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 acne, excessive 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.