Are Novel Vitamin K Analogues the New Hope for Brain Disorders?

Vitamin K, which is known for its blood and bone health, could also enhance the brain cell regeneration and protection. Naturally occurring Vitamin K compound such as menaquinone 4 may not be strong enough to treat nervous disorders on their own. Scientists are seeking novel methods to improve its medicinal benefits (1^✔ ✔Trusted Source
A New Class of Vitamin K Analogues Containing the Side Chain of Retinoic Acid Have Enhanced Activity for Inducing Neuronal Differentiation

Go to source). Diseases of progressive neuron loss such as Alzheimer's and Parkinson's, induce cumulative decline of brain cells, causing serious symptoms like memory loss and motor dysfunction. Such conditions crucially shrink patient’s quality of life and often require continuous attention and care.

However, current medications may help manage symptoms, they can't provide persistent cures, featuring for the need of new treatments.

Vitamin K Brings About Neuronal Development

In a new pioneering study published online in the journal ACS Chemical Neuroscience, a team of researchers led by Associate Professor Yoshihisa Hirota and Professor Yoshitomo Suhara from the Department of Bioscience and Engineering, Shibaura Institute of Technology, Japan, has designed and synthesized novel vitamin K analogues with enhanced neuroactive properties. Also, they report a unique mechanism of action by which vitamin K induces neuronal differentiation.

Giving further insight into their work, Dr. Hirota explains, “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.”

A Breakdown Compound of Vitamin A Fosters Neurogenesis

To improve the potency of vitamin K, the researchers synthesized 12 vitamin K hybrid homologs conjugated with retinoic acid—an active metabolite of vitamin A known to promote neuronal differentiation, a carboxylic acid moiety, or a methyl ester side chain and compared the neuronal differentiation-inducing activity of the hybrid homologs.

Vitamin K and retinoic acid regulate transcriptional activity via the steroid and xenobiotic receptor (SXR) and retinoic acid receptor (RAR), respectively. The researchers assessed SXR and RAR transcriptional activity in mouse neural progenitor cells treated with the newly synthesized compounds.

Retinoic Acid and Methyl Ester Exhibit Higher Nerve Cell Specialization

Notably, the biological activity of vitamin K and retinoic acid was preserved in the hybrid homologs. Further, the researchers examined the differentiation of neural stem cells treated with the homologs by quantifying the expression of microtubule-associated protein 2 (Map2), a marker of neural growth expressed by neurons.

Compound that possessed both the conjugated structure of retinoic acid and a methyl ester side chain exhibited a three-fold higher neuronal differentiation activity compared with the control and significantly higher activity than natural vitamin K compounds, hereafter referred to as Novel vitamin K analog (Novel VK).

The Role of Glutamate Receptors in the Brain Communication

To further elucidate the mechanism by which vitamin K exerts neuroprotective effects, the researchers compared the gene expression profiles of neural stem cells treated with MK-4, a neuronal differentiation-inducing compound, and a compound that suppresses the differentiation of stem cells into neurons.

The transcriptomic analysis revealed that metabotropic glutamate receptors (mGluRs) mediate vitamin K-induced neuronal differentiation through downstream epigenetic and transcriptional regulation. The effects of MK-4 were specifically mediated by mGluR1.

Notably, mGluR1 has been previously implicated in synaptic transmission, and mGluR1-deficient mice exhibit motor and synaptic dysfunction, which are characteristic features of neurodegenerative diseases.

Vitamin K Analogues Have Strong Affinity with Glutamate Receptors

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.

Vitamin K Derived Drug Improves Quality of Life

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.

Reference:

1. A New Class of Vitamin K Analogues Containing the Side Chain of Retinoic Acid Have Enhanced Activity for Inducing Neuronal Differentiation - (https://pubs.acs.org/doi/10.1021/acschemneuro.5c00111)

Source-Eurekalert