Amelioration of functional deficits from spinal cord trauma with systemically administered NBQX, an antagonist of non-N-methyl-D-aspartate receptors

Excitatory amino acid (EAA) receptors play a significant role in delayed neuronal death after ischemic and traumatic injury to the CNS. Recent data based on focal microinjection experiments have demonstrated that 2,3-dihydro-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), a highly selective and potent antagonist of non-N-methyl-D-aspartate ionotropic EAA receptors, i.e., those preferring alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) or kainate, can reduce histopathology and functional deficits after traumatic spinal cord injury (SCI). Thus, non-NMDA receptors at or near the injury site appear to be important in secondary injury processes that contribute significantly to the consequences of SCI. We have now examined the effects of systemic NBQX, using intravenous infusion, the most commonly used and temporally efficient clinical mode of drug administration. Standardized contusive SCI was produced at the T8 vertebral level in Sprague-Dawley rats. Beginning at 15 min postinjury, NBQX was administered intravenously at 1 mg/kg/min for 30 min. Behavioral tests of hindlimb functional deficits were performed at 1 day and weekly for 1 month after SCI. Spinal cord tissue was then examined morphometrically to compare lesion size and amount of spared tissue. We found that intravenous administration of NBQX significantly reduced functional impairment after SCI. The effects included more rapid and extensive recovery of hindlimb reflexes, more rapid establishment of a reflex bladder, and a more rapid and greater degree of recovery of coordinated use of hindlimbs in open field locomotion, swimming, and maintaining position on an inclined plane. The profile of effects was similar to that seen with focal microinjection of NBQX, suggesting that even with systemic administration, the drug acts mainly at the injury site. Further, the results support a therapeutic potential for NBQX, or similar drugs that antagonize non-NMDA receptors and inhibit secondary injury processes after SCI. (C) 1996 Academic Press, Inc.