Researchers in Japan have developed synthetic vitamin K compounds that are three times more effective than natural versions at promoting neuron growth. These analogues, combined with retinoic acid, could offer new treatments for neurodegenerative diseases like Alzheimer's. The study highlights their ability to cross the blood-brain barrier and activate key brain receptors.
Neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's disease cause progressive neuron loss, leading to memory decline, cognitive impairment, and movement difficulties. Current treatments only manage symptoms, underscoring the need for therapies that regenerate brain cells.
In a study published in ACS Chemical Neuroscience, scientists from Japan's Shibaura Institute of Technology, led by Associate Professor Yoshihisa Hirota and Professor Yoshitomo Suhara, synthesized 12 hybrid vitamin K analogues. These compounds link vitamin K with retinoic acid, a vitamin A metabolite that aids neuronal differentiation, along with carboxylic acid or methyl ester side chains.
The analogues maintained the functions of both parent molecules, influencing gene transcription via steroid and xenobiotic receptor (SXR) and retinoic acid receptor (RAR). Testing in mouse neural progenitor cells showed one hybrid—designated Novel VK, combining retinoic acid with a methyl ester side chain—induced a threefold increase in neuronal differentiation compared to controls and outperformed natural vitamin K. This was measured by elevated expression of microtubule-associated protein 2 (Map2), a marker of neuron growth.
Further analysis revealed vitamin K promotes differentiation through metabotropic glutamate receptor 1 (mGluR1), involved in synaptic communication. Structural simulations confirmed Novel VK's stronger binding to mGluR1. In cells and mice, Novel VK converted efficiently to bioactive menaquinone 4 (MK-4), crossed the blood-brain barrier, and achieved higher brain MK-4 levels than natural vitamin K, with stable pharmacokinetics.
Dr. Hirota explained, "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."
The work, supported by funds from the Mishima Kaiun Memorial Foundation and Japan Society for the Promotion of Science grants, suggests potential for drugs that slow disease progression. Dr. Hirota added, "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."