4-Aminopyridine ameliorates mobility but not disease course in an animal model of multiple sclerosis
4-Aminopyridine ameliorates mobility but not disease course in an animal model of multiple sclerosis
复制标题
DOI：
10.1016/j.expneurol.2013.05.016
复制
发表时间：
2013-10-01
影响因子：
5.3
通讯作者：
Meuth, Sven G.
中科院分区：
文献类型：
--
作者：
Goebel, Kerstin;Wedell, Jan-Hendrik;Meuth, Sven G.
多发性硬化症（MS）脱髓鞘后的神经病理学变化导致轴膜通道重组，导致传导变化，包括传导失败。已经发现电压敏感性钾通道（K-v）的药理学调节改善实验诱导的脱髓鞘中的传导，并在MS患者中产生症状改善。在此，我们使用自身免疫性炎性神经变性的动物模型，即实验性自身免疫性脑脊髓炎（EAE），来测试K-v抑制剂4-氨基吡啶（4-AP）对MOG（35-55）免疫的C57 B1/6小鼠中的各种疾病和免疫参数以及移动性的影响。我们质疑4-AP具有相关免疫调节或神经保护作用的假设，4-AP的预防性或治疗性治疗均不能改变EAE的发病率或病程。脱髓鞘和神经元损伤的组织学体征以及脑体积变化的MRI成像未改变。虽然与对照组相比，4-AP的应用显著降低了刺激的CD 4（+）T细胞的外向电流，但它未能影响这些细胞中的细胞内钙浓度。相容地，Kv通道抑制既不影响CD 4（+）T细胞效应器功能（增殖、IL 17或IFN γ产生）。然而，重要的是，尽管疾病严重程度评分相同，但4-AP治疗的动物显示出改善的活动性，如通过2种独立方法评估的，I）足迹和2）旋转杆分析（0.332 +/- 0.03，n = 7对比0.399 +/- 0.08，n = 14，p < 0.001，我们的数据表明，4-AP虽然没有明显的免疫调节或直接的神经保护作用，但显著改善了传导异常，从而改善了步态和协调。该实验模型中活动性的改善支持4-AP用于MS对症治疗的试验数据和临床经验。（C）2013 Elsevier Inc. All rights reserved.
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, Kv channel inhibition neither influenced CD4(+) T cell effector functions (proliferation, IL17 or IFN gamma production). Importantly however, despite equal disease severity scores 4-AP treated animals showed improved mobility as assessed by 2 independent methods, I) 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. (C) 2013 Elsevier Inc. All rights reserved.