A modified flavonoid accelerates oligodendrocyte maturation and functional remyelination.Su W, Matsumoto S, Banine F, Srivastava T, Dean J, Foster S, Pham P, Hammond B, Peters A, Girish KS, Rangappa KS, Basappa, Jose J, Hennebold JD, Murphy MJ, Bennett-Toomey J, Back SA, Sherman LS. Glia. 2019 Sep 6. doi: 10.1002/glia.23715. [Epub ahead of print]
Myelination delay and remyelination failure following insults to the central nervous system (CNS) impede axonal conduction and lead to motor, sensory and cognitive impairments. Both myelination and remyelination are often inhibited or delayed due to the failure of oligodendrocyte progenitor cells (OPCs) to mature into myelinating oligodendrocytes (OLs). Digestion products of the glycosaminoglycan hyaluronan (HA) have been implicated in blocking OPC maturation, but how these digestion products are generated is unclear. We tested the possibility that hyaluronidase activity is directly linked to the inhibition of OPC maturation by developing a novel modified flavonoid that functions as a hyaluronidase inhibitor. This compound, called S3, blocks some but not all hyaluronidases and only inhibits matrix metalloproteinase activity at high concentrations. We find that S3 reverses HA-mediated inhibition of OPC maturation in vitro, an effect that can be overcome by excess recombinant hyaluronidase. Furthermore, we find that hyaluronidase inhibition by S3 accelerates OPC maturation in an in vitro model of perinatal white matter injury. Finally, blocking hyaluronidase activity with S3 promotes functional remyelination in mice with lysolecithin-induced demyelinating corpus callosum lesions. All together, these findings support the notion that hyaluronidase activity originating from OPCs in CNS lesions is sufficient to prevent OPC maturation, which delays myelination or blocks remyelination. These data also indicate that modified flavonoids can act as selective inhibitors of hyaluronidase activity and can promote OPC maturation, making them excellent candidates to accelerate myelination or promote remyelination following perinatal and adult CNS insults.
Hyaluronic acid is a molecule that gets deposited around inflammaed blood vessels during immune attack, it is also the stuff of cosmetics used to enhance lips size, remove crows feet and wrinkles. It is broken down by hyaluonidase, which is used in emergencies to dissolve the fillers if you get it into an artery or view. In this study they find that hyalunoidase is involved in the myelin production and so if they block this they have a remyelination compound. This is great and they are off to test this new agent in a colony of monkeys that get demyelinating disease.
The problem is now join the queue. We have loads of candidates. Which ones are better in terms of activity and which ones are better safety. We are in the era of remyelination trials and sadly if we dont get them right we will be in the era of throwing them in the bin trials. How best to monitor the studies is key. I guess watch this space in a few years time.
As to the title if there is an hyaluronidase blocker and it blocks the breakdown of hyalouronic acid you could keep those big lips (Yuck) that bit longer.