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.
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.
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“Ophthalmic acid is a tripeptide composed of L-2-aminobutyric acid, L-glutamic acid, and glycine. It is structurally similar to glutathione but lacks the thiol group. The levels of ophthalmic acid in the brain can serve as a marker of oxidative stress, but it's less clear whether increasing ophthalmic acid specifically is directly beneficial or achievable through supplementation or diet.
Currently, there is no direct evidence on how to increase ophthalmic acid levels in the brain through diet, supplements, or lifestyle changes. However, the following strategies may support related pathways, like glutathione metabolism or oxidative stress regulation, which could influence ophthalmic acid indirectly:
1. Nutrient Support for Glutathione Production
Since ophthalmic acid is related to glutathione synthesis, supporting this pathway might indirectly affect ophthalmic acid levels:
N-acetylcysteine (NAC): This is a precursor to glutathione and is commonly used to support antioxidant pathways.
Selenium and Vitamin E: These antioxidants play a role in protecting cells from oxidative stress, which is connected to glutathione levels.
Alpha-lipoic acid: Another potent antioxidant that supports glutathione synthesis and recycling.
2. Managing Oxidative Stress
Reducing oxidative stress through diet and lifestyle could help maintain a balance in tripeptide-related systems like ophthalmic acid and glutathione:
Antioxidant-rich diet: Foods high in antioxidants, such as berries, leafy greens, and nuts, may help protect the brain from oxidative damage.
Exercise: Regular physical activity has been shown to reduce oxidative stress in the brain and may influence related biochemical pathways.
3. Exploring Research on Related Amino Acids
Since ophthalmic acid is composed of L-glutamic acid, glycine, and L-2-aminobutyric acid, consuming these amino acids may support its production:
Glycine-rich foods: Gelatin, bone broth, and other sources of collagen contain high amounts of glycine.
Glutamic acid: Found in protein-rich foods like meat, fish, dairy, and fermented products.
4. Experimental Research
Research on specific pharmacological interventions that target glutathione or related pathways may eventually offer insights into ophthalmic acid regulation. However, currently, no well-established methods exist to specifically boost ophthalmic acid levels in the brain.
If you’re looking to enhance brain health and manage oxidative stress more broadly, focusing on a nutrient-rich diet, antioxidants, and maintaining a healthy lifestyle may offer benefits.
Since research on ophthalmic acid is still in early stages, it's important to follow developments in the field for more targeted approaches in the future.”
L-2-aminobutyric acid (AABA), also known as α-aminobutyric acid, is a naturally occurring non-proteinogenic amino acid. While it's not one of the standard 20 amino acids incorporated into proteins, it does occur in various natural contexts. Here are a few ways in which it is found:
In Plants: L-2-aminobutyric acid is found in certain plants, though it is not a common amino acid. It is produced as part of metabolic processes, particularly in stress responses, where it helps plants manage environmental stress factors like drought or high salt levels.
In Microorganisms: Certain bacteria and fungi can produce L-2-aminobutyric acid as part of their metabolism. For example, it has been found in some microbial fermentation processes, which may be related to glutathione metabolism.
In the Human Body: L-2-aminobutyric acid is produced endogenously in humans. It plays a role in glutathione metabolism and is structurally similar to glutamate and GABA, two important neurotransmitters. It’s also a precursor in the synthesis of ophthalmic acid, which is a marker of oxidative stress.
Although L-2-aminobutyric acid occurs in nature, its role is more of a metabolic intermediate than a common dietary amino acid like those used in protein synthesis.
If you’re interested in increasing this compound, promoting overall health through a diet rich in protein, antioxidants, and maintaining good metabolic function may indirectly support the systems where L-2-aminobutyric acid plays a role.L-2-aminobutyric acid (AABA), also known as α-aminobutyric acid, is a naturally occurring non-proteinogenic amino acid. While it's not one of the standard 20 amino acids incorporated into proteins, it does occur in various natural contexts. Here are a few ways in which it is found:
In Plants: L-2-aminobutyric acid is found in certain plants, though it is not a common amino acid. It is produced as part of metabolic processes, particularly in stress responses, where it helps plants manage environmental stress factors like drought or high salt levels.
In Microorganisms: Certain bacteria and fungi can produce L-2-aminobutyric acid as part of their metabolism. For example, it has been found in some microbial fermentation processes, which may be related to glutathione metabolism.
In the Human Body: L-2-aminobutyric acid is produced endogenously in humans. It plays a role in glutathione metabolism and is structurally similar to glutamate and GABA, two important neurotransmitters. It’s also a precursor in the synthesis of ophthalmic acid, which is a marker of oxidative stress.
Although L-2-aminobutyric acid occurs in nature, its role is more of a metabolic intermediate than a common dietary amino acid like those used in protein synthesis.
If you’re interested in increasing this compound, promoting overall health through a diet rich in protein, antioxidants, and maintaining good metabolic function may indirectly support the systems where L-2-aminobutyric acid plays a role.
I wonder if adding a few teaspoons of gelatine into eg curries, stews etc would be good to get extra glycine? I think most modern diets are deficient as we don’t eat the bony cuts of meat our grandparents stewed and ate.
Glutamic acid. I thought helps stop cancer growing too.
ChatGPT:
Dietary Sources of Glutamic Acid:
Animal Sources: Meat, fish, poultry, and eggs
Plant Sources: Soy products, tomatoes, mushrooms, and spinach
Fermented Foods: Foods like miso, soy sauce, and some cheeses contain higher levels of free glutamate, the active form of glutamic acid.
Potential Health Benefits:
Cognitive Function: As a precursor to glutamate, glutamic acid supports cognitive functions such as memory and learning.
Detoxification: It helps detoxify excess ammonia by converting it into glutamine.
Caution:
Excessive intake of free glutamic acid, often through additives like monosodium glutamate (MSG), can lead to issues such as headaches or nausea in sensitive individuals, although this is rare.
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