Researchers find sulfuretin molecule may promote myelin repair
Cell study shows sulfuretin may halt MS disease progression
Researchers at the Oregon Health & Science University have discovered a plant-derived small molecule that can promote the growth of cells that produce myelin, the protective coating around nerve fibers that’s damaged in multiple sclerosis (MS).
The naturally occurring molecule, sulfuretin, blocks the activity of an enzyme that is overactive in areas of myelin damage. This same enzyme also contributes to the growth and spread of cancer cells, meaning the discovery has implications beyond MS.
“We think this is a drug that could have impact in a lot of different areas,” Larry Sherman, PhD, professor in the Oregon National Primate Research Center at Oregon Health & Science University (OHSU), said in a university news story.
Details of the discovery were described in the study, “Distinct chemical structures inhibit the CEMIP hyaluronidase and promote oligodendrocyte progenitor cell maturation,” which was published in the Journal of Biological Chemistry.
MS is an autoimmune disorder marked by a mistaken immune attack on the myelin sheath, a fatty coating around nerve fibers that speeds the transmission of electrical impulses. The resulting inflammation damages myelin, the nerve fibers, and the cells that generate myelin, called oligodendrocytes, triggering the onset of MS symptoms.
Sulfuretin shows promise
Elevated production of an enzyme known as cell migration inducing and hyaluronan-binding protein, or CEMIP, which naturally degrades hyaluronic acid, has been implicated in the development of MS.
Hyaluronic acid is a long, chain-like molecule that is important for many natural functions, including tissue lubrication, cell migration, and wound repair.
Studies show that CEMIP expression is elevated in demyelinating MS lesions, resulting in the excess production of certain hyaluronic acid fragments that can directly block the maturation of oligodendrocytes. However, small molecules that suppress the activities of some hyaluronidases, including CEMIP, have boosted functional recovery in MS rodents.
Elevated hyaluronidase activity can also allow cancer cells to grow unchecked, leading to poor outcomes in several types of cancer. CEMIP appears to be involved in a range of other disorders, including osteoarthritis, brain injury caused by heavy alcohol use, and neurological disorders including Alzheimer’s disease.
Using therapeutic small-molecule inhibitors to target CEMIP hyaluronidase activity may be “an efficacious method to promote repair following [brain and spinal cord] insults, reduce cancer cell metastasis to the brain, and reverse other pathological conditions linked to elevated [hyaluronic acid degradation],” the researchers wrote.
“Now we have an inhibitor that could actually stop” such activity, said Sherman, who is also a professor of cell, developmental and cancer biology at the OHSU School of Medicine.
Sherman and colleagues screened a library of lab-made small-molecule compounds to identify potent CEMIP inhibitors. They also screened a large number of plant extracts, a move that built on the success of study co-author Angela Hoffman, PhD, a now-retired University of Portland professor who had been screening for plant-based hyaluronidase inhibitors.
“Over the years, her students have been grinding up these flowers, extracting molecules and testing to see if any of them blocked hyaluronidase activity,” Sherman said. “Finally, a couple of years ago, they found a compound that was promising.”
Researchers initially detected two lab-made compounds and one plant-derived compound — sulfuretin — that blocked the enzyme’s activity. Sulfuretin was significantly more potent at blocking CEMIP activity in mouse oligodendrocyte precursor cells (OPCs), and was also potent at promoting OPC maturation to mature oligodendrocytes, than the lab-made molecules.
“This discovery could be useful for Alzheimer’s or other neurodegenerative conditions,” Hoffman said. “As long as the underlying problem relates to hyaluronic acid being broken apart, this could be helpful for people.”
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