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 secondary axonal loss after spinal cord injury (SCI), recent data from in vitro models of white matter (WM) injury have implicated abnormal sodium influx as a key event. We hypothesized that blockade of sodium channels after SCI would reduce WM loss and long-term functional deficits. To test this hypothesis, a sufficient and safe dose (0.15 nmol) of the 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 TTX treatment significantly reduced tissue loss at the injury site, with greater effect on sparing of WM than gray matter. TTX did not change the pattern of chronic histopathology typical of this SCI model, but restricted 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 of coordinated hindlimb functions, more normal hindlimb reflexes, and earlier establishment of a reflex bladder. The results demonstrate that Na+ channels play a critical role in WM loss in vivo after SCI.
Teng
Y D
YD
Department of Cell Biology, Neurobiology Division, Georgetown University, Washington, D.C. 20007, USA.
Wrathall
J R
JR
D000818:Animals; D003288:Contusions / Q000188:drug therapy / Q000503:physiopathology; D005260:Female; D007091:Image Processing, Computer-Assisted; D016014:Linear Models; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008845:Microinjections; D009412:Nerve Fibers / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D013779:Tetrodotoxin / Q000494:pharmacology*; D013997:Time Factors
D026941:Sodium Channel Blockers; D013779:Tetrodotoxin