HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Long-term protection of central axons with phenytoin in monophasic and chronic-relapsing EAE.

Abstract
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.
AuthorsJoel A Black, Shujun Liu, Bryan C Hains, Carl Y Saab, Stephen G Waxman
JournalBrain : a journal of neurology (Brain) Vol. 129 Issue Pt 12 Pg. 3196-208 (Dec 2006) ISSN: 1460-2156 [Electronic] England
PMID16931536 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Mog protein, mouse
  • Myelin Proteins
  • Myelin-Associated Glycoprotein
  • Myelin-Oligodendrocyte Glycoprotein
  • Sodium Channel Blockers
  • Phenytoin
Topics
  • Action Potentials (physiology)
  • Administration, Oral
  • Animals
  • Axons (drug effects)
  • Cell Count (methods)
  • Cervical Vertebrae
  • Chronic Disease
  • Encephalomyelitis, Autoimmune, Experimental (drug therapy, pathology, physiopathology)
  • Immunohistochemistry (methods)
  • Injections, Subcutaneous
  • Mice
  • Mice, Inbred C57BL
  • Myelin Proteins
  • Myelin-Associated Glycoprotein (administration & dosage)
  • Myelin-Oligodendrocyte Glycoprotein
  • Neural Conduction
  • Phenytoin (administration & dosage)
  • Recurrence
  • Sodium Channel Blockers (administration & dosage)
  • Spinal Cord (drug effects, pathology, physiopathology)
  • Treatment Outcome

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: