Ion Channel Modulation as a Therapeutic Approach in Multiple Sclerosis.
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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Arnold
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Huynh
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MC
Kiernan
Wales Clinical School, Faculty of Medicine, University of New South Wales, Medical Professorial Unit, South Wing, Edmund Blackett Building, Sydney, NSW 2052, Australia. arun.krishnan@unsw.edu.au.
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Krishnan
D015761:4-Aminopyridine / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D006801:Humans; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism*; D013329:Structure-Activity Relationship
D026902:Potassium Channel Blockers; D015221:Potassium Channels; D015222:Sodium Channels; D015761:4-Aminopyridine