Effects of KCNQ (Kv7) Channel Openers in Levodopa-induced Dyskinesias
Therapeutics Development Initiative -- Academic Track, 2008
Retigabine, a novel well-tolerated antiepileptic drug with analgesic and anxiolytic effects, is an opener of neuronal Kv7 potassium channels. These channels (formely known as KCNQ or M-channels) are important for establishing and stabilizing the activity of neurons within various brain structures including the basal ganglia. With regard to the function of Kv7 channels and the pathophysiology of levodopa-induced dyskinesias, openers of these channels may provide novel therapeutic approaches for levodopa-induced dyskinesias.
Our first experiments with acute administrations revealed significant antidyskinetic effects of retigabine at well-tolerated doses in a pre-clinical model of levodopa-induced dyskinesias. However, it is necessary to examine the long-term effects of retigabine, because a loss of efficacy can occur during long-term treatment as known for the antidyskinetic effects of amantadine. The major aim of the present project is to examine if chronic treatment with retigabine (combined with levodopa) is effective and may delay or even prevent the development of levodopa-induced dyskinesias in a pre-clinical model of levodopa-induced dyskinesias with unilateral 6-OHDA lesions. Further experiments with acute and chronic treatment have to show if this drug influences the antiparkinsonian effects of levodopa or exerts antiparkinsonian effects by itself (i.e. without levodopa). The effects of retigabine will be compared to those of the glutamate receptor antagonist amantadine.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Dopamine replacement with levodopa remains the most effective pharmacotherapy of PD, but levodopa-induced dyskinesia is a common complication in long-term treatment. Once established, levodopa-induced dyskinesia is difficult to treat. Retigabine could improve the therapy of PD/levodopa-induced dyskinesias, if the experiments (1) show that retigabine prevents or delays the development of dyskinesias or decrease the severity during chronic treatment together with levodopa without a reduction of the antiparkinsonian efficacy of levodopa, and (2) exclude that retigabine worsens the symptoms of PD, or even show an antiparkinsonian effect of retigabine.
Based on our preliminary data, indicating acute antidyskinetic effects of retigabine in the levodopa-induced dyskinesia pre-clinical model, we expect that retigabine could provide advantages as add-on therapy to long-term treatment with levodopa. In addition to the observation that retigabine is well tolerated in humans, a further advantage of this Kv7 channel opener in the treatment of dyskinesias may be its analgesic efficacy against neuropathic or muscle-mediated pain, because dyskinesias are often associated with painful muscle spasms.
6-OHDA lesioned rodent models of PD received over 19 days of retigabine, amantadine (used as a reference drug) or placebo prior to levodopa. Abnormal involuntary movements (AIM) were assessed three times a week. Retigabine significantly reduced the severity of AIM and the maximum AIM score during the levodopa-induction period as compared to placebo, amantadine and a lower dose of retigabine. Unexpectedly, amantadine failed to reduce AIM under this regime. Four weeks later, in a second induction period in which all groups received levodopa only, AIM were significantly higher than in the first period only in placebo and retigabine/levodopa-treated rats, supporting an antidyskinetic efficacy of retigabine. Signs of unilateral parkinsonism were determined by different tests during chronic treatment as well as after acute injections. Single tests indicated a negative effect of retigabine and amantadine on PD signs, but on the whole there is no clear evidence that these compounds worsen PD. The results indicate that retigabine could represent an interesting candidate for the treatment of levodopa-induced dyskinesias, which is supported by the fact that Kv7.2-5 channel openers can decrease neuronal activity of striatal projection neurons. However, given the complex actions the drug had on PD signs, further work is necessary before retigabine could be recommended for clinical testing in PD.
Professor of Pharmacology and Toxicology at Institute of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Freie Universitat Berlin
Location: Berlin, Germany