2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and Contusions

Focal microinjection of 2, 3-dihyro-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), an antagonist of the AMPA/kainate subclass of glutamate receptors, reduces neurological deficits and tissue loss after spinal cord injury. Dose-dependent sparing of white matter is seen at 1 month after injury that is correlated to the dose-related reduction in chronic functional deficits. To determine whether NBQX exerts an acute effect on white matter pathology, female, adult Spague Dawley rats were subjected to a standardized weight drop contusion at T-8 (10 gm x 2.5 cm) and NBQX (15 nmol) or vehicle (VEH) solution focally injected into the injury site 15 min later. At 4 and 24 hr, tissue from the injury epicenter was processed for light and electron microscopy, and the histopathology of ventromedial white matter was compared. The axonal injury index, a quantitative representation of axoplasmic and myelinic pathologies, was significantly lower in the NBQX group at 4 hr (2.7 +/- 0.24, mean +/- SE) and 24 hr (1.4 +/- 0.19) than in VEH controls (3.8 +/- 0.33 and 2.1 +/- 0.20, respectively). Counts of glial cell nuclei indicated a loss of at least 60% at 4 and 24 hr after injury in the VEH group compared with uninjured controls. NBQX treatment reduced this glial loss by half. Immunohistochemistry revealed that the spared glia were primarily oligodendrocytes. Thus, the chronic effects of NBQX in reducing white matter loss after spinal cord injury appear to be attributable to the reduction of acute pathology and may be mediated through the protection of glia, particularly oligodendrocytes.

Topics: Animals; Brain; Cell Death; Contusions; Excitatory Amino Acid Antagonists; Female; Hindlimb; Immunohistochemistry; Neuroglia; Quinoxalines; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries

We have previously demonstrated that the glutamatergic receptor (AMPA) antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline (NBQX) reduces functional deficits in a standardized rat model of contusive spinal cord injury (SCI). NBQX not only acted to protect neurons from excitotoxicity but also, unexpectedly, enhanced sparing of white matter including axons of descending pathways. We have therefore investigated mechanisms through which NBQX could produce beneficial effects for white matter. We report here that NBQX elicits a rapid and selective induction of FGF2 mRNA levels in injured spinal cord. This novel effect could contribute to the therapeutic properties of NBQX in the treatment of SCI.

Topics: Animals; Contusions; Excitatory Amino Acid Antagonists; Fibroblast Growth Factors; Laminectomy; Quinoxalines; Rats; RNA, Messenger; Spinal Cord Injuries; Tissue Distribution

To investigate the role of non-N-methyl-D-aspartate (non-NMDA) types of excitatory amino acid (EAA) receptors in traumatic spinal cord injury, we administered 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline (NBQX), a potent and specific antagonist of non-NMDA receptors, to rats with a standardized contusive spinal cord injury. Focal infusion of NBQX into the injury site significantly reduced long-term hindlimb functional deficits as well as decreasing the time required for the rats to establish a reflex bladder. The results suggest that non-NMDA receptors at or near the injury site are involved in producing a portion of the functional deficits that result from contusive spinal cord injury.

Topics: Animals; Contusions; Female; Hindlimb; Motor Activity; Quinoxalines; Rats; Rats, Inbred Strains; Receptors, Amino Acid; Receptors, Cell Surface; Spinal Cord Injuries