Ion Channel Modulation as a Therapeutic Approach in Multiple Sclerosis

Author(s): R. Arnold, W. Huynh, M.C. Kiernan, A.V. Krishnan.

Journal Name: Current Medicinal Chemistry

Volume 22 , Issue 38 , 2015

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Abstract:

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.

Keywords: 4-aminopyridine, fampridine, ion channels, K+ channels, multiple sclerosis, Na+ channels, treatment.

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Article Details

VOLUME: 22
ISSUE: 38
Year: 2015
Page: [4366 - 4378]
Pages: 13
DOI: 10.2174/0929867322666151029104452
Price: $58

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