The potassium channel
family is the largest and fastest-growing family of ion channels. Evidence is accumulating
that modulation of potassium channels is a new approach to neuroprotection.
Potassium Channels and Neurodegenerative Diseases
by Chris Rundfeldt
Many different insults and
mechanisms can lead to neurodegeneration. Potas-sium channel openers may play a role in
counteracting or preventing this damage. A heterogeneous array of potassium channels,
classified according to their electrophysiological properties, has been identified.
Different potassium channels are involved in several steps within the pathophysiological
cascade that ultimately leads to cell death; therefore, several potassium channel openers
may interfere with different steps within the neurodegenerative cascade. However, it is
possible that in case of severe insults potassium channel opening may not lead to
neuroprotection, due to the fact that potassium channels are already endogenously
activated and the extracellular potassium concentration is already very high. Thus,
further channel opening may have no additional positive effects. Selective drugs for
individual channel subtypes should be used in predictive models of neurodegeneration;
however, the currently known potassium channel openers are few and nonselective. The
classes of drugs that need to be explored include potassium channel openers of the
ATP-sensitive, high-conductance calcium-sensitive, and inward rectifier or leakage types.
Selective openers for inward rectifier potassium channels are currently not available,
although activation of 5-HT1A receptors results in the induction of an inwardly
rectifying potassium current. Potent neuroprotective properties have been described for
different 5-HT1A agonists in models of focal and global ischemia. Retigabine, a
leakage-current potassium channel opener, has been shown to have neuroprotective effects
in animal models of neurodegeneration. Of the currently available potassium channel
openers, retigabine and BAY-X-3702 are active at nontoxic doses. Further research is
needed to develop selective, well-tolerated potassium channel openers. © 1999 Prous
Science. All rights reserved.
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