title: The K(V)7.2/3 preferring channel opener ICA 27243 attenuates L-DOPA-induced dyskinesia in hemiparkinsonian rats.
abstract: 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 KV7.2-7.5 channel opener retigabine after acute and chronic treatment in a rat model of LID. We hypothesized that this effect was mainly mediated by KV7.2/3 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 KV7.2/3 preferring channel opener ICA 27243 (N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzamide, 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 KV7.2/3 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.
authors.affiliation: Institute of Pharmacology and Toxicology, Department of Veterinary Medicine, Freie Universität Berlin, Koserstr. 20, 14195 Berlin, Germany. svenja.sander@fu-berlin.de
authors.forename: Svenja E
authors.initials: SE
authors.lastname: Sander
authors.forename: Catherine
authors.initials: C
authors.lastname: Lambrecht
authors.forename: Angelika
authors.initials: A
authors.lastname: Richter
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage*; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D005260:Female; D015640:Ion Channel Gating / Q000187:drug effects; D051658:KCNQ2 Potassium Channel / Q000819:agonists / Q000378:metabolism*; D051659:KCNQ3 Potassium Channel / Q000819:agonists / Q000378:metabolism*; D007980:Levodopa; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D011725:Pyridines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; C527835:N-(6-Chloropyridin-3-yl)-3,4-difluorobenzamide; D011725:Pyridines; D007980:Levodopa