Thursday, 11 December 2014

Estrogen receptor Beta for Remyelination

Moore SM, Khalaj AJ, Kumar S, Winchester Z, Yoon J, Yoo T, Martinez-Torres L, Yasui N, Katzenellenbogen JA, Tiwari-Woodruff SK. Multiple functional therapeutic effects of the estrogen receptor β agonist indazole-Cl in a mouse model of multiple sclerosis. Proc Natl Acad Sci U S A. 2014. pii: 201411294. [Epub ahead of print

Currently available immunomodulatory therapies do not stop the pathogenesis underlying multiple sclerosis (MS) and are only partially effective in preventing the onset of permanent disability in patients with MS. Identifying a drug that stimulates endogenous remyelination and/or minimizes axonal degeneration would reduce the rate and degree of disease progression. Here, the effects of the highly selective estrogen receptor (ER) β agonist indazole chloride (Ind-Cl) on functional remyelination in chronic experimental autoimmune encephalomyelitis (EAE) mice were investigated by assessing pathologic, functional, and behavioral consequences of both prophylactic and therapeutic (peak EAE) treatment with Ind-Cl. Peripheral cytokines from autoantigen-stimulated splenocytes were measured, and central nervous system infiltration by immune cells, axon health, and myelination were assessed by immunohistochemistry and electron microscopy. Therapeutic Ind-Cl improved clinical disease and rotorod performance and also decreased peripheral Th1 cytokines and reactive astrocytes, activated microglia, and T cells in brains of EAE mice. Increased callosal myelination and mature oligodendrocytes correlated with improved callosal conduction and refractoriness. Therapeutic Ind-Cl-induced remyelination was independent of its effects on the immune system, as Ind-Cl increased remyelination within the cuprizone diet-induced demyelinating model. We conclude that Ind-Cl is a refined pharmacologic agent capable of stimulating functionally relevant endogenous myelination, with important implications for progressive MS treatment.


We all want to see remyelination and repair and this is another example of a treatment that is reported to stimulate repair. 

You ask me to comment on this paper. However, I don't know what to say besides this is yet another example of an immunosuppressive compound used in EAE. 

Does it stimulate repair...maybe and maybe not. 

In this study they report that in a chemical demyelinating model that treatment with indazole chloride aided the repair process. This suggested there may indeed be some meat to the story. 

However, in EAE it is impossible to truly understand if repair is due to the drug or there is repair because the immune response has been silenced. This could allow the natural repair processes to occur. Alternatively, there was no damage that developed because the drug stopped the inflammatory response so rather than reversing damage it simple did not happen in the first place because no damaging immune response happened in the first place. 

We have seen this experimental design for countless drugs in the past and will see it again in the future. We have seen the lack of demyelination irrespective of whether the drug is supposed to be immunosuppressive or a repair agent. When immunosuppression is induced there is limited demyelination, axonal loss, cytokine production etc etc etc.

Simply the informative type of experiment in EAE has not been done.

The development of demyelination should be allowed to occur after this damage has abated, then putative remyelinating drug should be given. 

If it dampens the clinical course, then an immunosuppressive control should be used to likewise similarly dampen the clinical course. Then you can see if there is induced repair or repair simple because you have silenced the inflammatory response. Ideally we should be waiting to see if gliotic/astrocytic scarred lesions can be repaired, because this will inform a lot about what value we can get in MS. If long-term demyelinated gliotic lesions can be repaired then this gives hope for MS. Otherwise we get endless false claims. 

I am not trying to be a grumpy old mouse, but until we get a change in experimental design that really dissociates immunosuppression away from repair we will be no the wiser. Check out the paper and then look at some papers where they claim their drug say suppresses immune function e.g. Th17 and see how similar the outcomes are

 Whether this type of agent can cause remyelination, it may do. I know of  other data  of other classes of drugs against the same target, some of it published, with similar claims.

1 comment:

  1. Thank you - this kind of analysis is exactly what makes this blog valuable. Everybody can read an abstract, on PubMed, but only a specialist can place it in context.

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