DOSE-DEPENDENT REDUCTION OF TISSUE LOSS AND FUNCTIONAL IMPAIRMENT AFTER SPINAL-CORD TRAUMA WITH THE AMPA KAINATE ANTAGONIST NBQX

Initial studies on the role of glutamate receptors in traumatic spinal cord injury (SCI) implicated the NMDA subclass of ionotropic glutamat e receptors in contributing to functional deficits. Recently we obtain ed evidence suggesting that non-NMDA ionotropic receptors may particip ate in producing a portion of the behavioral impairment after SCI. To test this hypothesis we have conducted a dose-response experiment, foc ally injecting 3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQ X; 1.5, 5, or 15 nmol), a highly selective antagonist of alpha-amino-3 -hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptors, or vehicle alone, into the injury site beginning at 15 min after a st andardized contusive SCI. Behavioral tests of hindlimb reflex and coor dinated sensorimotor function were performed 1 d after injury and week ly thereafter. At 4 weeks, spinal cord tissue was examined using quant itative histopathological and immunocytochemical techniques. We found a dose-dependent reduction in tissue loss at the thoracic injury site, with greater residual amounts of both gray matter and myelinated whit e matter. The maximum dose (15 nmol) significantly reduced the average length of the lesions and doubled the area of residual white matter a t the epicenter. Serotonin immunoreactivity caudal to the lesion, used as a marker for descending motor control axons, was also increased in a dose-related manner and nearly tripled with the highest dose of NBQ X as compared to controls. Most importantly, the reduced tissue loss i n NBQX-treated groups was correlated with reduced functional deficits. There was a dose-dependent enhancement of speed and degree of recover y of both reflex and coordinated hindlimb motor activity, and reductio n in the time required for establishing a reflex bladder. The long-ter m functional deficits at 4 weeks after SCI were reduced in a dose-rela ted manner. Further, regression analyses demonstrated a significant co rrelation between the increase in amount of residual tissue and improv ement in hindlimb function. Our results suggest that in this type of i ncomplete contusive SCI, a large and functionally important proportion of the tissue loss appears to be due to secondary injury mediated by local AMPA/kainate receptors.