Nerve transmitter receptor inhibits myelinating cell formation-Block it to get remyelination

The neurotransmitter acetyl choline binds to muscarinic receptors.

Clemastine  is a muscarinic receptor blocker and stimulates remyelination

Benztropine is remyelinating agent that is a muscarinic receptor blocker too. However, these are dirty drugs and bind to many things, meaning the potential for unwanted side effects.
There are five types of Muscarinic receptors M1-M5 
Which ones are the important ones?….Interested? Read On
In this study they looked and found that M3 was the most expressed muscarinic receptor, followed by abit of M1. In mouse (see above) there is abit of M1, M2, M3 and M4. However not all cells had M3. 

They demonstrate that M3R signaling acts to delay OPC differentiation and ultimately contributes to delayed remyelination

This was true in mice and humans

They used Solifenacin an M1/M3 blocker and this promoted remyelination 

There are number of M3 blockers. However if you look above, you can see the major cell type that expresses these receptors in mouse and human is the nerve. Therefore,  M3 blockers will have unwanted effects on nerves. There was great variability in the expression of M3 receptors between different OPC suggesting that perhaps we need something more universal. 

Welliver RR, Polanco JJ, Seidman RA, Sinha AK, O’Bara MA, Khaku ZM, Santiago González DA, Nishiyama A, Wess J, Feltri ML, Paez PM, Sim FJ. Muscarinic receptor M3R signaling prevents efficient remyelination by human and mouse oligodendrocyte progenitor cells. J Neurosci. 2018 Jun 29. pii: 1862-17. 

Muscarinic receptor antagonists act as potent inducers of oligodendrocyte differentiation and accelerate remyelination. However, the use of muscarinic antagonists in the clinic is limited by poor understanding of the operant receptor subtype, and questions regarding possible species differences between rodents and humans. Based on high selective expression in human oligodendrocyte progenitor cells (OPCs), we hypothesized that M3R is the functionally relevant receptor. Lentiviral M3R knock-down in human primary CD140a/PDGFαR+ OPCs resulted in enhanced differentiation in vitro and substantially reduced the calcium response following muscarinic agonist treatment. Importantly, following transplantation in hypomyelinating shiverer/rag2 mice, M3R knock-down improved remyelination by human OPCs. Furthermore, conditional M3R ablation in adult NG2-expressing OPCs increased oligodendrocyte differentiation and led to improved spontaneous remyelination in mice. Together, we demonstrate that M3R receptor mediates muscarinic signaling in human OPCs that act to delay differentiation and remyelination, suggesting that M3 receptors are viable targets for human demyelinating disease.

SIGNIFICANCE STATEMENT The identification of drug targets aimed at improving remyelination in patients with demyelination disease is a key step in development of effective regenerative therapies to treat diseases such as multiple sclerosis. Muscarinic receptor antagonists have been identified as effective potentiators of remyelination but the receptor subtypes that mediate these receptors are unclear. The genetic M3R ablation (removal) in both mouse and human cells results in improved remyelination and is mediated by acceleration of oligodendrocyte commitment from oligodendrocyte progenitor cells. Therefore, M3R therefore represents an attractive target for induced remyelination in human disease.

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  • All these drugs are anticholinergics. In "Stornoway healthcare professionals day: What does the future hold?" Prof G warned against long term use of anticholinergics. Where does that leave those of us already using them in the hopes of seeing remyelination?

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