Traumatic axonal injury induces calcium influx modulated by tetrodotoxin-sensitive sodium channels

John A. Wolf, Peter K. Stys, Theresa Lusardi, David Meaney, Douglas H. Smith

Research output: Contribution to journalArticlepeer-review

289 Scopus citations

Abstract

Diffuse axonal injury (DAI) is one of the most common and important pathologies resulting from the mechanical deformation of the brain during trauma. It has been hypothesized that calcium influx into axons plays a major role in the pathophysiology of DAI. However, there is little direct evidence to support this hypothesis, and mechanisms of potential calcium entry have not been explored. In the present study, we used an in vitro model of axonal stretch injury to evaluate the extent and modulation of calcium entry after trauma. Using a calcium-sensitive dye, we observed a dramatic increase in intra-axonal calcium levels immediately after injury. Axonal injury in a calcium-free extracellular solution resulted in no change in calcium concentration, suggesting an extracellular source for the increased post-traumatic calcium levels. We also found that the post-traumatic change in intra-axonal calcium was completely abolished by the application of the sodium channel blocker tetrodotoxin or by replacement of sodium with N-methyl-D-glucamine. In addition, application of the voltage-gated calcium channel (VGCC) blocker ω-conotoxin MVIIC attenuated the post-traumatic increase in calcium. Furthermore, blockade of the Na+-Ca2+ exchanger with bepridil modestly reduced the calcium influx after injury. In contrast to previously proposed mechanisms of calcium entry after axonal trauma, we found no evidence of calcium entry through mechanically produced pores (mechanoporation). Rather, our results suggest that traumatic deformation of axons induces abnormal sodium influx through mechanically sensitive Na+ channels, which subsequently triggers an increase in intra-axonal calcium via the opening of VGCCs and reversal of the Na+-Ca2+ exchanger.

Original languageEnglish (US)
Pages (from-to)1923-1930
Number of pages8
JournalJournal of Neuroscience
Volume21
Issue number6
StatePublished - Mar 15 2001
Externally publishedYes

Keywords

  • Axon
  • Brain trauma
  • Calcium
  • Diffuse axonal injury
  • Injury
  • Mechanoporation
  • Mechanosensitivity
  • Sodium channels

ASJC Scopus subject areas

  • Neuroscience(all)

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