Could there be a new MS drug on the way?
Scientists from the University at Buffalo in New York find that the receptor muscarinic type 3 (M3R) is a “key regulator” of remyelination, which is the process that replenishes lost myelin.
M3R is found on the surface of oligodendrocyte progenitor cells (OPCs), the precursors to the cells that make myelin.
A receptor is a cell-surface protein that triggers certain cell functions when it encounters and binds to a matching unique molecule.
The scientists showed that blocking M3R increased remyelination in mice that had human OPCs transplanted into them.
Senior study author Fraser J. Sim, an associate professor of pharmacology and toxicology, and his colleagues report their findings in a paper now published in The Journal of Neuroscience.
Multiple sclerosis and myelin loss
Many experts believe that the disease develops because the immune system attacks myelin and the cells that make it as though they were a threat.
As myelin is destroyed, it forms lesions that weaken signals that travel along the nerve fibers, leading to disrupted communication between brain cells. Scientists have learned that the disease also damages the nerve cells themselves.
MS has many symptoms, and they can range from mild to severe and depend on which part of the central nervous system is affected.
Common early symptoms include: problems with vision and pain in the eye; weak and stiff muscles, sometimes with painful spasms; tingling in the limbs, face, and trunk; difficulties with balance; and bladder problems.
As the disease progresses, these symptoms may be accompanied by extreme fatigue, changes in mood and concentration, and difficulties with planning and decision-making.
The symptoms can come and go, or they can persist and worsen. They may also vary from person to person, and they can also change in the same individual over time.
Estimates suggest that there are up to 350,000 people living in the United States who have been diagnosed with MS, with women twice as likely to be affected as men.
Oligodendrocytes and myelination
MS arises not just because the myelin degrades, but also because there is a failure to repair it. This has made scientists wonder if destruction of the cells responsible for remyelination might not be the only factor.
They started to investigate the possibility that the precursors of myelinating cells — the OPCs — were failing to multiply and mature. The result would be a shortage of cells for repairing myelin damage.
Eventually, they discovered that blocking muscarinic receptors was a powerful way to get OPCs to mature and speed up remyelination.
But as the authors note, translating this laboratory success into the clinic has been constrained by “poor understanding” of the muscarinic receptor subtype involved and questions about “species differences between rodents and humans.”
In earlier work, the team had reported that solifenacin — a drug that was already approved for treating bladder problems — blocked the receptor and promoted remyelination in animals.
However, in that study it was not clear “which specific receptor the drug worked on,” explains Prof. Sim. In order to limit undesirable side effects, it would be better to know precisely which receptor subtype to target.
M3R has role in myelin production
In the latest study, the researchers worked with mouse OPCs, human OPCs, and mice with human OPCs transplanted into them.
They discovered that activating the M3R receptor led to cell signals in OPCs that “act to delay differentiation and remyelination.”
Further experiments demonstrated that blocking M3R increased remyelination by human OPCs transplanted into mice.
Prof. Sim explains that their new findings put the field in a better position for carrying out clinical trials of drugs that target M3R in MS patients.
“This work establishes that M3R has a functional role and if blocked, could improve myelin repair.”
Prof. Fraser J. Sim