Dose-dependent reduction of tissue loss and functional impairment after spinal cord trauma with the AMPA/kainate antagonist NBQX

Abstract

Initial studies on the role of glutamate receptors in traumatic spinal cord injury (SCI) implicated the NMDA subclass of ionotropic glutamate receptors in contributing to functional deficits. Recently we obtained evidence suggesting that non-NMDA ionotropic receptors may participate in producing a portion of the behavioral impairment after SCI. To test this hypothesis we have conducted a dose-response experiment, focally injecting 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX; 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 standardized contusive SCI. Behavioral tests of hindlimb reflex and coordinated sensorimotor function were performed 1 d after injury and weekly thereafter. At 4 weeks, spinal cord tissue was examined using quantitative 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 white matter. The maximum dose (15 nmol) significantly reduced the average length of the lesions and doubled the area of residual white matter at 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 NBQX as compared to controls. Most importantly, the reduced tissue loss in NBQX-treated groups was correlated with reduced functional deficits. There was a dose-dependent enhancement of speed and degree of recovery of both reflex and coordinated hindlimb motor activity, and reduction in the time required for establishing a reflex bladder. The long-term functional deficits at 4 weeks after SCI were reduced in a dose-related manner. Further, regression analyses demonstrated a significant correlation between the increase in amount of residual tissue and improvement in hindlimb function. Our results suggest that in this type of incomplete 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.

Neuropsin promotes oligodendrocyte death, demyelination and axonal degeneration after spinal cord injury

“…Several lines of evidence have suggested that glutamate excitotoxicity plays a key role not only in neuronal cell death but also in delayed post traumatic spinal cord white matter degeneration (Faden and Simon, 1988;Wrathall et al, 1994;Agrawal and Fehlings, 1997;Wrathall et al, 1997). Oligodendrocytes are highly vulnerable to excitotoxic signals mediated by glutamate receptors of the AMPA and kainate classes compared to astrocytes (Oka et al, 1993;Yoshioka et al, 1996;Agrawal and Fehlings, 1997;Matute -27 -et al, 1997;McDonald et al, 1998).…”

Post-traumatic moderate systemic hypothermia reduces TUNEL positive cells following spinal cord injury in rat

“…44 The administration of NBQX (a non-NMDA receptor antagonist) within 4 h of injury improves neurological prognosis. 45 Therefore, inhibition of post-traumatic glutamate release may be one of the possible mechanisms of the neuroprotective effect of hypothermia. Although systemic hypothermia has been reported to have a neuroprotective effect through inhibiting TPC, the pyramidal tract in rodents runs in ventral region of the dorsal column.…”

Nervous System-Specific Expression of a Novel Serine Protease: Regulation in the Adult Rat Spinal Cord by Excitotoxic Injury

“…We show that the novel serine protease MSP is present at high levels in the normal brain and spinal cord and is upregulated severalfold in spinal cord neurons and glia by K A-mediated excitotoxic injury. There is considerable evidence for a role of non-NMDA receptors in the response of the spinal cord white and gray matter to injury (Gomez-Pinilla et al, 1989;Rothstein et al, 1993;Wrathall et al, 1994;Agrawal and Fehlings, 1997). Further, it has been demonstrated in vitro that spinal motor neurons are selectively vulnerable to AMPA/kainate receptor-mediated injury because of the expression of AMPA/kainate receptors gating channels with direct Ca 2ϩ permeability (Carriedo et al, 1996).…”