Jr. Wrathall et al., DOSE-DEPENDENT REDUCTION OF TISSUE LOSS AND FUNCTIONAL IMPAIRMENT AFTER SPINAL-CORD TRAUMA WITH THE AMPA KAINATE ANTAGONIST NBQX, The Journal of neuroscience, 14(11), 1994, pp. 6598-6607
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.