord.

Methods: Infrarenal aortic isolation was performed in New Zealand white rabbits. Group A animals (n = 7) were pretreated with the segmental infusion of MK-801, a noncompetitive NMDA receptor antagonist, followed by segmental aspartate (50 mmol) infusion for 10 minutes. Group B animals (n = 6) received pretreatment with CGS19755, a competitive NMDA receptor antagonist, followed by the same aspartate infusion as group A. Group C animals (n = 7) received vehicle only, followed by aspartate infusion as a control group. In addition, group D animals (n = 6) were pretreated with MK-801 that was administrated intravenously 1 hour before aspartate infusion. Neurologic status was assessed at 12, 24, and 48 hours after operation by using the Tarlov score. The spinal cords were procured at 48 hours for histopathologic analysis to determine the extent of excitotoxic neuronal injury.

Results: Most of the animals in groups A and D revealed full recovery or mild motor disturbance. Group B and C animals exhibited paraplegia or paraparesis with marked neuronal necrosis. In the Tarlov score at 48 hours, group A animals represented better neurologic function than group C (P < .01) and similar motor function to group D animals. Severe histopathologic change was not observed in groups A and D. Animals in groups A and D showed a greater number of motor neurons than animals in groups B and C (P < .01). The difference could be due to chance between group A and D animals (P = .08).

Conclusions: These results showed that the segmental infusion of noncompetitive NMDA receptor antagonist as an intraoperative spinoplegia could have a protective effect on the spinal cord neurons against excitotoxic neuronal injury in vivo. On the other hand, efficacy of the use of competitive antagonist was suggested to be limited in this model, probably because of the insurmountable obstacle of the blood-brain barrier.

Clinical relevance: Paraplegia is a devastating complication during surgical repair of the thoracic and thoracoabdominal aortas. Excitatory amino acids neurotoxicity through the N-methyl-D-aspartate (NMDA) receptor is no doubt the pathologic hallmark of ischemic and postischemic spinal cord injury. Systemic administration of either a competitive or noncompetitive NMDA antagonist has been reported to have neuroprotective effect, in terms of preoperative treatment, with dose-related central sympathomimetic and sedative effects. Local administration, particularly of a noncompetitive NMDA antagonist, infused segmentally after aortic clamping could therefore be a potent intraoperative pharmacologic strategy to minimize the effective dose that retains NMDA antagonism without undesirable adverse effects. Our ability to reproduce this model could facilitate pharmacologic prevention or provide a new surgical technique as a spinoplegia for NMDA receptor-mediated neuronal injury.