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 channel blocker, reduces neurological deficits and tissue loss after spinal cord injury (SCI). Significant sparing of white matter (WM) is seen at 8 weeks after injury and is correlated to a reduction in functional deficits. To determine whether TTX exerts an acute effect on WM pathology, Sprague Dawley rats were subjected to a standardized weight-drop contusion at T8 (10 gm x 2.5 cm). TTX (0. 15 nmol) or vehicle solution was injected into the injury 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 immunohistochemistry. By 4 hr after SCI, axonal counts revealed reduced numbers of axons and significant loss of large (>/=5 micrometer)-diameter axons. TTX treatment significantly reduced the loss of large-diameter axons. In addition, TTX significantly attenuated axoplasmic pathology at both 4 and 24 hr after injury. In particular, the development of extensive periaxonal spaces in the large-diameter axons was reduced with TTX treatment. In contrast, 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 injury 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 after SCI.
Neurobiology Division, Department of Cell Biology, Georgetown University, Washington, DC 20007, USA.
L J
LJ
Rosenberg
Y D
YD
Teng
J R
JR
Wrathall
D000818:Animals; D001369:Axons / Q000473:pathology*; D003288:Contusions; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D007278:Injections, Spinal; D008845:Microinjections; D009186:Myelin Sheath / Q000473:pathology; D009336:Necrosis; D009457:Neuroglia / Q000145:classification / Q000473:pathology; D009836:Oligodendroglia / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology*; D013119:Spinal Cord Injuries / Q000473:pathology*; D013779:Tetrodotoxin / Q000008:administration & dosage / Q000633:toxicity*
D005904:Glial Fibrillary Acidic Protein; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin