eAbstracts: The Therapeutic Mode of Action of 4-aminopyridine in Cerebellar Ataxia

Journal:The Journal of Neuroscience (May 26, 2010)

Authors: Alviña K, Khodakhah K

Purpose: To “show that, in contrast to what is commonly believed, therapeuticconcentrations of 4-AP do not increase the inhibitory driveof cerebellar Purkinje cells.”

Results: “4-AP restores the severelydiminished precision of pacemaking in Purkinje cells of EA2mutant mice by prolonging the action potential and increasingthe action potential afterhyperpolarization. Consistent withthis mode of action, the therapeutic efficacy of 4-AP was comparable,and not additive, to chlorzoxazone, an activator of Ca²⁺-dependentK⁺ channels that also restores the precision of Purkinje cellpacemaking. The likely target of 4-AP at the concentrationsused are the K_v1 family of K⁺ channels, possibly the K_v1.5 subtype.Because at higher concentrations 4-AP blocks a large array ofK⁺ channels and is a proconvulsant, use of selective K_v1 channelblockers is likely to be a safer substitute for treatment ofcerebellar ataxia.”

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