Novel Vitamin K Analogs Show Promise in Neurodegenerative Disease treatment
Researchers have developed novel vitamin K analogs with significantly enhanced neuroprotective and neuronal differentiation-inducing properties, offering a potential new avenue for treating neurodegenerative diseases like Alzheimer’s.The study, conducted at the Shibaura Institute of Technology and published in ACS Chemical Neuroscience, details the creation and testing of hybrid compounds combining structural elements of vitamin K and retinoic acid.
Vitamin K and retinoic acid exert their biological effects by regulating transcriptional activity through the steroid and xenobiotic receptor (SXR) and retinoic acid receptor (RAR), respectively.The researchers synthesized hybrid homologs of these compounds and found that they retained the biological activity of both parent molecules when tested on mouse neural progenitor cells. Specifically, a compound incorporating both the conjugated structure of retinoic acid and a methyl ester side chain demonstrated a three-fold increase in neuronal differentiation activity compared to controls and outperformed natural vitamin K compounds – designated as a “Novel vitamin K analog” (Novel VK).Neuronal differentiation was quantified by measuring the expression of microtubule-associated protein 2 (Map2), a key marker of neuronal growth.
To understand how vitamin K exerts its neuroprotective effects, the team compared gene expression profiles of neural stem cells treated with MK-4, a known differentiation-inducing compound, to those treated with a differentiation-suppressing compound. This analysis revealed that metabotropic glutamate receptors (mGluRs) play a crucial role in mediating vitamin K-induced neuronal differentiation, operating through downstream epigenetic and transcriptional regulation. The effect was specifically linked to mGluR1, a receptor previously associated with synaptic transmission and whose deficiency in mice leads to motor and synaptic dysfunction – hallmarks of neurodegenerative diseases.
Further inquiry using structural simulations and molecular docking studies confirmed a direct interaction between Novel VK and mGluR1, revealing a stronger binding affinity than observed with natural vitamin K. Crucially, the researchers demonstrated that Novel VK is readily converted to the bioactive MK-4 both in vitro and in vivo. Cellular uptake studies showed a concentration-dependent increase in intracellular MK-4 levels, and mice treated with Novel VK exhibited a more stable pharmacokinetic profile, efficient blood-brain barrier penetration, and higher brain concentrations of MK-4 compared to controls.
these findings illuminate the mechanism behind vitamin K’s neuroprotective effects and suggest that structurally modified analogs like Novel VK can significantly enhance these benefits.As Dr. Hirota, the lead researcher, states, “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 coudl 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.” The study represents a promising step towards the growth of novel therapeutic agents for neurological diseases,offering hope for improved treatments and a better future for patients and their families.
Source: Shibaura Institute of Technology. Hirota, Y., et al. (2025). A New Class of Vitamin K Analogues Containing the Side Chain of Retinoic Acid Have Enhanced Activity for Inducing Neuronal Differentiation. ACS Chemical Neuroscience. doi.org/10.1021/acschemneuro.5c00111.
