title: 4-Aminopyridine ameliorates mobility but not disease course in an animal model of multiple sclerosis.
abstract: Neuropathological changes following demyelination in multiple sclerosis (MS) lead to a reorganization of axolemmal channels that causes conduction changes including conduction failure. Pharmacological modulation of voltage-sensitive potassium channels (K(V)) has been found to improve conduction in experimentally induced demyelination and produces symptomatic improvement in MS patients. Here we used an animal model of autoimmune inflammatory neurodegeneration, namely experimental autoimmune encephalomyelitis (EAE), to test the influence of the K(V)-inhibitor 4-aminopyridine (4-AP) on various disease and immune parameters as well as mobility in MOG₃₅₋₅₅ immunized C57Bl/6 mice. We challenged the hypothesis that 4-AP exerts relevant immunomodulatory or neuroprotective properties. Neither prophylactic nor therapeutic treatment with 4-AP altered disease incidence or disease course of EAE. Histopathological signs of demyelination and neuronal damage as well as MRI imaging of brain volume changes were unaltered. While application of 4-AP significantly reduced the standing outward current of stimulated CD4(+) T cells compared to controls, it failed to impact intracellular calcium concentrations in these cells. Compatibly, KV channel inhibition neither influenced CD4(+) T cell effector functions (proliferation, IL17 or IFNγ production). Importantly however, despite equal disease severity scores 4-AP treated animals showed improved mobility as assessed by 2 independent methods, 1) foot print and 2) rotarod analysis (0.332 ± 0.03, n=7 versus 0.399 ± 0.08, n=14, p<0.001, respectively). Our data suggest that 4-AP while having no apparent immunomodulatory or direct neuroprotective effects, significantly ameliorates conduction abnormalities thereby improving gait and coordination. Improvement of mobility in this experimental model supports trial data and clinical experience with 4-AP in the symptomatic treatment of MS.
authors.affiliation: University of Muenster, Department of Neurology, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany. Electronic address: kerstin.goebel@ukmuenster.de.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Göbel
authors.forename: Jan-Hendrik
authors.initials: JH
authors.lastname: Wedell
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Herrmann
authors.forename: Lydia
authors.initials: L
authors.lastname: Wachsmuth
authors.forename: Susann
authors.initials: S
authors.lastname: Pankratz
authors.forename: Stefan
authors.initials: S
authors.lastname: Bittner
authors.forename: Thomas
authors.initials: T
authors.lastname: Budde
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
authors.forename: Cornelius
authors.initials: C
authors.lastname: Faber
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects*; D009186:Myelin Sheath / Q000187:drug effects / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D026902:Potassium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D026902:Potassium Channel Blockers; D015761:4-Aminopyridine
keywords: 4-Aminopyridine; EAE; Mobility; Multiple sclerosis; Symptomatic treatment