Journal
CURRENT MEDICINAL CHEMISTRY
Volume 22, Issue 38, Pages 4366-4378Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/0929867322666151029104452
Keywords
4-aminopyridine; fampridine; ion channels; K+ channels; multiple sclerosis; Na+ channels; treatment
Funding
- Early Career Post-Doctoral Fellowship of the National Health and Medical Research Council of Australia [1091006]
- University of Sydney Post-Doctoral Research Fellowship
- National Health and Medical Research Council of Australia Program [1037746]
- Career Development Fellowship of the National Health and Medical Research Council of Australia [1065663]
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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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