Phenytoin protects central axons in experimental autoimmune encephalomyelitis.
Axon degeneration is a major contributor to non-remitting deficits in multiple sclerosis (MS). Thus the development of therapies to provide protection of axons has elicited considerable interest. Voltage-gated sodium channels have been implicated in the injury cascade leading to axonal damage, and sodium-channel blockers have shown efficacy in ameliorating axonal damage in disease models following anoxia, trauma and damaging levels of nitric oxide (NO). Here we discuss studies in our laboratory that examined the protective effects of phenytoin, a well-characterized sodium-channel blocker, in the inflammatory/demyelinating disorder experimental autoimmune encephalomyelitis (EAE), a model of MS. Administration of phenytoin to C57/Bl6 mice inoculated with rat myelin oligodendrocyte glycoprotein (MOG) provides improved clinical status, preservation of axons, enhanced action potential conduction and reduced immune infiltrates compared to untreated mice with EAE. Moreover, continuous treatment with phenytoin provides these protective actions for at least 180 days post-MOG injection. The withdrawal of phenytoin from mice inoculated with MOG, however, is accompanied by acute exacerbation of EAE, with significant mortality and infiltration of immune cells in the CNS. Our studies demonstrate the efficacy of phenytoin as a neuroprotectant in EAE. Our results also, however, indicate that we need to learn more about the long-term effects of sodium-channel blockers, and of their withdrawal, in neuroinflammatory disorders.
Black
Joel A
JA
Department of Neurology and Center for Neuroscience and Regeneration Research, Yale School of Medicine, New Haven, CT 06510, United States. joel.black@yale.edu
Waxman
Stephen G
SG
D000818:Animals; D001369:Axons / Q000187:drug effects*; D002490:Central Nervous System / Q000166:cytology* / Q000187:drug effects; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D010672:Phenytoin / Q000627:therapeutic use*
D010672:Phenytoin