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Flavonoids are chemicals found in fruits and vegetables that have been used in some consumer health products, such as nutritional supplements and cosmetics. Scientists at Oregon Health & Science University (OSHU) have modified a flavonoid to create a drug that they believe could treat multiple sclerosis (MS) by restoring the protective sheath around neurons called myelin.
The drug, called S3, reverses a mechanism that blocks the growth of myelin-producing glial cells, called oligodendrocytes. This helped to create new myelin sheaths in mice, the team reported in the Glia newspaper.
In 2005, Larry Sherman, Ph.D., and scientists at his lab discovered that the accumulation in the brain of a molecule called hyaluronic acid (HA) inhibits the maturation of oligodendrocyte progenitors into myelin-forming cells. The phenomenon can be observed in myelin lesions in people with MS and in mice with a similar condition.
A family of enzymes called hyaluronidases can degrade HA. Scientists later found that HA fragments were responsible for the inactivity of myelin genes in immature oligodendrocytes. They hypothesized that blockage of hyaluronidase could promote remyelination.
Guided by this index, researchers led by OHSU selected the modified S3 flavonoid. In studies in mice, the drug lifted the restrictive influence of HA and triggered precursor cells to form functional myelin sheaths.
"This does not just show that myelin is coming back, but it is causing axons to shoot at a much faster rate," Sherman said in a statement. "That's exactly what you want functionally."
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Damage to myelin is a hallmark of MS; his healing has become a popular strategy among scientists trying to treat this neurodegenerative disease. A research team led by the University of Maryland's Faculty of Medicine recently discovered that hair follicle stem cells containing the CD34 surface protein could repair myelin in mice. Scientists from the University of Chicago have shown that a derivative of the drug for hypertension Wytensin (guanabenz) could be used to protect oligodendrocytes from inflammatory damage and prevent myelin loss.
On the industry side, Convelo Therapeutics recently partnered with Roche's Genentech to discover new remyelinating therapies for neurological conditions such as MS. The startup target focuses on inhibiting CYP51, TM7SF2 and EBP, brain enzymes that contribute to cholesterol production. Blocking of these enzymes has been shown to be responsible for the formation and remyelination of oligodendrocytes.
Sherman and his colleagues at OHSU have now started using S3 on macaque monkeys with a natural disease similar to MS, called Japanese macaque encephalomyelitis.
"I think we'll know in about a year if it's the exact drug to try in clinical trials on humans," Sherman said. "If that's not the case, mouse studies have taught us that this approach can work. The question is whether this drug can be adapted to larger human brains. "
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