Expert Interview

Michael Martini on therapy options for patients with Parkinson disease and levodopa-induced dyskinesia

An interview with Michael Martini


Michael Martini is a MD/PhD student at Icahn School of Medicine at Mount Sinai in New York. He

recently coauthored the manuscript "Recent Advances in the Development of Experimental Therapeutics for Levodopa-Induced Dyskinesia."* We took a moment to sit down with Mr. Martini to discuss some of the potential therapies for patients with Parkinson disease (PD).

How can targeting serotonergic neurons help control levodopa-induced dyskinesia (LID)?

Serotonergic neurons appear to have an interesting relationship with dyskinesia in patients with PD. One potential reason for this might be because the serotonergic neurons possess the molecular machinery to convert L-dopa into dopamine, contributing to dopaminergic transmission in the brain.

However, dopaminergic neurons possess auto receptors, which essentially act as an off switch when too much dopamine is being transmitted. This negative feedback loop works to stabilize dopaminergic transmission.

When a patient with early PD takes an oral dose of L-dopa, it is converted into dopamine in the central serotonergic neurons and the excess dopamine is buffered by retained dopaminergic neurons.

As PD advances, more significant destruction of these dopaminergic terminals means a loss in the capacity to buffer excess dopamine, which in turn can lead to dyskinesia.

I believe that there are particularly exciting results in preclinical and clinical studies exploiting this framework. For example, we have learned that there is a synergistic effect on dyskinesia reduction that occurs when agonists of 5-HT1A and 1B receptors are administered to animal models of PD.

This presumably occurs because the serotonergic autoreceptors are being stimulated by the serotonin agonists. This may explain why previous studies using sarizotan, which is only a 5-HT1A agonist, did not show significant LID reduction. More recent clinical studies have taken advantage of this synergistic effect by giving eltoprazine, which is a dual 5-HT1A/1B agonist. Clinical trials with eltoprazine showed significant reduction in LID symptoms on two different clinical scales—the Clinical Dyskinesia Rating Scale and the Rush Dyskinesia Rating Scale.

You also discussed alpha-lipoic acid as a treatment option. How can this work to delay the onset of LID?

Alpha-lipoic acid research revolves around the central finding that patients treated with L-dopa have been shown to have enhanced processes of oxidative stress occurring in their brains.

There are a few possible reasons for this reaction. It might be that these patients have lower antioxidant levels or excessive oxidation of dopamine or disruptions in the mitochondrial transport chain.

Other studies have found increased markers of oxidation and neuroinflammation present, which may suggest that monitoring these oxidative stress markers could be useful in some patients with PD who are receiving L-dopa.

Some early studies found that alpha-lipoic acid could reduce reactive oxygen species and spare dopaminergic neurons in primate models of PD.

Recently we found more promising results when administering alpha-lipoic acid with L-dopa. Co-treatment had a dose-dependent anti-dyskinetic effect.

When sampling of biomarkers and metabolites was done, the results corroborated the idea that alpha-lipoic acid might reduce oxidative stress and apoptosis to achieve neuroprotection.

It is also important to note this distinction with alpha-lipoic acid: among experimental Parkinson therapeutics it might be a disease-modifying agent. This is noteworthy when considering that most other therapies are simply just trying to alleviate symptoms of PD and dyskinesia.

More work still needs to be done in this area, including full-scale clinical studies to substantiate these claims in humans. But I do believe that the results to date are exciting.

What other pharmacological approaches to LID look promising?

There is another approach to LID that I believe to be promising, even though it is still a ways off from being clinically developed—it relates to beta-arrestin signaling.

Recent studies have elucidated that in addition to their roles as G-protein coupled receptors, dopamine receptors are also capable of signaling through a distinct beta-arrestin2-dependent pathway, in addition to the canonical G-protein pathway.

This is important because a lot of traditional dopamine agonists, including L-dopa, signal through dopamine D1/D2 receptors.

Other studies have also suggested that this G-protein independent pathway, the beta-arrestin pathway, along with traditional G-protein pathway, are important in regulating downstream responses at dopamine receptors. They play significant roles in converting dopamine signaling into motor function, which sheds new light on the known functions of beta-arrestins.

Some promising and exciting preclinical data has emerged, suggesting that beta-arrestin signaling is critical for locomotion in L-dopa and that when it is removed, locomotor responses to L-dopa are decreased and there is an increased propensity towards LID in these models.

Further validation for targeting beta-arrestin signaling at the dopamine receptors was provided in primate models of PD, where genetic overexpression of beta-arrestin reduced dyskinesias and rescued locomotion when L-dopa was given.

I think we are at an exciting point in terms of the number of promising avenues that we have in devising potential strategies for treating LID. I think that innovations in this area have progressed significantly in recent years and I hope that at least a few of these experimental therapies might end up helping patients in the future.

*Martini ML, Neifert SN, Mocco J, et al. Recent Advances in the Development of Experimental Therapeutics for Levodopa-Induced Dyskinesia. J Mov Disord. 2019;12

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