Glutamate Antagonists

Glutamate antagonists are one of the many approved therapies for controlling the symptoms of Parkinson’s disease. They are usually given at the early stages of the disease or in combination with Duodopa (carbidopa-levodopa).

Amantadine is an example of a glutamate antagonist currently being used in the treatment of Parkinson’s symptoms. It is available commercially as Symmetrel, Gocovri, and Osmolex ER. All of these medications have been approved by the U.S. Food and Drug Administration, and authorized by the European Medicines Agency to treat Parkinson’s.

How glutamate antagonists work

Low doses of glutamate antagonists have been shown to slow down the rate of nerve cell loss in the brain, thereby slowing down the progression of Parkinson’s.

Glutamate antagonists work by inhibiting the activity of glutamate receptors in the brain. These receptors are broadly classified into two main subtypes: N-methyl-D-aspartate (NMDA) and 3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors.

Researchers have shown using animal models that the inhibition of NMDA receptors can result in potentially improved motor function. Exactly how glutamate antagonists work is not fully understood, but several mechanisms have been proposed. One possible way they work is by reducing the activity of another neurotransmitter called acetylcholine. Reduced acetylcholine results in increased dopamine activity and thus confers antiparkinsonian benefits.

Animal studies have also shown that blocking specific NMDA receptor-subtypes can help to reduce Parkinson’s symptoms while still preserving glutamate activity that’s required for motor nerve signals in the brain.

Glutamate antagonists in clinical trials

Amantadine has been tested in several clinical trials. For example, a Phase 2/3 clinical trial (NCT01397422) demonstrated that amantadine reduced levodopa-induced dyskinesia in 83 patients with Parkinson’s. Another Phase 3 trial (NCT02136914) showed similar results in 126 patients, and that amantadine increased the duration of levodopa’s effects.

Apart from amantadine, several other glutamate antagonists have been the subjects of clinical trials but the results have not been published. These are summarized below.

Memantine is a low-affinity NMDA receptor antagonist that has been investigated for its potential antiparkinsonian effects. An interventional clinical trial (NCT00375778) completed in 2006 sought to evaluate the effect of memantine on brain activity using positron emission tomography. A Phase 4 clinical trial (NCT00855686) completed in 2009 enrolled 199 participants to evaluate the safety and efficacy of memantine in treating patients with Parkinson’s disease dementia.

Talampanel is an AMPA glutamate receptor antagonist that has undergone a Phase 2 clinical trial (NCT00108667) in patients on levodopa therapy. Talampanel was shown to have antiparkinsonian effects in primates, but the results of the human study have not been published.

Dextromethorphan, a treatment commonly found in cough medicine, is also an NMDA receptor antagonist that was the subject of a completed Phase 2 clinical trial (NCT00001365) for the treatment of Parkinson’s and other similar disorders.

A Phase 2 clinical trial (NCT01767129) investigated the effect of a combination of dextromethorphan and quinidine in 14 Parkinson’s disease patients undergoing levodopa therapy. Initial results showed evidence of reduced levodopa-induced dyskinesia in Parkinson’s patients. A larger study with a longer treatment duration is needed to further confirm these findings.


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