Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment.
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by demyelination, with a relative sparing of axons. In MS patients, many neurologic signs and symptoms have been attributed to the underlying conduction deficits. The idea that neurologic function might be improved if conduction could be restored in CNS demyelinated axons led to the testing of potassium (K(+)) channel blockers as a symptomatic treatment. To date, only 2 broad-spectrum K(+) channel blockers, 4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-DAP), have been tested in MS patients. Although both 4-AP and 3,4-DAP produce clear neurologic benefits, their use has been limited by toxicity. Here we review the current status of basic science and clinical research related to the therapeutic targeting of voltage-gated K(+) channels (K(v)) in MS. By bringing together 3 distinct but interrelated disciplines, we aim to provide perspective on a vast body of work highlighting the lengthy and ongoing process entailed in translating fundamental K(v) channel knowledge into new clinical treatments for patients with MS and other demyelinating diseases. Covered are (1) K(v) channel nomenclature, structure, function, and pharmacology; (2) classic and current experimental morphology and neurophysiology studies of demyelination and conduction deficits; and (3) a comprehensive overview of clinical trials utilizing 4-AP and 3,4-DAP in MS patients.
MS Center of Excellence-East, Research and Neurology Services, VA Maryland Health Care System, USA. sjudge@umaryland.edu
Susan I V
SI
Judge
Christopher T
CT
Bever
D015761:4-Aminopyridine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000077770:Amifampridine; D000818:Animals; D006801:Humans; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000502:physiology
D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D015761:4-Aminopyridine; D000077770:Amifampridine