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Brain. 2004 Feb;127(Pt 2):294-303. Epub 2003 Dec 8.

Co-localization of sodium channel Nav1.6 and the sodium-calcium exchanger at sites of axonal injury in the spinal cord in EAE.

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  • 1Department of Neurology, PVA/EPVA Center for Neuroscience Research, Yale School of Medicine, New Haven, CT 06510, USA.


Axonal degeneration contributes to the development of non-remitting neurological deficits and disability in multiple sclerosis, but the molecular mechanisms that underlie axonal loss in multiple sclerosis are not clearly understood. Studies of white matter axonal injury have demonstrated that voltage-gated sodium channels can provide a route for sodium influx into axons that triggers reverse operation of the Na(+)/Ca(2+) exchanger (NCX) and subsequent influx of damaging levels of intra-axonal calcium. The molecular identities of the involved sodium channels have, however, not been determined. We have previously demonstrated extensive regions of diffuse expression of Na(v)1.6 and Na(v)1.2 sodium channels along demyelinated axons in experimental allergic encephalomyelitis (EAE). Based on the hypothesis that the co-localization of Na(v)1.6 and NCX along extensive regions of demyelinated axons may predispose these axons to injury, we examined the expression of myelin basic protein, Na(v)1.2, Na(v)1.6, NCX and beta-amyloid precursor protein (beta-APP), a marker of axonal injury, in the spinal cord dorsal columns of mice with EAE. We demonstrate a significant increase in the number of demyelinated axons demonstrating diffuse Na(v)1.6 and Na(v)1.2 sodium channel immunoreactivity in EAE (92.2 +/- 2.1% of beta-APP positive axons were Na(v)1.6-positive). Only 38.0 +/- 2.9% of beta-APP positive axons were Na(v)1.2 positive, and 95% of these co-expressed Na(v)1.6 together with Na(v)1.2. Using triple-labelled fluorescent immunohistochemistry, we demonstrate that 73.5 +/- 4.3% of beta-APP positive axons co-express Na(v)1.6 and NCX, compared with 4.4 +/- 1.0% in beta-APP negative axons. Our results indicate that co-expression of Na(v)1.6 and NCX is associated with axonal injury in the spinal cord in EAE.

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