Antidystonic effects of K(v)7 (KCNQ) channel openers in the dt(sz) mutant, an animal model of primary paroxysmal dystonia.
Background and purpose:Mutations in neuronal K(v)7 (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 K(v)7 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 K(v)7.2/7.3 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 K(v)7 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 K(v)7 channel activators are interesting candidates for the treatment of dystonia-associated dyskinesias and probably of other types of dystonias. The established analgesic effects of K(v)7 channel openers might contribute to improvement of these disorders which are often accompanied by painful muscle spasms.British Journal of Pharmacology (2006) 149, 747-753. doi:10.1038/sj.bjp.0706878; published online 3 October 2006.[1]References
- Antidystonic effects of K(v)7 (KCNQ) channel openers in the dt(sz) mutant, an animal model of primary paroxysmal dystonia. Richter, A., Sander, S.E., Rundfeldt, C. Br. J. Pharmacol. (2006) [Pubmed]
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