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 delay ed neuronal death after ischemic and traumatic injury to the CNS. Rece nt data based on focal microinjection experiments have demonstrated th at ,3-dihydro-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), a highly selective and potent antagonist of non-N-methyl-D-aspartate ionotropi c EAA receptors, i.e., those preferring alpha-amino-3-hydroxy-5-methyl -4-isoxazole propionic acid (AMPA) or kainate, can reduce histopatholo gy and functional deficits after traumatic spinal cord injury (SCI). T hus, non-NMDA receptors at or near the injury site appear to be import ant in secondary injury processes that contribute significantly to the consequences of SCI. We have now examined the effects of systemic NBQ X, using intravenous infusion, the most commonly used and temporally e fficient clinical mode of drug administration. Standardized contusive SCI was produced at the T8 vertebral level in Sprague-Dawley rats. Beg inning 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 N BQX 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 loco motion, swimming, and maintaining position on an inclined plane. The p rofile of effects was similar to that seen with focal microinjection o f NBQX, suggesting that even with systemic administration, the drug ac ts mainly at the injury site. Further, the results support a therapeut ic potential for NBQX, or similar drugs that antagonize non-NMDA recep tors and inhibit secondary injury processes after SCI. (C) 1996 Academ ic Press, Inc.