4-Aminopyridine ameliorates mobility but not disease course in an animal model of multiple sclerosis

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• 作者：Kerstin G?bel ; Jan-Hendrik Wedell ; Alex ; er M. Herrmann ; Lydia Wachsmuth ; Susann Pankratz ; Stefan Bittner ; Thomas Budde ; Christoph Kleinschnitz ; Cornelius Faber ; Heinz Wiendl ; Sven G. Meuth
• 关键词：4-Aminopyridine ; Multiple sclerosis ; EAE ; Symptomatic treatment ; Mobility
• 刊名：Experimental Neurology
• 出版年：2013
• 出版时间：October, 2013
• 年：2013
• 卷：248
• 期：Complete
• 页码：62-71
• 全文大小：1494 K

文摘

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 MOG_35-55 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, K_V channel inhibition neither influenced CD4⁺ T cell effector functions (proliferation, IL17 or IFN¦Ã 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 ¡À 0.03, n = 7 versus 0.399 ¡À 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.