UC Irvine scientists reveal ophthalmic acid's role in motor function control in Parkinson's disease
Brain molecule reverses movement deficits in animal models, offering new therapeutic target
October 04, 2024
Irvine, Calif. — A research team from UC 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 disease and other movement disorders.
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 neurodegenerative 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 dopamine-producing those neurons die. The current front-line drug for treatment, L-dopa, replaces lost dopamine and has a duration of two to three hours. While initially successful, L-dopa's effects fade over time and long-term use can lead to dyskinesia — involuntary, erratic muscle movements in the patient’s face, arms, legs and torso.
'Ground-breaking discovery'
“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 Amal Alachkar, PhD, the study's co-corresponding author and a professor in the School of Pharmacy & Pharmaceutical Sciences.
“Remarkably, ophthalmic acid not only enabled movement, but also far surpassed L-dopa in sustaining positive effects," she said. "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 the current 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.”
Further studies needed
The study also called for further research in animal models to validate and broaden the applicability of the results.
Dr. Claire Henchcliffe, chair of the UC Irvine School of Medicine's Department of Neurology and a leader in Parkinson's disease treatment and clinical research, said the study results challenge a central dogma in approaches to the disorder, the second most common age-related neurodegenerative condition in North America.
"The finding that ophthalmate has a key activity in motor control offers an intriguing alternative approach to the current dopamine-centered paradigms for Parkinson's," said Henchcliffe, who was not involved in the study.
"The investigators are cautious and highlight the many questions yet to be addressed, including how it is made, how it is controlled, and what is the extent of its various possible effects. Nonetheless, this report is extremely important: It should stimulate investigation into other preclinical models of Parkinson’s disease and preparations for next steps on a potential path to therapy."
The study team members from the School of Pharmacy & Pharmaceutical Sciences included doctoral student and lab assistant Sammy Alhassen,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, as well as Geoffrey Abbott, PhD, professor of physiology & biophysics and vice dean of basic science research in the School of Medicine.
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.
Related stories
About UCI Health
UCI Health, one of California’s largest academic health systems, is the clinical enterprise of the University of California, Irvine. The system comprises its main campus UCI Medical Center, a 459-bed, acute care hospital in Orange, Calif., four hospitals and affiliated physicians of the UCI Health Community Network in Orange and Los Angeles counties and ambulatory care centers across the region. Recognized as a Top Hospital by The Leapfrog Group, UCI Medical Center provides tertiary and quaternary care and is home to Orange County’s only National Cancer Institute-designated comprehensive cancer center, high-risk perinatal/neonatal program and American College of Surgeons-verified Level I adult and Level II pediatric trauma center, gold level 1 geriatric emergency department and regional burn center. UCI Health serves a region of nearly 4 million people in Orange County, western Riverside County and southeast Los Angeles County. Follow us on Facebook, Instagram, LinkedIn and Twitter.
