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Volume 39 Number 2, March/April 2002
Pages 233 — 242

Sodium channels as molecular targets in multiple sclerosis
Stephen G. Waxman, MD, PhD
Department of Neurology and Paralyzed Veterans of America/Eastern Paralyzed Veterans Association Center for Neuroscience Research, Yale University School of Medicine, New Haven, CT 06510, and Rehabilitation Research and Development Center, VA Connecticut Healthcare System, West Haven, CT 06516
Abstract — Sodium channels are expressed at high density in myelinated axons and play an obligatory role in conducting action potentials along axons within the mammalian brain and spinal cord. It is not surprising, therefore, that they are involved in several aspects of the pathophysiology of multiple sclerosis (MS). First, the deployment of additional sodium channels to demyelinated parts of the axon (which had expressed low densities of sodium channels when covered by the myelin) provides a molecular substrate for the restoration of action potential conduction, a process that contributes to remissions in patients with MS. Second, there is evidence for changes in the expression pattern of sodium channels within Purkinje cells, both in animal models of MS and in human MS. It has been hypothesized that dysregulated sodium channel expression may contribute to symptom production in MS. If this hypothesis is correct, subtype-specific channel blockade may be therapeutically effective as a symptomatic treatment for ataxia and other cerebellar symptoms in MS. Finally, a noninactivating sodium conductance can trigger calcium-mediated axonal injury via reverse sodium-calcium exchange. Identifying the underlying channel may permit the development of therapeutic strategies that will prevent or retard axonal degeneration in MS.

Key words: action potential, demyelination, molecular plasticity, sodium channels, neuroprotection, nodes of Ranvier, remission, multiple sclerosis.

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