title: Tapered withdrawal of phenytoin removes protective effect in EAE without inflammatory rebound and mortality.
abstract: Axon degeneration has been identified as a major contributor to non-remitting neurological deficits in patients with multiple sclerosis (MS), which has elicited substantial interest in the development of neuroprotective therapies. Sodium channel blockers, including phenytoin, carbamazepine, flecainide and lamotrigine, have been shown to protect axons from degeneration, attenuate immune cell infiltrates and slow the acquisition of neurological deficits in mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. However, the sudden withdrawal of sodium channel blockers, phenytoin and carbamazepine, is associated with severe exacerbation of EAE characterized by massive inflammatory infiltrates and high mortality. In the present study, we asked whether a slow, tapered withdrawal of phenytoin treatment from mice with EAE produced sudden worsening similar to that of sudden withdrawal. Our results demonstrate that gradual withdrawal of phenytoin treatment from mice with EAE is associated with worsening of clinical scores which approach non-treated levels, but was not associated with increased immune cell infiltrates or deaths as have been observed with abrupt withdrawal. These observations support sodium channel blockers as a potential therapeutic agent in the treatment of MS, but indicate caution if treatment is ceased.
authors.affiliation: Department of Neurology and Center for Neuroscience Research, Yale University School of Medicine, New Haven, CT 06510, United States; Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT 06516, United States.
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Neurology and Center for Neuroscience Research, Yale University School of Medicine, New Haven, CT 06510, United States; Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT 06516, United States.
authors.forename: P
authors.initials: P
authors.lastname: Zwinger
authors.affiliation: Department of Neurology and Center for Neuroscience Research, Yale University School of Medicine, New Haven, CT 06510, United States; Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT 06516, United States.
authors.forename: J A
authors.initials: JA
authors.lastname: Black
authors.affiliation: Department of Neurology and Center for Neuroscience Research, Yale University School of Medicine, New Haven, CT 06510, United States; Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT 06516, United States. Electronic address: stephen.waxman@yale.edu.
authors.forename: S G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D009460:Neurologic Examination; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010446:Peptide Fragments / Q000633:toxicity; D010672:Phenytoin / Q000008:administration & dosage*; D013997:Time Factors
chemical_list: D063308:Myelin-Oligodendrocyte Glycoprotein; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D010672:Phenytoin
keywords: Axonal degeneration; Experimental autoimmune encephalomyelitis; Immune cell; Phenytoin; Sodium channel