Effects of the sodium channel blocker tetrodotoxin on acute white matter pathology after experimental contusive spinal cord injury

Focal microinjection of tetrodotoxin (TTX), a potent voltage-gated sodium c hannel blocker, reduces neurological deficits and tissue loss after spinal cord injury (SCI). Significant sparing of white matter (WM) is seen at 8 we eks after injury and is correlated to a reduction in functional deficits. T o determine whether TTX exerts an acute effect on WM pathology, Sprague Daw ley rats were subjected to a standardized weight-drop contusion at T8 (10 g m x 2.5 cm). TTX (0.15 nmol) or vehicle solution was injected into the inju ry site 5 or 15 min later. At 4 and 24 hr, ventromedial WM from the injury epicenter was compared by light and electron microscopy and immunohistochem istry. By 4 hr after SCI, axonal counts revealed reduced numbers of axons a nd significant loss of large (greater than or equal to 5 pm)diameter axons. TTX treatment significantly reduced the loss of large-diameter axons. In a ddition, TTX significantly attenuated axoplasmic pathology at both 4 and 24 hr after injury. In particular, the development of extensive periaxonal sp aces in the large-diameter axons was reduced with TTX treatment. In contras t, there was no significant effect of TTX on the loss of WM glia after SCI. Thus,the long-term effects of TTX in reducing WM loss after spinal cord in jury appear to be caused by the reduction of acute axonal pathology. These results support the hypothesis that TTX-sensitive sodium channels at axonal nodes of Ranvier play a significant role in the secondary injury of WM aft er SCI.