Glutamate Modulation for the Treatment of Levodopa Induced Dyskinesia: A Brief Review of the Drugs Tested in the Clinic

Abstract

Levodopa is the standard treatment for Parkinson’s disease, but its use is marred by the emergence of dyskinesia, for which treatment options remain limited. Here, we review the glutamatergic modulators that were assessed for their antidyskinetic potential in clinical trials, including N-methyl-D-aspartate (NMDA) antagonists, agonists at the glycine-binding site on NMDA receptors, metabotropic glutamate (mGlu) 4 agonists, mGlu₅ antagonists, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonists and glutamate release inhibitors. Several agents that were investigated are not selective for their targets, raising uncertainty about the extent to which glutamatergic modulation contributed to their effects. Except for amantadine, the use of glutamatergic modulators for the treatment of dyskinesia in Parkinson’s disease remains largely investigational, with promising results obtained with mGlu₅ negative allosteric modulation.

Plain language summary

Long-term treatment of Parkinson’s disease results in abnormal involuntary movements called ‘dyskinesia’. The chemical substance ‘glutamate’ is deeply involved in the normal functioning of the brain and the drug amantadine, which is used in the clinic to alleviate dyskinesia, is believed to elicit its effects through modulation of glutamate within the brain. In addition to amantadine, several drugs that interact with glutamate have been tested in the clinic, with variable efficacy. Here, we aim to review the pharmacological mechanisms of these drugs and to discuss their efficacy, or lack thereof, in the treatment of dyskinesia in Parkinson’s disease.

Keywords:

• amantadine
• AMPA
• dyskinesia
• glutamate
• glycine
• levodopa
• mGlu₄
• mGlu₅
• NMDA
• Parkinson’s disease

Financial & competing interests disclosure

I Frouni holds a scholarship from Parkinson Canada. P Huot has research support from Parkinson Canada, Fonds de Recherche Québec – Santé, the Natural Sciences and Engineering Research Council of Canada, Parkinson Québec, Healthy Brains for Healthy Lives, the Weston Brain Institute and the Michael J Fox Foundation for Parkinson’s Research. P Huot has received payments from Neurodiem, AbbVie, adMare BioInnovations and Sanford Burnham Prebys. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.