Abstract
Dystonia is a hyperkinetic disabling movement disorder. In the dtsz hamster, a model of paroxysmal dystonia, pronounced antidystonic effects of the KV7.2-5 potassium channel opener retigabine and aggravation of dystonia by a selective KV7.2-5 blocker indicated a pathophysiological role of an abnormal expression of KV7 channels. We therefore investigated the expression of KV7 subunits in brains of dystonic hamsters. While KV7.2 and KV7.3 subunits were unaltered, lower KV7.5 mRNA levels became evident in motor areas and in limbic structures of dystonic hamsters. The KV7.2/3 subunit-preferring channel opener N-(6-chloropyridin-3-yl)-3,4- difluorobenzamide (ICA 27243; 10-30 mg/kg i.p.) failed to reduce the severity of dystonia in mutant hamsters, suggesting that the previously observed antidystonic action of retigabine is mediated by the activation of KV7.5 channels. The experiments indicate a functional relevance for KV7.5 channels in paroxysmal dystonia. We suggest that compounds highly selective for subtypes of KV7 channels, i.e. for KV7.5, may provide new therapeutic approaches.
Keywords: animal model, dyskinesia, dystonia, ICA 27243, KCNQ, voltage-gated potassium channels.
CNS & Neurological Disorders - Drug Targets
Title:Lower KV7.5 Potassium Channel Subunit Expression in an Animal Model of Paroxysmal Dystonia
Volume: 15 Issue: 1
Author(s): Svenja E. Sander, Mustansir Diwan, Roger Raymond, José N Nobrega and Angelika Richter
Affiliation:
Keywords: animal model, dyskinesia, dystonia, ICA 27243, KCNQ, voltage-gated potassium channels.
Abstract: Dystonia is a hyperkinetic disabling movement disorder. In the dtsz hamster, a model of paroxysmal dystonia, pronounced antidystonic effects of the KV7.2-5 potassium channel opener retigabine and aggravation of dystonia by a selective KV7.2-5 blocker indicated a pathophysiological role of an abnormal expression of KV7 channels. We therefore investigated the expression of KV7 subunits in brains of dystonic hamsters. While KV7.2 and KV7.3 subunits were unaltered, lower KV7.5 mRNA levels became evident in motor areas and in limbic structures of dystonic hamsters. The KV7.2/3 subunit-preferring channel opener N-(6-chloropyridin-3-yl)-3,4- difluorobenzamide (ICA 27243; 10-30 mg/kg i.p.) failed to reduce the severity of dystonia in mutant hamsters, suggesting that the previously observed antidystonic action of retigabine is mediated by the activation of KV7.5 channels. The experiments indicate a functional relevance for KV7.5 channels in paroxysmal dystonia. We suggest that compounds highly selective for subtypes of KV7 channels, i.e. for KV7.5, may provide new therapeutic approaches.
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Cite this article as:
Sander E. Svenja, Diwan Mustansir, Raymond Roger, Nobrega N José and Richter Angelika, Lower KV7.5 Potassium Channel Subunit Expression in an Animal Model of Paroxysmal Dystonia, CNS & Neurological Disorders - Drug Targets 2016; 15 (1) . https://dx.doi.org/10.2174/1871527315666151110124136
DOI https://dx.doi.org/10.2174/1871527315666151110124136 |
Print ISSN 1871-5273 |
Publisher Name Bentham Science Publisher |
Online ISSN 1996-3181 |
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