Potential therapeutic mechanism of K(+) channel block for MS

While the potential use of K(+) channel blockers in MS has been explored over many years, the approval in the US, and more recently in the UK, of fampyra (fampridine, 4-aminopyridine, 4-AP) as a symptomatic treatment for walking disability, has reawakened interest. Recent years have seen a real improvement in the treatment options for relapsing remitting MS, but the disease remains inadequately treated, with the progressive phase (characterised by irreversible functional loss) lacking any effective therapy. Whether the symptomatic relief afforded by 4-AP translates into neuroprotection, remains poorly investigated, although there is no clear reason why this would be expected. Importantly, future clinical studies may shed light on this question. This review includes an overview of axonal K(+) channel expression and pharmacology, and the logic of the use of K(+) channel blockers derived from observations in experimental studies of demyelination and synaptic transmission. It provides an insight into the probable biophysical actions of 4-AP, and how its action may aid in the symptomatic treatment of MS. The key message of this review is that 4-AP is a blocker of neuronal K(+) channels, and its administration is known to be of value in the symptomatic treatment of some patients. The details of the mechanism underlying the beneficial effects remain somewhat vague, and the molecular target has not been properly defined. The useful mechanism is likely to include an action on synaptic function, but whether it is the presynaptic terminal or the presynaptic axon that is the primary target is unknown. It is argued that because of the apparent inability of 4-AP to increase safety factor in experimental demyelination when clinically relevant concentrations are used, it cannot be the ideal pharmacological agent for treating demyelination by the widening of axonal action potentials. That said, it remains a possibility that the useful therapeutic effect of 4-AP may involve subtle changes in axonal excitability mediated by a selective K(+) channel block, exploiting a naturally occurring redundancy of synaptic function.