A Richter1, S E Sander, C Rundfeldt. 1. Institute of Pharmacology and Toxicology, Department of Veterinary Medicine, Freie Universität Berlin, Berlin, Germany. richtera@zedat.fu-berlin.de
Abstract
BACKGROUND AND PURPOSE: Mutations in neuronal Kv7 (KCNQ) potassium channels can cause episodic neurological disorders. Paroxysmal dyskinesias with dystonia are a group of movement disorders which are regarded as ion channelopathies, but the role of Kv7 channels in the pathogenesis and as targets for the treatment have so far not been examined. EXPERIMENTAL APPROACH: In the present study, we therefore examined the effects of the activators of neuronal Kv7.2/7.3 channels retigabine (5, 7.5, 10 mg kg(-1) i.p. and 10, 20 mg kg(-1) p.o.) and flupirtine (10, 20 mg kg(-1) i.p.) and of the channel blocker 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE-991, 3 and 6 mg kg(-1) i.p.) in the dt sz mutant hamster, a model of paroxysmal dyskinesia in which dystonic episodes occur in response to stress. KEY RESULTS: Retigabine (10 mg kg(-1) i.p., 20 mg kg(-1) p.o.) and flupirtine (20 mg kg(-1) i.p.) significantly improved dystonia, while XE-991 caused a significant aggravation in the dt sz mutant. The antidystonic effect of retigabine (10 mg kg(-1) i.p.) was counteracted by XE-991 (3 mg kg(-1) i.p.). CONCLUSIONS AND IMPLICATIONS: These data indicate that dysfunctions of neuronal Kv7 channels deserve attention in dyskinesias. Since retigabine and flupirtine are well tolerated in humans, the present finding of pronounced antidystonic efficacy in the dt sz mutant suggests that neuronal Kv7 channel activators are interesting candidates for the treatment of dystonia-associated dyskinesias and probably of other types of dystonias. The established analgesic effects of Kv7 channel openers might contribute to improvement of these disorders which are often accompanied by painful muscle spasms.
BACKGROUND AND PURPOSE: Mutations in neuronal Kv7 (KCNQ) potassium channels can cause episodic neurological disorders. Paroxysmal dyskinesias with dystonia are a group of movement disorders which are regarded as ion channelopathies, but the role of Kv7 channels in the pathogenesis and as targets for the treatment have so far not been examined. EXPERIMENTAL APPROACH: In the present study, we therefore examined the effects of the activators of neuronal Kv7.2/7.3 channels retigabine (5, 7.5, 10 mg kg(-1) i.p. and 10, 20 mg kg(-1) p.o.) and flupirtine (10, 20 mg kg(-1) i.p.) and of the channel blocker 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE-991, 3 and 6 mg kg(-1) i.p.) in the dt sz mutant hamster, a model of paroxysmal dyskinesia in which dystonic episodes occur in response to stress. KEY RESULTS:Retigabine (10 mg kg(-1) i.p., 20 mg kg(-1) p.o.) and flupirtine (20 mg kg(-1) i.p.) significantly improved dystonia, while XE-991 caused a significant aggravation in the dt sz mutant. The antidystonic effect of retigabine (10 mg kg(-1) i.p.) was counteracted by XE-991 (3 mg kg(-1) i.p.). CONCLUSIONS AND IMPLICATIONS: These data indicate that dysfunctions of neuronal Kv7 channels deserve attention in dyskinesias. Since retigabine and flupirtine are well tolerated in humans, the present finding of pronounced antidystonic efficacy in the dt sz mutant suggests that neuronal Kv7 channel activators are interesting candidates for the treatment of dystonia-associated dyskinesias and probably of other types of dystonias. The established analgesic effects of Kv7 channel openers might contribute to improvement of these disorders which are often accompanied by painful muscle spasms.
Authors: Maria Virginia Soldovieri; Maria Roberta Cilio; Francesco Miceli; Giulia Bellini; Emanuele Miraglia del Giudice; Pasqualina Castaldo; Ciria C Hernandez; Mark S Shapiro; Antonio Pascotto; Lucio Annunziato; Maurizio Taglialatela Journal: J Neurosci Date: 2007-05-02 Impact factor: 6.167