The KV7.2/3 preferring channel opener ICA 27243 attenuates L-DOPA-induced dyskinesia in hemiparkinsonian rats

Spontaneous involuntary dystonic and choreatic movements induced by L-DOPA (L-DOPA-induced dyskinesias (LID)) represent a severe complication of long-time pharmacotherapy in Parkinson's disease that deserves novel therapeutics. Previous studies demonstrated antidyskinetics effect of the K(V)7.2-7.5 channel opener retigabine after acute and chronic treatment in a rat model of LID. We hypothesized that this effect was mainly mediated by K(V)7.2/3 channels located on striatal projection neurons, as an increased activity of these neurons seems to be involved in the pathophysiology of LID. We therefore examined the acute effects of the K(V)7.2/3 preferring channel opener ICA 27243 (N-(6-chloro-pyridin-3-yl)-3,4-difluorobenzamide, 5-15 mg/kg i.p.) on LID in this animal model. Ten and 15 mg ICA 27243 significantly reduced abnormal involuntary movements (AIM) while no negative impact on the antiparkinsonian effect of L-DOPA was observed. However, at the end of the testing session (180 min) AIM scores increased after application of both doses. Further studies have to clarify if this can be avoided by a different application regime. Nevertheless, the present results suggest that selective openers of K(V)7.2/3 channels might be interesting candidates for the treatment of LID as antidyskinetic effects occurred at well-tolerated doses and did not interfere with the antiparkinsonian effect of L-DOPA. (C) 2013 Elsevier Ireland Ltd. All rights reserved,