Blocking Protein Receptor Called M3R Seen to Promote Remyelination in Mice Model, Study Reports

Blocking Protein Receptor Called M3R Seen to Promote Remyelination in Mice Model, Study Reports

Blocking a protein receptor called muscarinic type 3 (M3R) could be an effective way to promote remyelination in multiple sclerosis (MS) patients, according to a State University of New York at Buffalo (UB) study in mice.

The research, “Muscarinic receptor M3R signaling prevents efficient remyelination by human and mouse oligodendrocyte progenitor cells,” was published in the Journal of Neuroscience.

MS is characterized by the progressive loss of the protective layer of nerve fibers, called myelin, that is essential for effective transmission of nerve impulses. Its loss, called demyelination, leads to MS symptoms. As a result, understanding how to trigger remyelination, the formation of new myelin sheaths, is regarded as key for more effective MS treatments.

Remyelination spontaneously occurs in MS lesions, but becomes increasingly incomplete and eventually fails. The process involves the transformation — or differentiation — of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes, which ultimately produce myelin.

Muscarinic receptors (MRs) are one of two types of receptors that bind the neurotransmitter acetylcholine. Research has shown that MR blockers induce the differentiation of OPCs and speed remyelination. However, their use in the clinical setting has been precluded by the lack of information on what receptor subtype is involved.

M3R receptors control processes such as muscle contraction, sweating, food intake, and body weight. As they are plentiful on OPCs, scientists hypothesized that M3Rs may be the functionally relevant MR subtype in remyelination.

The UB team found that genetically manipulating in the lab (in vitro) human OPCs so as to reduce the amount of M3R augmented the cells’ differentiation into oligodendrocytes. The investigators also demonstrated that transferring OPCs with lower M3R levels to mice with myelin deficits improved remyelination. Selective removal of M3Rs from adult OPCs also boosted their differentiation and resulted in better remyelination in the mice.

Overall, the findings show that M3R in oligodendrocyte progenitor cells “act to delay differentiation and remyelination, suggesting that M3 receptors are viable targets for human demyelinating disease,” the researchers wrote.

“This work establishes that M3R has a functional role and if blocked, could improve myelin repair,” Fraser J. Sim, PhD, the study’s senior author, said in a UB news release, written by Ellen Goldbaum. “It better positions the field for clinical trials that will be aimed at blocking these receptors in MS patients.”

The findings build on prior work by Sim’s team, which showed that M3R activation blocks oligodendrocyte differentiation in both humans and rodents. The team also demonstrated that solifenacin, a medication available as VESIcare (marketed by Astellas Pharma) and approved to treat overactive bladder, blocked M3Rs and promoted remyelination in an animal model.

“That work identified solifenacin as a possible drug useful for remyelination, but we really weren’t sure which specific receptor the drug worked on,” Sim said. Lack of specificity for a single receptor type could induce unwanted side effects in patients, he added.

The research team recently was awarded $1.7 million in funding from the National Institutes of Health (NIH) to further investigate the role of M3R in remyelination and to evaluate its potential as a therapeutic target.

“The hope is that this will identify new and more attractive drug targets beyond M3R,” Sim said. “The grant also is geared toward understanding how the receptors are activated in disease. If we can understand that, then we might have another opportunity for targeting this pathway in MS.”

José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has studied Biochemistry also at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario, in London, Ontario. His work ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has studied Biochemistry also at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario, in London, Ontario. His work ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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5 comments

  1. Snehangshu Bhattacharyya says:

    A very hopeful research and opportunity to invent a promising drug that can cure fully a MS patient .

  2. Of course, re-myeliation of neurons is, indeed, profoundly important to arrest further deep damage to the neurons, and maybe nerve death, or severe nerve damage to afflict us with agonizing chronic neuropathic pain, and disability, for example. But, with all respect, what we all REALLY need is central nervous repair, the kind stem-cell research has at least alluded to. We need miraculous CURE, not just re-myelination that slows down the inevitable. We, of the tragically marginalized disabled by the unfeeling and the notorious extortionists, need CURE, to save the quality of our lives we have so dearly worked and paid for in a multiplicity of ways. What can you regularly post on THAT, to salvage our Spirits? Don’t you desperately want to be removed from a wheelchair or walker? What is the marriage of medicine and technology aggressively doing so as to restore our hope? Otherwise, what’s the point. We all respect and understand your commitment to reporting all, and with gratitude, but we desperately crave hope. CRAVE, do you understand? I would think you acutely do.

  3. Rocco Zingaro says:

    No one understands the loss of hope that all of us afflicted with this disease feels, not our partners nor family and friends. The fact that we struggle every day on coping with even the little things as part of our daily lives is unfathomable. To see our bodies reduced to something that isn’t even recognizable from what we used to be is disheartening. So many years of researching and we’re not even close in getting a Stem Cell program in place is shameful. The FDA needs to wake up and get with the program and leave it up to us who are suffering in making decisions of what we will and won’t sign up to do as far as a regiment to treat MS. The drug companies are the biggest lobbyists that have the biggest influence in decision making and will keep a grip on assuring they survive by pushing their drugs that do just enough in keeping the hope inside all of us alive.

  4. Grant Madden says:

    Stem cells is the future I think.Drug free therapies are good and low risk.More development needed but still effective to a certain degree.

  5. Christopher says:

    Hi all.

    For the time being this is very important research to keep us all going until something better, or a cure.

    To be sure, stem cell therapy has a lot of promise, and it has been written about extensively in the media especially to promote it and cause excitement in the myriad possibilities. But as of now that’s pretty much all it is… promise and possibility. Right now there are a few ways that stem cell therapy is able to help repair damage in the body, but unfortunately none of those ways include the nervous system. There are places you can go that charge thousands of dollars, and they make lofty promises of healing and repair, but none of them work. Depending on the type of cell and method of infusion, at best the cells do absolutely nothing and at worst cause malignant lymphomas among other serious medical problems. Science just hasn’t figured out how to control the cells well enough to tell them where to go and when to stop replicating. We are still 20 – 40 years away from where stem cell therapy is viable and effective for repair of most organs. For repair of nervous tissue we are much closer to effective therapies using genetic engineering. The main reason for this has to do with the complex nature of both the nerves and the different types of stem cells themselves. It would take too long to go into a lesson on the different types of stem cells and how they might be modified for repair strategies, but there’s plenty of information on the internet to make most people fairly well educated on the subject. Stem cell therapies for MS damage, as well as any other repair mechanisms or cures, are taking a long time because the science is incredibly complicated, and drugs take a few years to prove safe and effective… not because anyone is purposely marginalizing people who are suffering, or because the FDA doesn’t care, or big pharma isn’t going after cures because they would be put out of business. Some of those things do happen, but not as widespread as you may think. If there were cures, nobody could keep it a secret and most of us would be cured by now. It takes an enormous amount of time and money to work on cures. And unfortunately there’s no shortage of life-altering diseases out there–I’m sure people with ALS, MD, or CF feel the same way as many of us do. The most important thing is to get the word out and make as many people aware as possible. You never know if one of those people may be inspired to become a researcher. and be the one to discover a cure. Heck… learn biology and research for yourself and maybe you’ll find something others missed.

    Will there be a cure tomorrow, or next month, or next year? Most likely not. But those drugs that “only” remyelinate, or keep hope alive… are causing remyelination, and keeping more than just hope alive. They are keeping us alive long enough to hopefully see a cure. Just 25 years ago–which is nothing as far as time–there was nothing, and unless you were really lucky you were guaranteed a short life. Everyone with MS wants to be the way they used to be. But the fact is that we’re not and it’s very hard to deal with. But be assured that there are literally thousands of people working on it day and night, and without them we would be totally screwed. I personally stay up into the wee hours every night doing research, even though it’s probably not good for my health. I’m just not giving up… and neither should any of us.

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