The therapeutic mode of action of 4-aminopyridine in cerebellar ataxia.
Episodic ataxia type 2 (EA2) is a hereditary cerebellar ataxia associated with mutations in the P/Q-type voltage-gated calcium (Ca(2+)) channels. Therapeutic approaches for treatment of EA2 are very limited. Presently, the potassium (K(+)) channel blocker 4-aminopyridine (4-AP) constitutes the most promising treatment, although its mechanism of action is not understood. Here we show that, in contrast to what is commonly believed, therapeutic concentrations of 4-AP do not increase the inhibitory drive of cerebellar Purkinje cells. Instead, 4-AP restores the severely diminished precision of pacemaking in Purkinje cells of EA2 mutant mice by prolonging the action potential and increasing the action potential afterhyperpolarization. Consistent with this mode of action, the therapeutic efficacy of 4-AP was comparable, and not additive, to chlorzoxazone, an activator of Ca(2+)-dependent K(+) channels that also restores the precision of Purkinje cell pacemaking. The likely target of 4-AP at the concentrations used are the K(v)1 family of K(+) channels, possibly the K(v)1.5 subtype. Because at higher concentrations 4-AP blocks a large array of K(+) channels and is a proconvulsant, use of selective K(v)1 channel blockers is likely to be a safer substitute for treatment of cerebellar ataxia.
Alviña
Karina
K
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Khodakhah
Kamran
K
D015761:4-Aminopyridine / Q000627:therapeutic use*; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D002524:Cerebellar Ataxia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002531:Cerebellum / Q000473:pathology; D002753:Chlorzoxazone / Q000494:pharmacology / Q000627:therapeutic use; D002819:Chorea / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005106:Exploratory Behavior / Q000187:drug effects; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018408:Patch-Clamp Techniques / Q000379:methods; D026902:Potassium Channel Blockers / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
D026902:Potassium Channel Blockers; D015761:4-Aminopyridine; D002753:Chlorzoxazone