R. Arnold, W. Huynh, M.C. Kiernan and A.V. Krishnan Pages 4366 - 4378 ( 13 )
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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> channels that may in turn hinder neural transmission. From a therapeutic perspective, the potent K<sup>+</sup> 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.
4-aminopyridine, fampridine, ion channels, K<sup>+</sup> channels, multiple sclerosis, Na<sup>+</sup> channels, treatment.
, , , Wales Clinical School, Faculty of Medicine, University of New South Wales, Medical Professorial Unit, South Wing, Edmund Blackett Building, Sydney, NSW 2052, Australia.