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Mechanisms of Disease: sodium channels and neuroprotection in multiple sclerosis—current status

Nature Clinical Practice Neurology volume 4, pages 159–169 (2008)Cite this article

Abstract

Sodium channels can provide a route for a persistent influx of sodium ions into neurons. Over the past decade, it has emerged that sustained sodium influx can, in turn, trigger calcium ion influx, which produces axonal injury in neuroinflammatory disorders such as multiple sclerosis (MS). The development of sodium channel blockers as potential neuroprotectants in MS has proceeded rapidly, and two clinical trials are currently ongoing. The route from the laboratory to the clinic includes some complex turns, however, and a third trial was recently put on hold because of new data that suggested that sodium channel blockers might have multiple, complex actions. This article reviews the development of the concept of sodium channel blockers as neuroprotectants in MS, the path from laboratory to clinic, and the current status of research in this area.

Key Points

  • Voltage-gated sodium channels can contribute to axonal injury in multiple sclerosis (MS) by providing a pathway for sustained sodium influx that drives the Na+/Ca2+ exchanger to import calcium into axons

  • Sodium channel blockers protect axons from degeneration in several in vitro models of axonal injury, and they prevent axon degeneration, maintain impulse conduction, and improve clinical status in experimental autoimmune encephalomyelitis, a mouse model of MS

  • Sodium channels regulate the function of macrophages and microglia, so, in addition to a direct protective effect on axons, sodium channel blockers might have an immunomodulatory action

  • Sudden withdrawal of the sodium channel blockers phenytoin and carbamazepine from mice with experimental autoimmune encephalomyelitis results in acute clinical exacerbation, accompanied by increased inflammatory infiltrate within the CNS

  • Until more is known about the effects of sodium channel blocker withdrawal in humans with MS, clinical studies should monitor patients closely both in terms of neurological function and axonal loss and with respect to immune and inflammatory status

  • If withdrawal of the sodium channel blocker is necessary in patients with MS treated with carbamazepine or phenytoin for trigeminal neuralgia or other positive disturbances, these medications should be discontinued via a gradual taper

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Figure 1: The central role of sodium channels in the axon degeneration cascade.
Figure 2: Treatment with phenytoin is protective in a mouse model of multiple sclerosis.
Figure 3: Withdrawal of phenytoin is followed by exacerbation in mice with experimental autoimmune encephalomyelitis.48
Figure 4: Sodium channels are expressed in, and regulate the function of, human macrophages.

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Author notes

  1. Department of Neurology, LCI 707, Yale Medical School, PO Box 20818, New Haven, CT 06520–8018, USA stephen.waxman@yale.edu

Authors and Affiliations

  1. SG Waxman is the Bridget Flaherty Professor of Neurology, Neurobiology and Pharmacology at Yale Medical School, New Haven, CT, and Director of the Center for Neuroscience and Regeneration Research, VA Connecticut Healthcare, West Haven, CT, USA.,

    Stephen G Waxman

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Waxman, S. Mechanisms of Disease: sodium channels and neuroprotection in multiple sclerosis—current status. Nat Rev Neurol 4, 159–169 (2008). https://doi.org/10.1038/ncpneuro0735

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