Objective/Rationale:
Levodopa is the most effective drug to treat symptoms of Parkinson’s disease, however long-term use leads to disabling levodopa-induced dyskinesia (LID) in the vast majority of patients. NMDA receptor antagonists have been shown to be efficacious in reducing LID in pre-clinical and clinical models. Xenon, a noble gas with anesthetic and analgesic properties, has been demonstrated in pre-clinical models to have potent neuroprotective effects at sub-anaesthetic concentrations, attributed to its NMDA receptor antagonistic properties. We hypothesize that inhalation of non-anesthethic concentrations of xenon could prevent and/or reduce LID, without disrupting the therapeutic effect of levodopa.
Project Description:
The effect of xenon on LID will be studied in a pre-clinical model of levodopa-induced dyskinesia. A xenon/oxygen mixture will be administered to the pre-clinical models in combination with levodopa, followed by an evaluation of abnormal involuntary movements, which are dyskinetic-like features analogous to LID in patients. Furthermore, open-field and the rotorod test will be performed to assess locomotion and motor performances.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
One of the key challenges in the current long-term levodopa treatment of Parkinson’s disease is reducing or avoiding treatment-induced complications such as dyskinesia, which affects the long term efficacy of the treatment. This project allows us to assess the potential anti-dyskinetic effects of xenon, resulting in a novel approach in reducing LID and ensuring long-term efficacy of levodopa as an anti-parkisonian therapy.
Anticipated Outcome:
This project is designed to provide us with a fast and straightforward answer to whether xenon, at non-anesthetic concentrations, has the potential to be a new, efficacious and safe therapy for dyskinesia. Since xenon is market-approved for anesthesia and has a demonstrated safe profile, positive preliminary results could lead to a follow-up study in a pre-clinical model and eventually in a controlled clinical study.
Final Outcome
This study confirmed that xenon (xenon-O2 50%/50%) reduces L-DOPA-induced abnormal involuntary movements (AIMs) in the 6-OHDA-lesioned rat model of Parkinson’s disease. The criterion for success was that xenon should at least display comparable efficacy than amantadine. We achieved this goal and delivered data that confirmed our hypothesis. Indeed, xenon (xenon-O2 50%/50%) reduced L-DOPA-induced abnormal involuntary movements (AIMs) in the 6-OHDA-lesioned rat model of Parkinson’s disease, with comparable efficacy than amantadine. Furthermore, the antiparkinsonian effect of L-dopa was fully preserved and xenon (xenon-O2 50%/50%) did not sedate the animals after the gas exposure as they were performing equally well on the rotarod than after amantadine.