LOCAL BLOCKADE OF SODIUM-CHANNELS BY TETRODOTOXIN AMELIORATES TISSUE LOSS AND LONG-TERM FUNCTIONAL DEFICITS RESULTING FROM EXPERIMENTAL SPINAL-CORD INJURY
Yd. Teng et Jr. Wrathall, LOCAL BLOCKADE OF SODIUM-CHANNELS BY TETRODOTOXIN AMELIORATES TISSUE LOSS AND LONG-TERM FUNCTIONAL DEFICITS RESULTING FROM EXPERIMENTAL SPINAL-CORD INJURY, The Journal of neuroscience, 17(11), 1997, pp. 4359-4366
Although relatively little is known of the mechanisms involved in seco
ndary axonal loss after spinal cord injury (SCI), recent data from in
vitro models of white matter (WM) injury have implicated abnormal sodi
um influx as a key event. We hypothesized that blockade of sodium chan
nels after SCI would reduce WM loss and long-term functional deficits.
To test this hypothesis, a sufficient and safe dose (0.15 nmol) of th
e potent Na+ channel blocker tetrodotoxin (TTX) was determined through
a dose-response study. We microinjected TTX or vehicle (VEH) into the
injury site at 15 min after a standardized contusive SCI in the rat.
Behavioral tests were performed 1 d after injury and weekly thereafter
. Quantitative histopathology at 8 weeks postinjury showed that mt tre
atment significantly reduced tissue loss at the injury site, with grea
ter effect on sparing of WM than gray matter. TTX did not change the p
attern of chronic histopathology typical of this SCI model, but restri
cted its extent, tripled the area of residual WM at the epicenter, and
reduced the average length of the lesions. Serotonin immunoreactivity
caudal to the epicenter, a marker for descending motor control axons,
was nearly threefold that of VEH controls. The increase in WM at the
epicenter was significantly correlated with the decrease in functional
deficits. The TTX group exhibited a significantly enhanced recovery o
f coordinated hindlimb functions, more normal hindlimb reflexes, and e
arlier establishment of a reflex bladder. The results demonstrate that
Na+ channels play a critical role in WM loss in vivo after SCI.