Levodopa is the most effective drug to treat symptoms of Parkinson’s disease, however long-term use leads to disabling L-DOPA-induced dyskinesia (LID) in the vast majority of patients. NMDA receptor antagonists have been shown to be efficacious in reducing LID in pre-clinical models and humans. XENON, a noble gas with anesthetic and analgesic properties, has been demonstrated in pre-clinical models to have potent neuroprotective effects at sub-anesthetic concentrations, attributed to its NMDA receptor antagonistic properties.
We hypothesize that inhalation of sub-anesthethic concentrations of XENON could prevent and/or reduce LID, without disrupting anti-parkisonnian effect of L-DOPA.
Project Description:
In a first series of experiments, supported by the TDI 2011 grant from MJFF, we demonstrated that L-DOPA-induced abnormal involuntary movements in 6-OHDA-lesioned rats were reduced following exposure to a sub-anesthetic concentration of xenon (Xe-O2 50%/50%) with comparable efficacy to amantadine.
The present project aims at (i) confirming data obtained in 6-OHDA-lesioned pre-clinical models using an identical protocol in the gold standard non-human pre-clinical models of LID, (ii) in the same model, assessing dose- and time- dependent effects of xenon and identifying the optimal dosing regimen.
The development and implementation of this project will occur in collaboration with Dr. Erwan Bezard, MOTAC Neuroscience Ltd. and Air Liquide.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
One of the key challenges in the current long-term L-DOPA 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 sub-anesthetic concentrations of xenon, resulting in a novel approach in reducing LID and ensuring long-term efficacy of L-DOPA as anti-parkisonnian therapy.
Anticipated Outcome:
This project is designed to provide us with a fast and straightforward answer to the question whether xenon, at sub-anesthetic concentrations, has the potential to be a new, efficacious and safe antidyskinetic therapy. Since xenon is market-approved for anesthesia and has a demonstrated safe profile, positive preliminary results could relatively fast lead to a follow-up study in a controlled clinical study.
Final Outcome
In this study, we assessed the ability of anesthetic gas xenon to prevent dyskinesia -- drug-induced involuntary movements -- in a pre-clinical model of levodopa-induced dyskinesia. We demonstrated that xenon significantly reduced dyskinesia without making levodopa less effective in improving motor symptoms. This effect of xenon is comparable to that of amantadine, a drug used to improve dyskinesia in Parkinson's disease (PD). These findings support data obtained earlier in a different pre-clinical model of Parkinson's. We also identified the optimal concentration of xenon and duration of treatment. Contrary to our expectations, we found that the most effective dose of xenon doesn't have a sustainable anti-dyskinetic effect. Further studies are needed to better evaluate the therapeutic potential of xenon in PD and understand its mechanism of action.
October 2014