Neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s disease occur when neurons gradually deteriorate and die. This progressive loss of brain cells leads to severe symptoms including memory decline, cognitive impairment, and difficulty with movement. Over time, these conditions can greatly diminish quality of life and often leave patients dependent on continuous care. Current medications can help ease symptoms but do not stop or reverse the underlying disease, highlighting the urgent need for new therapeutic approaches. One promising strategy focuses on stimulating neuronal differentiation, the process of forming new neurons that could replace those lost and potentially slow or counteract neurodegeneration.
Vitamin K, a fat-soluble nutrient best known for its role in blood clotting and bone health, has recently attracted attention for its influence on brain cell development and protection. However, naturally occurring vitamin K forms such as menaquinone 4 (MK-4) may not be potent enough for effective use in regenerative therapies targeting neurodegenerative disorders.
In a groundbreaking study published in ACS Chemical Neuroscience, researchers from the Department of Bioscience and Engineering at Shibaura Institute of Technology in Japan, led by Associate Professor Yoshihisa Hirota and Professor Yoshitomo Suhara, created and tested new vitamin K analogues with stronger neuroactive effects. The team also identified a distinct mechanism through which vitamin K promotes neuronal differentiation.
Explaining their findings, Dr. Hirota noted, “The newly synthesized vitamin K analogues demonstrated approximately threefold greater potency in inducing the differentiation of neural progenitor cells into neurons compared to natural vitamin K. Since neuronal loss is a hallmark of neurodegenerative diseases such as Alzheimer’s disease, these analogues may serve as regenerative agents that help replenish lost neurons and restore brain function.”
To boost vitamin K’s biological impact, the team produced 12 hybrid vitamin K homologs by linking them with retinoic acid (an active metabolite of vitamin A that encourages neuronal differentiation), a carboxylic acid group, or a methyl ester side chain. They then evaluated how effectively each compound promoted neuronal differentiation.
Vitamin K and retinoic acid influence gene transcription through the steroid and xenobiotic receptor (SXR) and retinoic acid receptor (RAR), respectively. The researchers measured SXR and RAR activity in mouse neural progenitor cells treated with the newly developed compounds and found that the hybrids maintained the biological functions of both parent molecules. They also measured the expression of microtubule-associated protein 2 (Map2), a neuronal growth marker, to track cell differentiation. One compound, which combined retinoic acid with a methyl ester side chain, produced a threefold increase in neuronal differentiation compared with the control and showed significantly stronger activity than natural vitamin K. This enhanced version was designated as the Novel 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, to those treated with a compound that suppresses it. Transcriptomic analysis revealed that vitamin K-induced neuronal differentiation is mediated by metabotropic glutamate receptors (mGluRs) through downstream epigenetic and transcriptional processes. The effect of MK-4 was specifically linked to mGluR1. Previous studies have shown that mGluR1 plays a key role in synaptic communication, and that mice lacking this receptor experience motor and synaptic impairments similar to those seen in neurodegenerative disorders.
Delving deeper, the researchers conducted structural simulations and molecular docking studies to elucidate whether the vitamin K homolog interacts with mGluR1. Indeed, their analysis revealed a stronger binding affinity between Novel VK and mGluR1. Finally, the researchers examined the cellular uptake of Novel VK and its conversion to bioactive MK-4 in cells and mice. They noted a significant concentration-dependent increase in the intracellular concentration of MK-4. Moreover, Novel VK converted to MK-4 more easily than natural vitamin K. Further, in vivo experiments in mice showed that Novel VK exhibited a stable pharmacokinetic profile, crossed the blood-brain barrier, and achieved higher MK-4 concentration in the brain compared to the control.
Overall, the study sheds light on the mechanism by which vitamin K and its structural analogues exert neuroprotective effects, paving the way for the development of novel therapeutic agents that can delay or reverse neurodegenerative diseases.
Concluding with the long-term implications of their work, Dr. Hirota says, “Our research offers a potentially groundbreaking 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 also significantly reduce the growing societal burden of healthcare expenditures and long-term caregiving.”
We hope their research translates into clinically meaningful treatments for patients battling neurological diseases.
Funding information
This study was partly supported by a fund for the Mishima Kaiun Memorial Foundation and the Suzuken Memorial Foundation, KOSÉ Cosmetology Research Foundation, Koyanagi Foundation, Research Grants from the Toyo Institute of Food Technology, the Science Research Promotion Fund and the Takahashi Industrial and Economic Research Foundation. This study was partly supported by a Fund for the Promotion of Joint International Research (Fostering Joint International Research (A)) [grant number 18KK0455] and a Grant-in-Aid for Scientific Research (C) [grant numbers 20K05754 and 18K11056, 21K11709, and 24K14656], Grant-in-Aid for Early-Career Scientists [grant number 23K14091] from the Japan Society for the Promotion of Science (JSPS).
