Identifying myelin repair agents. First we need to know if they are drugs.

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Fed up with COVID classics, how about some mouse remyelination studies?

Being a scientist I know that the mechanism is often more important that the therapeutic aspect and therefore basic scientists often do not think of the practicalities of their discoveries. Many remyelinating agents have been shown to influence the signalling cascades of myelinating cells and whilst they may work wonders in cell assays or in animal models where side effects of long-term use is not a concern, the question is whether they will work in humans. For example we have just heard about Bexarotene, it gives a hint of efficacy in humans but will go no where because of the side effects. This was perhaps not surprising as RXR target of the drug is every where.

Therefore, if you go fishing for drugs to use in humans, you have to consider if they can be useful. Otherwise you spend alot of time going down a dead-end road. This study does just that. But before we get our hopes up we have to look at what they find. I have been guilty of this we have found treatment effects and when you try and sell the idea to pharma they say it is brick dust and will never be a drug as you can’t formaulate it to get any form of useful delivery as a pill or injection. Worse they can cause side effects

Identification of novel myelin repair drugs by modulation of oligodendroglial differentiation competence.Manousi A, Göttle P, Reiche L, Cui QL, Healy LM, Akkermann R, Gruchot J, Schira-Heinen J, Antel JP, Hartung HP, Küry P.EBioMedicine. 2021 Mar 10;65:103276. doi: 10.1016/j.ebiom.2021.103276.

Background: In multiple sclerosis loss of myelin and oligodendrocytes impairs saltatory signal transduction and leads to neuronal loss and functional deficits. Limited capacity of oligodendroglial precursor cells to differentiate into mature cells is the main reason for inefficient myelin repair in the central nervous system. Drug repurposing constitutes a powerful approach for identification of pharmacological compounds promoting this process.

Methods: A phenotypic compound screening using the subcellular distribution of a potent inhibitor of oligodendroglial cell differentiation, namely p57kip2, as differentiation competence marker was conducted. Hit compounds were validated in terms of their impact on developmental cell differentiation and myelination using both rat and human primary cell cultures and organotypic cerebellar slice cultures, respectively. Their effect on spontaneous remyelination was then investigated following cuprizone-mediated demyelination of the corpus callosum.

Findings: A number of novel small molecules able to promote oligodendroglial cell differentiation were identified and a subset was found to foster human oligodendrogenesis as well as myelination ex vivo. Among them the steroid danazol and the anthelminthic parbendazole were found to increase myelin repair.

Interpretation: We provide evidence that early cellular processes involved in differentiation decisions are applicable for the identification of regeneration promoting drugs and we suggest danazol and parbendazole as potent therapeutic candidates for demyelinating diseases.

Funding: This work was supported by the Jürgen Manchot Foundation, Düsseldorf; Research Commission of the Medical Faculty of Heinrich-Heine-University Düsseldorf; Christiane and Claudia Hempel Foundation; Stifterverband/Novartisstiftung; James and Elisabeth Cloppenburg, Peek and Cloppenburg Düsseldorf Stiftung and International Progressive MS Alliance (BRAVEinMS).

This study used the capacity of p57kip2 protein’s subcellular localization to serve as early differentiation competence marker. They identified four compounds with oligodendroglial differentiation promoting competence in the rat system, namely danazol, parbendazole, methiazole and nocodazole, with the first three also being able to promote human oligodendroglial cell maturation as well as developmental myelination of organotypic slice cultures. Moreover, danazol and parbendazole also promoted remyelination in the cuprizone-mediated mouse model of demyelination..

The use of danazol is limited by masculinizing side effects such as acneexcessive hair growth, and voice deepening. Danazol has a complex mechanism of action, and is characterized as a weak androgen and anabolic steroid, a weak progestogen, a weak antigonadotropin, a weak steroidogenesis inhibitor, and a functional antiestrogen. Danazol was discovered in 1963 and was introduced for medical use in 1971 Due to their improved side-effect profiles, particularly their lack of masculinizing side effects, danazol has largely been replaced by gonadotropin-releasing hormone analogues (GnRH analogues) in the treatment of endometriosis. To me this suggests that unless you want to be Barry White (he had a very deep voice) this is unlikely, in my opinion, to go anywhere soon. In the studies they used 100mg/kg but the human dose is max 400mg so about 6mg/kg or 3mg/kg twice a day.

Next up we have parbendazole, it is so odd it doesn’t have a Wiki page, but it is used as a veterinary product to get rid of worms. This is brick dust and doesnt dissolve in water and carries a warning of toxicity if swallowed and has suspected of damaging fertility or the unborn child. So whilst I bet some people will read this paper and be off to the pet shop to get some Bob Martins 3-1 worming tablets. My advice is to wait and see what the scientistcs can find in terms of the molecular mechansim for repair and get an agent suitable for human use. Here they acknowledge problems and say the fertilitiy issues is seen at 60mg/kg so 20mg/kg in mice would be OK, but with the rule of 12 to scale mouse to human i.e. 120mg/kg would it be OK?

As they say “it must be considered that these hit compounds may only act as leading substances of which derivates shall be developed and tested”. lets hope they can find safer agents. This is the start of a long hunt. Agents found many years ago have still yet to be come available and shows you that animal studies take time to become a clinical reality but you have to start somewhere.

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MouseDoctor

17 comments

  • To be honest I haven’t yet had time to look through all of this post – has Ursolic Acid been mentioned? (it is found naturally in such things such as apple peel and rosemary. In mouse studies it has shown to have remyelination properties. I realise that this is a mouse study but does anyone know of any more about this?
    Wow I would love to be in such a human trial….. Or will this be a forever no go as the pharma’s won’t make the big bucks from apple peel…….. 🤔

    • In did KETO in combination with Clemastine and N-acetyl-d-Glucosamine for 3 months, this did nothing for me. I do not take Ursolic Acid as a suplement but i do eat lots of herbs that contain it. I prefer these forms in hope of better absorption and I have so much sups already, i feel a bit silly. For now desperate as i am, i still won’t try anything based on a mouse study unless, Mousedoctor gets really excited about it 🙂

        • I would have thought anything suggesting remyelination is something to get excited about!
          I am taking Ursolic supplements, I would love to take more but can’t afford to – actually it’s one of only a few supplements I can tolerate.
          Fingers crossed there’s someone out there that’s interested to discover more about the healing properties in such foods…. Apple peel could end up a big deal! 🍏

  • There are a lot more than the 4 suggested. You know this.

    Why is there always the negativity around remyelination on this blog.

    It’s early days, as everyone knows, a lot of focus going into this area now.

    • Not sure it is always negativity….Metformin discovery we were upbeat…but here the agents aren’t going anywhere quick….do you want me to get excited about that?
      However, getting excited about something that is unlikely to work, you will blame me when it fails after 5-10 years of development

      • How can you know is it’s unlikely to work? The research hasn’t been done yet fully, it may not work obviously but a lot of the research is early days with some promising findings.

        I mean how long can metformin and clementine trials be talked about for? No doubt now COVID will get blamed for the trial not starting, although other trials have started during the COVID era. My money is on a drug maker making similar products to metformin and clementine for example, tweeking the dose or ingredients, repackage and sell for extortionate prices. Then ‘aahhhh there’s no point in a metformin trial now’ when there’s been years missed.

        There are plenty of existing drugs being researched with new knowledge being found more than ever, better techniques to view remyelination of nerves, surely it’s a good thing to be looking into.

        Or do we just give up on it now then and not bother?

        • The son/daughter of these agents…may work isn’t that the point.

          Yes COVID will be blamed for the delay,because it did delay. Other trials may have started but I would guess not many in the UK.

          Pharma tweak repackage….yep thats what they do.

          Surely good thing…yep

          Do we just give up…absolutely not…but you can ask questions

          • Not really. Any agent ‘may work’ your answer to every question might as well be let’s wait until phase 3 trials are complete and the drugs are passed off.

            Agents have been found to remyelinate so it’s not like it’s such a long shot it just needs further research.

            It just feels like your approach is beaten before it’s even started.

            I’m not saying give people false hope in anyway, just there are a lot of positives towards myelin repair that don’t get a mention.

      • I’m not saying give people false hope in anyway, just there are a lot of positives towards myelin repair that don’t get a mention.

        Then it is your job to point these out,

        • Just a quick search of trials and research on google, maybe all these articles are wrong, however

          -More money, research and interest going into this area

          -Big pharma acknowledgement that myelin repair is an unmet need

          -Better ways to view myelin repair in the brain and how the OPC’s work in the brain

          -Thousands of approved compounds tested and some shown to enhance or regrown myelin –

          Clementine
          CDB
          Theophylline
          Metformin
          Cambinol
          miconazole
          clobetasol
          RXR agonist
          NAC
          Taurine
          Plus many more

          -Lifestyle factors – exercise, sleep, diet, fasting etc and there effects on myelin repair

          -BTKi shown to promote remyelination

          -Better understanding of the environment around brain lesions and what maybe
          stopping to remyelination process

          -Myelin repair possible in animal models and trails showing also in humans

          -More understanding of how oligodendrocytes work

          -The impact of aging on myelin repair

          -Humans Trials going right now that may enhance myelin repair

          -Possibility’s of stems cells being used

          -Other neuro degenerative researchers
          understanding the role myelin plays in diseseaes such as alzimers ‘may’ lead to more research in the area.

          Plus more areas of research

          We need to look at these areas to get more of an understanding, as a scientist you don’t need me to tell you this, I thought research would be a positive thing and something that perks your ears up.

          Its clearly early days but where do you start, straight in at a phase 3 trial? Researchers have to start somewhere. I don’t know if you think it’s possible but some researchers clearly do, it’s probably not going to be a miracle cure, but it might just enhance natural myelin repair to allow better nerve signalling and help slow down MS.

          Who knows I just wouldn’t write it off. No doubt there will be some failings along the way.

          • If we report every study in animal then you have “cure of the week”…if it reaches the media I may comment on it but you will get bored with cure of the week being as it will be 5-15years from being approved for people with MS. clemastine data was not that impressive, but Clemastine ontrial again CDB I guess is cannabidiol…in the states this is a schedule 1 drug and sativex contains cannabidiol is there recovery? Theophyllin inhibits phosphdiesterase so does ibudilast, Cambinol ceramide and spingomyelinase, miconazole anti-fungal used for treament of thrush etc., clobetasol a strong steroid, RXR has failed because it is too toxic etc. Neutriceuticals are unlikely to make it and for cheap out of patent drugs they are unlikely to get past a phase II trial. COVID-19 has shown us that doctors throwing drugs at clinical problems in tiny studies gets us essentially nowhere as it creates falsoe hope. All the early promise of COVID-19 have largely fallen by the wayside when phase III trials are done. These cost millions so unless govenrments or pharma fund them they dont get done. Statins are in phase III if thsi si positive it will be interesting to see how practise changes.

            However, I will say remylination is not an area of our current research interest

  • Yes, we have to start somewhere. But – “There were 3.4 million experiments on animals in the UK in 2019 (latest Home Office statistics)

    Every minute of every day, 6 animals are used in research in the UK. ”

    That is a lot of suffering when you know the outcome is likely to be zilch, Are you guys in support of organisations like https://www.animalfreeresearchuk.org ? (where the quote comes from). As we go forward this century, surely we need to aim to ‘do no harm’ as much as possible. To all sentient beings, not just homo sapiens.

  • I tried to submit a comment but a notification came up to say it was a duplicate! It wasn’t. 🙁

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