Time course studies on the effectiveness of tetrodotoxin in reducing consequences of spinal cord contusion

Focal injection of the sodium channel blocker tetrodotoxin (TTX) into the i njury site at either 5 or 15 min after a standardized thoracic contusion sp inal cord injury (SCI) reduces white matter pathology and loss of axons in the first 24 hr after injury. Focal injection of TTX at 15 min after SCI al so reduces chronic white matter loss and hindlimb functional deficits. We h ave now tested the hypothesis that the reduction in chronic deficits with T TX treatment is associated with long-term preservation of axons after SCI a nd compared both acute (24 hr) and chronic (6 weeks) effects of TTX adminis tered at 15 min prior to and 5 min or 4 hr after SCI. Our results indicate a significant reduction of acute white matter pathology in rats treated wit h TTX at 15 min before and 5 min after injury but no effect when treatment was delayed until 4 hr after contusion. Compared with injury controls, grou ps treated with TTX at 5 min and 4 hr after injury did not show a significa nt deficit reduction, nor was there a significant sparing of white matter a t 6 weeks compared with injury controls. In contrast, the group treated wit h TTX at 15 min before SCI demonstrated significantly reduced hindlimb func tional deficits beginning at 1 week after injury and throughout the 6 weeks of the study. This was associated with a significantly higher axon density in the ventromedial white matter at 6 weeks. The results demonstrate that blockade of sodium channels preserves axons from loss after SCI and points to the importance of time of administration of such drugs for therapeutic e ffectiveness. (C) 2001 Wiley-Liss, Inc.