Combining flavonoid with vitamin B6 may help preserve cognitive function

• A new study of mice shows that a naturally occurring flavonoid can slow down the degradation of vitamin B6 in the brain.
• A deficiency in vitamin B6 has long been associated with poorer cognitive function.
• Vitamin B6 supplementation alone to improve cognition has yielded mixed results in trials.
• The study’s authors hope that greater cognitive benefits may be achieved by combining the flavonoid with B6 supplementation.

Insufficient vitamin B6 is linked to cognitive impairment, and a new study presents a novel approach to maintaining adequate B6 levels.

The study in mice finds that a naturally occurring flavonoid, 7,8-dihydroxyflavone , can directly bind to and inhibit a B6-degrading enzyme, thus helping to preserve levels of B6 in the brain.

The enzyme is pyridoxal phosphatase (PDXP).

The study follows previous work from the same team led by Antje Gohla, PhD, at the Institute of Pharmacology and Toxicology of the Universitet Würzburg in Germany. That work demonstrated improved spatial learning and memory capacity in mice when their pyridoxal phosphatase was de-activated.

The study is published in eLife .

Connecting B6 and cognitive health

Jacqueline Becker, PhD , neuropsychologist and health services researcher at the Icahn School of Medicine at Mount Sinai’s Division of General Internal Medicine, was not involved in the study.

“Several studies have examined the impact of B6 on cognition,” said Becker. “Specifically, that maintaining adequate levels of B vitamins, and vitamin B6 in particular, is essential for optimal neurotransmitter synthesis and homocysteine metabolism, and thus may have a direct impact on cognitive function.”

“Vitamin B6 deficiency has long been linked to cognitive impairment, particularly in areas that correlate with hippocampal functioning,” Becker said.

The hippocampus is believed to be important for age-dependent memory consolidation and learning and, therefore, cognition.

In the brain, said Becker, B6 “aids in the synthesis of neurotransmitters — e.g., serotonin, dopamine, gamma-aminobutyric acid — and helps reduce homocysteine levels in the blood.”

She noted as well that B6 is linked to mood, a known factor in cognitive health.

“Cognitive dysfunction is a cardinal symptom of depression, particularly deficits in attention and psychomotor speed,” she pointed out.

The problem with B6 supplementation alone

So far, the benefits of enhancing levels of B6 via supplementation as a therapeutic method are unclear. Clinical trials have yielded mixed results, “particularly in areas that correlate with hippocampal functioning,” according to Becker.

The new study may help explain that. Gohla said her team found that “PDXP is substantially upregulated — [or strengthened] — in the hippocampus of middle-aged compared to young mice.”

This aligns with age-related memory loss that occurs with aging.

Said Gohla, “This suggests that a therapeutic vitamin B6 supplementation alone may not be sufficient to elevate the levels of B6 in the brain — simply because the supplemented B6 would be immediately degraded by hyperactive PDXP.”

“In contrast,” the study finds, “combining B6 supplements with PDXP inhibitors that block B6 degradation may be much more effective in boosting cellular B6 levels.”

Mice vs. humans

In the team’s previous work, they found the spatial learning and memory capacity of mice was improved when PDXP was genetically switched off. Their performance was compared to mice with PDXP intact.

The researchers assessed the cognitive functioning of mice using a Barnes maze that provides a means to measure “hippocampus-dependent spatial reference memory by evaluating the ability to learn and remember the location of a hidden escape zone using a set of visual cues,” said Gohla.

In the “maze,” mice are placed on a platform with unpleasantly bright lighting. While there were a number of possible “escape” holes for the mice on the platform, only some were available for use.

“The [PDXP-less] mice learn to locate the correct escape hole with the help of visual cues, such as colored shapes or patterns, that are placed around the platform,” said Gohla.

In the new study, the subject mice were sacrificed, and the researchers used small-molecule screening, protein crystallography, and biolayer interferometry to observe 7,8-dihydroxyflavone directly affecting the action of pyridoxal phosphatase.

Given the differences between mice and humans, there may be concerns that the study’s findings will not be applicable to people.

Becker said, however, that, “the two functions of B6 in cognition mentioned — i.e., neurotransmitter synthesis and homocysteine metabolism — are thought to be mechanistically interchangeable between mice and humans.”

“So it is conceivable that [the research] would translate barring obvious environmental confounders (e.g., alcohol consumption, poor diet, etc.),” Becker said.

The future of 7,8-dihydroxyflavone

“We expect,” said Gohla, “that 7,8-dihydroxyflavone will inhibit PDXP in the brain and, together with supplemented B6, increase cellular B6 levels. If and how this may then increase cognition is an unresolved question that we will address in future work.”

She pointed out the complexities involved, saying, “there are many B6-dependent enzymes in the brain, including those that regulate neurotransmitter levels and neuronal signaling.”

Among the things that are not known are whether a single enzyme or transmitter is a vital element, or whether multiple such factors are involved.

“More studies,” Becker said, “are needed to determine the actual role of B6 supplementation in neurodegenerative diseases, as well as its bioavailability in synthetic (vs. dietary) forms and the appropriate doses.”

Becker hypothesized that the therapeutic potential of B6 management will need to be evaluated on an individual basis.

She suggested that the most benefit would likely occur when it is “combined with appropriate diet/nutrition and lifestyle that is optimized to support cognition and mental health — for example, considering other B vitamins (e.g., B12) and other micronutrients that are critical for brain health (e.g., folic acid , etc.).”