Summary: Researchers have discovered a way to increase vitamin B6 levels in cells by inhibiting its breakdown, potentially improving memory and learning. Their study found that a natural substance, 7,8-Dihydroxyflavone, inhibits the enzyme pyridoxal phosphatase, thereby enhancing vitamin B6 in nerve cells. This advance could lead to new treatments for mental disorders and neurodegenerative diseases.
Highlights:
- Vitamin B6 is linked to brain metabolism, memory, learning and mental health.
- Researchers found that 7,8-dihydroxyflavone inhibits the enzyme that breaks down vitamin B6.
- This discovery could pave the way for new drug treatments for brain disorders.
Source: University of Würzburg
Vitamin B6 is important for brain metabolism. So, in various mental illnesses, low levels of vitamin B6 are associated with impaired memory and learning abilities, depressed mood and even full-blown depression. In older adults, a lack of vitamin B6 is linked to memory loss and dementia.
Although some of these observations were made decades ago, the exact role of vitamin B6 in mental illness is still largely unclear. What is clear, however, is that increased intake of vitamin B6 alone, for example in the form of dietary supplements, is not sufficient to prevent or treat disorders of brain function.
Published in eLife
A research team from the Medical University of Würzburg has discovered another way to increase vitamin B6 levels in cells more effectively: namely by specifically inhibiting its intracellular breakdown. Antje Gohla, professor of biochemical pharmacology at the Department of Pharmacology and Toxicology at the Julius-Maximilians-Universität Würzburg (JMU), is responsible for this.
Other participants come from the Rudolf Virchow Center for Integrative and Translational Bioimaging at JMU, the Leibniz-Forschungsinstitut für Molekulare Pharmakologie-FMP Berlin and the Institute for Clinical Neurobiology at the University Hospital Würzburg. The team has now published the results of their research in the scientific journal eLife.
Enzyme blocking improves learning ability
“We have already been able to show in previous studies that the genetic suppression of pyridoxal phosphatase, an enzyme that degrades vitamin B6, in mice improves the spatial learning and memory capacity of the animals,” explains Antje Gohla.
To determine whether such effects can also be achieved by pharmacological agents, scientists searched for substances that bind and inhibit pyridoxal phosphatase.
With success: “In our experiments, we identified a natural substance capable of inhibiting pyridoxal phosphatase and thus slowing down the degradation of vitamin B6,” explains the pharmacologist. The working group actually managed to increase vitamin B6 levels in nerve cells involved in learning and memory processes. The name of this natural substance: 7,8-Dihydroxyflavone.
New approach to drug therapy
7,8-Dihydroxyflavone has already been described in numerous other scientific articles as a molecule capable of improving learning and memory processes in disease models linked to mental disorders. The new knowledge of its effect as a pyridoxal phosphatase inhibitor now opens new explanations for the effectiveness of this substance.
This could improve the mechanistic understanding of mental disorders and represent a new drug approach for the treatment of brain disorders, the scientists write in their study.
The team also considers it a great success that 7,8-Dihydroxyflavone was identified for the first time as an inhibitor of pyridoxal phosphatase – after all, this class of enzymes is considered particularly difficult for drug development.
A long road to a medicine
When will people benefit from this discovery? “It’s too early to tell,” says Marian Brenner, one of the study’s first authors. However, there is considerable evidence to suggest that it may be beneficial to use vitamin B6 in combination with pyridoxal phosphatase inhibitors to treat various mental disorders and neurodegenerative diseases.
As a next step, Gohla and his team now want to develop improved substances that inhibit this enzyme precisely and very effectively. Such inhibitors could then be used to specifically test whether increasing cellular levels of vitamin B6 is useful in mental or neurodegenerative diseases.
About this neuroscience research news
Author: Esther Knemeyer Pereira
Source: University of Würzburg
Contact: Esther Knemeyer Pereira – University of Würzburg
Picture: Image is credited to Neuroscience News
Original research: Free access.
“7,8-dihydroxyflavone is a direct inhibitor of human and murine pyridoxal phosphatase” by Antje Gohla et al. eLife
Abstract
7,8-dihydroxyflavone is a direct inhibitor of human and murine pyridoxal phosphatase.
Vitamin B6 deficiency has been associated for decades with cognitive impairment linked to human brain disorders. However, the molecular mechanisms linking vitamin B6 to these pathologies remain poorly understood, and we also do not know whether vitamin B6 supplementation improves cognition.
Pyridoxal 5′-phosphate phosphatase (PDXP), an enzyme that controls levels of pyridoxal 5′-phosphate (PLP), the co-enzymatically active form of vitamin B6, may represent an alternative therapeutic entry point in pathologies associated with vitamin B6.
However, pharmacological inhibitors of PDXP to test this concept are lacking. We now identify an age-dependent decline in PDXP and PLP levels in the murine hippocampus, supporting the development of PDXP inhibitors.
By combining small molecule screening, protein crystallography, and biolayer interferometry, we discover, visualize, and analyze 7,8-dihydroxyflavone (7,8-DHF) as a direct and potent PDXP inhibitor. 7,8-DHF reversibly binds and inhibits PDXP with low micromolar affinity and sub-micromolar potency. In mouse hippocampal neurons, 7,8-DHF increases PLP in a PDXP-dependent manner.
These results validate PDXP as a drug target. It should be noted that 7,8-DHF is a well-studied molecule in models of brain disorders, although its mechanism of action is actively debated.
Our discovery of 7,8-DHF as a PDXP inhibitor provides new mechanistic insights into the controversy surrounding 7,8-DHF-mediated effects in the brain.