Brain Advance Access originally published online on August 24, 2006
Brain 2006 129(12):3196-3208; doi:10.1093/brain/awl216
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Long-term protection of central axons with phenytoin in monophasic and chronic-relapsing EAE
1 Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine New Haven 2 Rehabilitation Research Center, VA Connecticut Healthcare System West Haven, CT 3 Department of Surgery, Brown University School of Medicine Providence, RI, USA
Correspondence to: Joel A. Black, PhD, Neuroscience Research (127A), VA Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT 06518, USA E-mail: joel.black{at}yale.edu
Axonal degeneration is a major contributor to non-remitting deficits in multiple sclerosis, and there is thus considerable current interest in the development of strategies that might prevent axonal loss in neuroinflammatory disease. Dysregulation of sodium ion homeostasis has been implicated in mechanisms leading to axonal degeneration, and several studies have shown that blockade of sodium channels can ameliorate axon damage following anoxic, traumatic and nitric oxide-induced CNS injury. Two sodium channel blockers, phenytoin and flecainide, have been reported to protect axons in experimental autoimmune encephalomyelitis (EAE) for 30 days, but long-term protective effects have not been studied. We demonstrate here that oral administration of phenytoin provides long-term (up to 180 days) protection for spinal cord corticospinal tract (CST) and dorsal column (DC) axons in both monophasic (C57/BL6 mice) and chronic-relapsing (Biozzi mice) murine EAE. Untreated C57/BL6 mice exhibit a 40–50% loss of CST and DF axons at 90 and 180 days post-EAE induction via myelin-oligodendrocyte glycoprotein (MOG) injection. In contrast, only 4% of DF axons are lost at 90 days, and only 8% are lost at 180 days in phenytoin-treated C57/BL6 mice with EAE; only 21–29% of CST axons are lost at 90 and 180 days in phenytoin-treated C57/BL6 mice with EAE. Attenuation of dorsal column compound action potentials was ameliorated and clinical status was also significantly enhanced with phenytoin treatment at 90 and 180 days in this model. In addition, inflammatory cell infiltration into the dorsal columns was reduced in phenytoin-treated mice with EAE compared with untreated mice with EAE. Similar results were obtained in Biozzi mice with chronic-relapsing EAE followed for 120 days post-injection. These observations demonstrate that phenytoin provides long-term protection of CNS axons and improves clinical status in both monophasic and chronic-relapsing models of neuroinflammation.
Key Words: axon protection; EAE; inflammatory cell; multiple sclerosis; phenytoin; sodium channel
Abbreviations: EAE, experimental autoimmune encephalomyelitis; CAP, compound action potential; CST, corticospinal tract; DC, dorsal columns; DF, dorsal funiculus
Received March 22, 2006. Revised July 7, 2006. Accepted July 19, 2006.
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