DELAYED ANTAGONISM OF AMPA KAINATE RECEPTORS REDUCES LONG-TERM FUNCTIONAL DEFICITS RESULTING FROM SPINAL-CORD TRAUMA/

Excitatory amino acid (EAA) receptors play a significant role in delay ed neuronal death after ischemic and traumatic injury to the CNS. Foca l microinjection experiments have demonstrated that 2,3-dihydro-6-nitr o-7-sulfamoyl-benzo(f) quinoxaline (NBQX), a highly selective and pote nt antagonist of non-N-methyl-D-aspartate ionotropic EAA receptors, i. e., those preferring alpha-amino-3-hydroxy-5-methyl-4-isoxazole propio nic acid (AMPA) or kainate, can reduce histopathology and functional d eficits when administered at 15 min after traumatic spinal cord injury (SCI). Similarly, intravenous infusion of NBQX, beginning at 15 min p ostinjury (p.i.), results in a significant amelioration of the functio nal deficits produced by experimental SCI. However, if antagonists of AMPA/kainate receptors were to be used therapeutically for patients wi th SCI, administration would likely be delayed for several hours after injury. We therefore examined the effects of NBQX administered at 4 h after SCI on functional deficits and histopathology in a standardized rat model of contusive SCI. An incomplete SCI was produced in Sprague -Dawley rats at T8 with a weight-drop device (10 g x 2.5 cm). NBQX (15 nmol), or vehicle alone, was microinjected into the injury site 4 h l ater Recovery of hind limb reflexes, postural control, and locomotor f unction was determined by a battery of behavioral tests performed for 8 weeks. Spinal cord tissue was then fixed by perfusion and used for m orphometric and immunocytochemical analyses. Previous studies with acu te NBQX treatment showed significant functional improvement by 1 week; the effects of delayed NBQX treatment on functional deficits were not discernible until 3-4 weeks after SCI. Thereafter, significant reduct ions in hindlimb deficits were demonstrated in two independent studies . The nature and magnitude of the reductions in chronic deficits were similar to those observed previously when NBQX was administered acutel y at 15 min after SCI. Morphometric analyses showed that delayed treat ment with NBQX resulted in sparing of gray matter adjacent to the inju ry site but no significant effect on the area of white matter at the e picenter. However, serotonin immunoreactivity below the lesion, used a s a marker for preservation of one supraspinal pathway, was significan tly higher in the NBQX-treated group. These results support a therapeu tic potential for NBQX, and presumably other AMPA antagonists, in SCI by demonstrating effectiveness in a clinically relevant time frame. Th ey indicate the importance of assessing chronic functional deficits in evaluating the therapeutic potential of a treatment paradigm. Further , they suggest the intriguing hypothesis that mechanisms underlying ea rly functional recovery after SCI are, at least in part, distinct thos e from those involved in reducing chronic functional deficits. (C) 199 7 Academic Press.