Objective/Rationale:
Levodopa is the mainstay of treatment for the motor symptoms of Parkinson’s disease. Unfortunately one of the long term side effects of levodopa treatment is the development of disabling involuntary movements known as LIDs. LIDs present serious challenges to the control of PD symptoms and the quality of life of PD patients. While there are currently no drugs approved for the treatment of LIDs, the drug amantadine has been shown to modestly decrease LIDs and thus is widely prescribed for this indication. Amantadine is thought to work by inhibiting NMDA receptors in the brain. Unfortunately, the use of amantadine is associated with disturbing and common side-effects including confusion and hallucinations which often force discontinuation of the drug.
The long term goal of our work is to identify new drugs that can be used to reduce or even abolish LIDs. In this study we will test the hypothesis that the drug memantine will be effective in suppressing LIDs in an pre-clinical model of PD. Memantine is currently approved for the treatment of moderate to severe dementia in Alzheimer’s disease and has been tested as a treatment for dementia in PD as well as Lewy body dementia. Like amantadine, memantine inhibits NMDA receptors, providing a rationale for its use to treat dyskinesias. However, memantine is an especially attractive candidate for the treatment of LIDs, as it has been previously shown to be generally well tolerated and appears to have fewer side amantadine in PD patients. More importantly, memantine may actually improve cognitive deficits in PD if they are present.
Project Description:
We will test increasing doses of memantine in a validated and well characterized pre-clinical model of LIDs. We will also measure the effects of memantine on the anti-parkinsonian efficacy of levodopa and monitor subjects for any drug-related side-effects.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This project will provide key data to further develop memantine as a new potential treatment for LIDs in patients that hopefully will provide better efficacy and tolerability than currently available.
Anticipated Outcome:
If memantine has the predicted effect of reducing LIDs in this pre-clinical model and does not interfere with the efficacy of levodopa in reducing parkinsonism, the drug could move directly into clinical trials in PD.