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The Journal of Neuroscience, May 12, 2004, 24(19):4605-4613; doi:10.1523/JNEUROSCI.0515-03.2004

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Cellular/Molecular
Traumatic Axonal Injury Induces Proteolytic Cleavage of the Voltage-Gated Sodium Channels Modulated by Tetrodotoxin and Protease Inhibitors

Akira Iwata,¹ Peter K. Stys,³ John A. Wolf,¹ Xiao-Han Chen,¹ Andrew G. Taylor,² David F. Meaney,² and Douglas H. Smith¹

Departments of ¹Neurosurgery and ²Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, and ³Ottawa Health Research Institute, Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada, K1Y 4K9

We demonstrated previously that dynamic stretch injury of cultured axons induces structural changes and Ca²⁺ influx modulated by tetrodotoxin (TTX)-sensitive voltage-gated sodium channels (NaChs). In the present study, we evaluated potential damage to the NaCh -subunit, which can cause noninactivation of NaChs. In addition, we explored the effects of pre-injury and post-injury treatment with TTX and protease inhibition on proteolysis of the NaCh -subunit and intra-axonal calcium levels ([Ca²⁺]i) over 60 min after trauma. After stretch injury, we found that [Ca²⁺]i continued to increase in untreated axons for at least 60 min. We also observed that the III-IV intra-axonal loop of the NaCh -subunit was proteolyzed between 5 and 20 min after trauma. Pre-injury treatment of the axons with TTX completely abolished the posttraumatic increase in [Ca²⁺]i and proteolysis of the NaCh -subunit. In addition, both pre-injury and post-injury inhibition of protease activity attenuated long-term increases in [Ca²⁺]i as well as mitigating degradation of the NaCh -subunit. These results suggest a unique "feed-forward" deleterious process initiated by mechanical trauma of axons. Na⁺ influx through NaChs resulting from axonal deformation triggers initial increases in [Ca²⁺]i and subsequent proteolysis of the NaCh-subunit. In turn, degradation of the -subunit promotes persistent elevations in [Ca²⁺]i, fueling additional pathologic changes. These observations may have important implications for developing therapeutic strategies for axonal trauma.

Key words: axon trauma; diffuse axonal injury; sodium channels; calcium; proteolysis; protease inhibitors; noninactivation; tetrodotoxin; traumatic brain injury

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Received Feb 24, 2004; revised March 29, 2004; accepted March 29, 2004.

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