LOCAL BLOCKADE OF SODIUM-CHANNELS BY TETRODOTOXIN AMELIORATES TISSUE LOSS AND LONG-TERM FUNCTIONAL DEFICITS RESULTING FROM EXPERIMENTAL SPINAL-CORD INJURY

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.