Supercharged Vitamin K can help the brain heal itself

Vitamin K, a fat-soluble nutrient known for its role in blood clotting and bone health, has recently attracted attention for its effect on brain cell growth and protection. However, naturally occurring forms of vitamin K such as menaquinone 4 (MK-4) may not be potent enough for effective use in regenerative therapies targeting neurodegenerative disorders.

In a pioneering study published in ACS Chemical NeuroscienceResearchers from the Department of Biological Sciences and Engineering at Shibura Institute of Technology in Japan, led by Associate Professor Yoshihisa Hirota and Professor Yoshitomo Suhara, have created and tested new analogues of vitamin K with stronger neuroprotective effects. The team also identified a distinct mechanism by which vitamin K promotes neuronal differentiation.

Explaining their findings, Dr. Hirota noted, “Newly synthesized vitamin K analogues showed approximately three times greater efficacy in stimulating the differentiation of neural progenitor cells into neurons than natural vitamin K. Since neuronal loss is a hallmark of neurodegenerative diseases such as Alzheimer’s disease, these analogues may serve as regenerative agents.” It helps regenerate lost nerve cells and restore brain function.”

To enhance the biological effect of vitamin K, the team generated 12 hybrid vitamin K enantiomers by attaching them to retinoic acid (an active metabolite of vitamin A that promotes neuronal differentiation), a carboxylic acid group, or a methyl ester side chain. They then evaluated how effective each compound was in promoting neuronal differentiation.

Vitamin K and retinoic acid affect gene transcription through the steroidogenic and xenobiotic receptor (SXR) and retinoic acid receptor (RAR), respectively. The researchers measured SXR and RAR activity in neural progenitor cells of mice treated with the newly developed compounds, and found that the hybrids maintained the biological functions of both native molecules. They also measured the expression of microtubule-associated protein 2 (Map2), a marker of neuronal growth, to track cell differentiation. One compound, which combined retinoic acid with a methyl ester side chain, produced a threefold increase in neuronal differentiation compared to the control and showed much stronger activity than natural vitamin K. This improved version is designated as a vitamin K analog (Novel VK).

To better understand how vitamin K protects neurons, the team compared gene expression patterns in neural stem cells treated with MK-4, which promotes neuronal differentiation, with those treated with a compound that inhibits it. Transcriptional analysis revealed that vitamin K-induced neuronal differentiation is mediated by metabotropic glutamate receptors (mGluRs) through epigenetic and transcriptional processes. The effect of MK-4 has been specifically linked to mGluR1. Previous studies have shown that mGluR1 plays a key role in synaptic communication, and that mice lacking this receptor suffer from motor and synaptic impairments similar to those seen in neurodegenerative disorders.

Going deeper, the researchers performed structural simulations and molecular docking studies to clarify whether the vitamin K analogue interacts with mGluR1. In fact, their analysis revealed a stronger affinity between Novel VK and mGluR1. Finally, the researchers examined the cellular uptake of Novel VK and its conversion into bioactive MK-4 in cells and mice. They observed a significant concentration-dependent increase in intracellular MK-4 concentration. Furthermore, Novel VK was converted to MK-4 more easily than natural vitamin K. alive Experiments in mice showed that Novel VK showed a stable pharmacokinetic profile, crossed the blood-brain barrier, and achieved a higher concentration of MK-4 in the brain compared to control.

Overall, the study highlights the mechanism by which vitamin K and its structural analogues exert neuroprotective effects, paving the way for the development of new therapeutic agents that can delay or reverse neurodegenerative diseases.

Concluding on the long-term implications of their work, Dr. Hirota says: “Our research offers a potentially pioneering approach to treating neurodegenerative diseases. A vitamin K-derived drug that slows the progression of Alzheimer’s disease or improves its symptoms could not only improve the quality of life for patients and their families, but could also significantly reduce the growing societal burden of health care expenditures and long-term caregiving.” “The long one.”

We hope their research will translate into clinically useful treatments for patients with neurological diseases.

Financing information

This study was supported in part by the Fund of the Mishima Kayon Memorial Foundation, the Suzukin Memorial Foundation, the Kosei Cosmetic Research Foundation, the Koyanagi Foundation, and research grants from the Toyo Institute of Food Technology, the Scientific Research Promotion Fund, and the Takahashi Industrial and Economic Research Foundation. This study was supported in part by the Fund for the Promotion of Joint International Research (Joint International Research Promotion (A)) (Grant No. 18KK0455) and the Grant-in-Aid for Scientific Research (C) (Grant Nos. 20K05754, 18K11056, 21K11709, and 24K14656), Grant-in-Aid for Early Career Scientists (Grant No. 23K14091) from the Japan Society for the Promotion of Science (JSPS).