Anti-acetyl choline drug promotes remyelnation

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Deshmukh VA, Tardif V, Lyssiotis CA, Green CC, Kerman B, Kim HJ, Padmanabhan K, Swoboda JG, Ahmad I, Kondo T, Gage FH, Theofilopoulos AN, Lawson BR, Schultz PG, Lairson LL. A regenerative approach to the treatment of multiple sclerosis.Nature. 2013 Oct. doi: 10.1038/nature12647. [Epub ahead of print]

Progressive phases of multiple sclerosis are associated with inhibited differentiation of the progenitor cell population that generates the mature oligodendrocytes required for remyelination and disease remission. To identify selective inducers of oligodendrocyte differentiation, we performed an image-based screen for myelin basic protein (MBP) expression using primary rat optic-nerve-derived progenitor cells. Here we show that among the most effective compounds identified was benztropine, which significantly decreases clinical severity in the experimental autoimmune encephalomyelitis (EAE) model of relapsing-remitting multiple sclerosis when administered alone or in combination with approved immunosuppressive treatments for multiple sclerosis. Evidence from a cuprizone-induced model of demyelination, in vitro and in vivo T-cell assays and EAE adoptive transfer experiments indicated that the observed efficacy of this drug results directly from an enhancement of remyelination rather than immune suppression. Pharmacological studies indicate that benztropine functions by a mechanism that involves direct antagonism of M1 and/or M3 muscarinic receptors. These studies should facilitate the development of effective new therapies for the treatment of multiple sclerosis that complement established immunosuppressive approaches.

So the media are at it again and an “anti-Parkinson’s Disease drug reverses multiple sclerosis!”..Great…but again the media do their stuff and over-egg the plot. 


This is about a study in both chemical and autoimmune demyelinating models in mice and is hardly the control of multiple sclerosis and it is hardly reversal as the do not do back to normal, but it is encouraging. 



Benzatropine is an anti-cholinergic (Blocks the aceytlcholine) drug used in patients to reduce the side effects of anti-psychotic treatment, such as parkinsonism and dystonia. This was found following a screen to look for drugs that promote myelination
by oligodendrocyte. 


The study suggests that the compound promoted remyelination and was apparently not immunosuppressive and could work with other compounds to augment the clinical benefit, which was attributed to be due to remyelination. 

Let’s hope so, but I may need to change my view of how to interpret clinical EAE….or do they to do this?. It is interesting essentially no neurological disease yet the cords have just as much infiltration……….interesting.

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  • In Supporting Information, other compounds that induce OPC differentiation are listed. Interestingly, some of them are used to treat MS symptoms (gabapentin, Supplementary Table 1, and oxybutinin, Supplementary Table 2). Are there any data on remyelination in humans (MS patients) treated with these symptomatic medications?

    • Good point i dont know but idoubt it will have been looked at because how do you monitor remyelination. Best way is electrophysiogy

  • This paper has generated alot of interest . Elsewhere I could this quesion so post again here.

    "Disease while pretty much eliminating the relapse phase. In this model system, benztropine worked at least as well as the immunosuppressive drugs now in use to treat MS"

    Yes I agreed but they claimed it was not immunosuppressive when it looks like an immunosuppressive. This was also the case for the orignal stem cell papers. There were claims about repair but if you looked at the data to me the data showed immunosuppression. 5 years later and it was reported in loads of places that the stem cells were working by immunosuppression.

    In this study they report that there is no effect on immunosuppression and there is inflammation in the CNS but no clinical disease this is very unusual…I have seen it once with a drug that inhibited clinical but this was not reflected by such an inhibition infiltration and even then there was not such a great clinical effect.

    As they mention the drug can have side effects. Were these so high that they stressed the animal such that its EAE stopped. I believe this happens a lot in the EAE literature.
    You can show it works on the recceptor becaaus that is what makes the animals unwell and stressed. I do not know if this happens in this case. Lets say not until proven otherwise

    The human dose is 1-5mg/day so that is about 0.1mg/kg- 0.01mg/kg and they used 10mg/kg so that is between 100 to 1000 times more than a human gets. Even allowing for a ten times difference from more to man this is a big dose and makes you concerned about the translatability and so do not start self-medicating as this is of unproven value andthe drugs will have side effects as they interfer with nerve signalling

    You can see the graphs so in figure 1.If they dose when dose was givenduring the time of disease induction it essentially wiped disease away, but when given after one of the control group when most of animals were probably healthy it did not stop them getting sick but animls did not relapse which would be immune driven. If the drug was just working by remyelination why the disconnect? If disease hasn't started in both cases there woulld be no demyelination and remyelination would therefore start at the same time in both cases but there is a big difference in the clinical profile…why?. As an immunosuppressive this data would be consistent with the literature that the therapeutic canbe too late for the first phase but can stp the second phase.

    As a word of caution the pictures are supposed to be representative of whats going on but they do not necessarilty mean anything as even in a sick mouse I could find an area with no infiltration and another area with infiltration.You cherry pick thepictures to show what you want to say. Hwever they have done quantitation so lets accept what was done.

    If you look at the myelin ratios they come pare treated to untreated during theattack and it looks different by treated animal looks just like the remission animal with no treatment is time the healer.

    So lets see this repeated. I bet if we did RXR-related drugs we could get a similar effect but in this case there is evidence that high doses are immunosuppressive.

    However the other data supports a potential to aid myelination whichis interesting

  • i want to ask about the anticholinergic antihestaminic effect of benztropine on decreasing the oedema and other inflammatory signs in the brain

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