Summary: A new study has discovered that ophthalmic acid, a molecule in the brain, acts like a neurotransmitter to regulate motor function, similar to dopamine. In Parkinson’s mouse models, this molecule improved movement for over 20 hours—far longer than the effects of the current treatment, L-dopa.
This finding challenges the long-held belief that dopamine is the only key player in motor control. Researchers are now exploring how to use ophthalmic acid as a potential treatment for movement disorders, offering hope for more effective therapies.
Key Facts:
- Ophthalmic acid acts like a neurotransmitter to control motor function.
- It improved movement for over 20 hours in Parkinson’s mouse models.
- This discovery opens up new possibilities for treating movement disorders like Parkinson’s.
Source: UC Irvine
A research team from the University of California, Irvine is the first to reveal that a molecule in the brain – ophthalmic acid – unexpectedly acts like a neurotransmitter similar to dopamine in regulating motor function, offering a new therapeutic target for Parkinson’s and other movement diseases.
In the study, published in the October issue of the journal Brain, researchers observed that ophthalmic acid binds to and activates calcium-sensing receptors in the brain, reversing the movement impairments of Parkinson’s mouse models for more than 20 hours.
The disabling neurogenerative disease affects millions of people worldwide over the age of 50. Symptoms, which include tremors, shaking and lack of movement, are caused by decreasing levels of dopamine in the brain as those neurons die. L-dopa, the front-line drug for treatment, acts by replacing the lost dopamine and has a duration of two to three hours.
While initially successful, the effect of L-dopa fades over time, and its long-term use leads to dyskinesia – involuntary, erratic muscle movements in the patient’s face, arms, legs and torso.
“Our findings present a groundbreaking discovery that possibly opens a new door in neuroscience by challenging the more-than-60-year-old view that dopamine is the exclusive neurotransmitter in motor function control,” said co-corresponding author Amal Alachkar, School of Pharmacy & Pharmaceutical Sciences professor.
“Remarkably, ophthalmic acid not only enabled movement, but also far surpassed L-dopa in sustaining positive effects. The identification of the ophthalmic acid-calcium-sensing receptor pathway, a previously unrecognized system, opens up promising new avenues for movement disorder research and therapeutic interventions, especially for Parkinson’s disease patients.”
Alachkar began her investigation into the complexities of motor function beyond the confines of dopamine more than two decades ago, when she observed robust motor activity in Parkinson’s mouse models without dopamine.
In this study, the team conducted comprehensive metabolic examinations of hundreds of brain molecules to identify which are associated with motor activity in the absence of dopamine. After thorough behavioral, biochemical and pharmacological analyses, ophthalmic acid was confirmed as an alternative neurotransmitter.
“One of the critical hurdles in Parkinson’s treatment is the inability of neurotransmitters to cross the blood-brain barrier, which is why L-DOPA is administered to patients to be converted to dopamine in the brain,” Alachkar said.
“We are now developing products that either release ophthalmic acid in the brain or enhance the brain’s ability to synthesize it as we continue to explore the full neurological function of this molecule.”
Team members also included doctoral student and lab assistant Sammy Alhassen, who is now a postdoctoral scholar at UCLA; lab specialist Derk Hogenkamp; project scientist Hung Anh Nguyen; doctoral student Saeed Al Masri; and co-corresponding author Olivier Civelli, the Eric L. and Lila D. Nelson Chair in Neuropharmacology – all from the School of Pharmacy & Pharmaceutical Sciences – as well as Geoffrey Abbott, professor of physiology & biophysics and vice dean of basic science research in the School of Medicine.
Funding: The study was supported by a grant from the National Institute of Neurological Disorders and Stroke under award number NS107671 and the Eric L. and Lila D. Nelson Chair in Neuropharmacology.
Alachkar and Civelli are inventors on a provisional patent that covers products related to ophthalmate and calcium-sensing receptors in motor function.
About this neuropharmacology and Parkinson’s disease research news
Author: Patricia Harriman
Source: UC Irvine
Contact: Patricia Harriman – UC Irvine
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Ophthalmate is a new regulator of motor functions via CaSR: implications for movement disorders” by Amal Alachkar et al. Brain
Abstract
Ophthalmate is a new regulator of motor functions via CaSR: implications for movement disorders
Dopamine’s role as the principal neurotransmitter in motor functions has long been accepted. We broaden this conventional perspective by demonstrating the involvement of non-dopaminergic mechanisms.
In mouse models of Parkinson’s disease, we observed that L-DOPA elicited a substantial motor response even when its conversion to dopamine was blocked by inhibiting the enzyme aromatic amino acid decarboxylase (AADC).
Remarkably, the motor activity response to L-DOPA in the presence of an AADC inhibitor (NSD1015) showed a delayed onset, yet greater intensity and longer duration, peaking at 7 h, compared to when L-DOPA was administered alone.
This suggests an alternative pathway or mechanism, independent of dopamine signalling, mediating the motor functions.
We sought to determine the metabolites associated with the pronounced hyperactivity observed, using comprehensive metabolomics analysis.
Our results revealed that the peak in motor activity induced by NSD1015/L-DOPA in Parkinson’s disease mice is associated with a surge (20-fold) in brain levels of the tripeptide ophthalmic acid (also known as ophthalmate in its anionic form).
Interestingly, we found that administering ophthalmate directly to the brain rescued motor deficits in Parkinson’s disease mice in a dose-dependent manner.
We investigated the molecular mechanisms underlying ophthalmate’s action and discovered, through radioligand binding and cAMP-luminescence assays, that ophthalmate binds to and activates the calcium-sensing receptor (CaSR).
Additionally, our findings demonstrated that a CaSR antagonist inhibits the motor-enhancing effects of ophthalmate, further solidifying the evidence that ophthalmate modulates motor functions through the activation of the CaSR.
The discovery of ophthalmate as a novel regulator of motor function presents significant potential to transform our understanding of brain mechanisms of movement control and the therapeutic management of related disorders.
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