摘要
离子通道功能障碍已被确定为在多发性硬化症的症状发展和神经退行性疾病的贡献者。分子层面的见解已被视为新的研究路线,离子通道调制代表一种治疗方法在多发性硬化症中。钠离子通道功能的研究表明在急性炎症发作期的钠离子通道病理封锁。复发通常与后续的改变,钠离子通道的表达和结构有关。然而,这些代偿性的变化也可能是有害的。具体而言,增加钠离子通道的表达可能有助于神经元的能量不足和级联的事件,可能最终导致神经退行性疾病和细胞凋亡。药物阻断钠离子通道在动物模型中表现出令人满意的效果,即使在随后的临床试验中获得了不同答案。在参与过程中的脱髓鞘,多发性硬化症病理特征的事件,也可能引起复杂的结构变化介导的钾离子通道,可能会阻碍神经传输。从治疗的角度来看,有效的钾离子通道阻断剂,4-氨基吡啶(4-AP),证明神经电生理和功能在脱髓鞘动物模型的改进。这些临床效果的实现与最近的氨吡啶缓释片的出现有关。改进4-AP释放形式,III期临床试验表明在提高多发性硬化症神经系统症状包括疲劳,行走速度和强度有明显作用。
关键词: 4-氨基吡啶、氨吡啶、离子通道、钾通道、多发性硬化,Na +通道,治疗。
Current Medicinal Chemistry
Title:Ion Channel Modulation as a Therapeutic Approach in Multiple Sclerosis
Volume: 22 Issue: 38
Author(s): R. Arnold, W. Huynh, M.C. Kiernan and A.V. Krishnan
Affiliation:
关键词: 4-氨基吡啶、氨吡啶、离子通道、钾通道、多发性硬化,Na +通道,治疗。
摘要: Ion channel dysfunction has been identified as a contributor to symptom development and neurodegeneration in multiple sclerosis (MS). The molecular insights have been translated into new lines of research, with ion channel modulation now representing a therapeutic approach in MS. Studies of Na+ channel function have demonstrated pathological blockade of Na+ channels during an acute inflammatory attack. Relapses are typically associated with subsequent alterations in Na+ channel expression and structure. However, these compensatory changes may also be deleterious. Specifically, increased Na+ channel expression may contribute to neuronal energy insufficiency and a cascade of events that may ultimately lead to neurodegeneration and apoptosis. Pharmacological blockade of Na+ channels in animal models of MS demonstrated encouraging results, although mixed results were obtained in subsequent clinical trials in MS patient cohorts. The process involved in demyelination, a characteristic event in MS pathology, may also induce complex structural changes mediated by K+ channels that may in turn hinder neural transmission. From a therapeutic perspective, the potent K+ channel blocker, 4-aminopyridine (4-AP), has demonstrated neurophysiological and functional improvements in animal models of demyelination. Clinical translation of these results was recently achieved with the advent of Fampridine PR, a modified release form of 4-AP, with phase III clinical trials that demonstrated improvement in neurological symptoms including fatigue, walking speed and strength in MS patients.
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Cite this article as:
R. Arnold, W. Huynh, M.C. Kiernan and A.V. Krishnan , Ion Channel Modulation as a Therapeutic Approach in Multiple Sclerosis, Current Medicinal Chemistry 2015; 22 (38) . https://dx.doi.org/10.2174/0929867322666151029104452
DOI https://dx.doi.org/10.2174/0929867322666151029104452 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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