Fachbereich Veterinärmedizin



    Common response to KCNQ2/3 channel openers in animal models of levodopa-induced dyskinesia and inborn paroxysmal dystonia? (2007)

    Sander, S. E.
    Richter, A.
    IBRO World Congress of Neuroscience
    Melbourne/Australia, 12. – 17.07.2007
    Institut für Pharmakologie und Toxikologie

    Koserstr. 20
    14195 Berlin
    +49 30 838 53221

    Abstract / Zusammenfassung

    Levodopa-induced dyskinesia and primary dystonia are basal ganglia disorders, which are characterized by involuntary hyperkinetic movements. Although their underlying pathophysiological mechanisms are diverse, they share some pathological features, e.g. a decreased basal ganglia output. Previous studies in dtsz hamsters, an animal model of inborn dystonia, demonstrated antidystonic effects of the KCNQ channel openers retigabine and flupirtine. These channels are located on striatal GABAergic projection neurons, which are thought to have an increased activity in patients with levodopa-induced dyskinesia and primary dystonia. Therefore, we investigated the antidyskinetic potency of these compounds in an animal model of levodopa-induced dyskinesia. Dyskinesia was induced in 6-OHDA-lesioned rats by administration 20 mg/kg levodopa and 15 mg/kg benserazide per day over a period of 20 days. For the experiments, retigabine (2.5 mg and 5 mg/kg i.p.) and flupirtine (5 mg and 10 mg/kg i.p.; 10 mg and 20 mg/kg s.c.) or vehicle were injected additionally to levodopa and benserazide. Three forms of dyskinesia (limb, axial and orolingual) were differed and rated by a score system over a period of 200 min. In comparison to vehicle, retigabine reduced the dyskinesia scores at dose of 2.5 mg/kg (110.-140. min) and 5 mg/kg (50. -110. min) significantly (at least p<0.05). Only the i.p. injection of 10 mg/kg i.p. Flupirtine caused an antidyskinetic effect (20. ? 80. min), but was accompanied by severe side effects. The well tolerated s.c. application of 10 mg/kg flupirtine reduced the severity of dyskinesia (20. and 80). 20 mg/kg showed an antidyskinetic efficacy between the 50. and 110. min but was again accompanied by phases of severe ataxia and heavy hypolocomotion. In our studies the KCNQ channel openers retigabine and flupirtine showed an antidyskinetic potency in an animal model of levodopa-induced dyskinesia.