Tuesday, 30 April 2013

Glaterimer acetate promotes remyelination

Rosato Siri MV, Badaracco ME, Pasquini JM.Glatiramer Promotes Oligodendroglial Cell Maturation In A Cuprizone-Induced Demyelination Model. Neurochem Int. 2013 Apr. doi:pii: S0197-0186(13)00131-9. 10.1016/j.neuint.2013.04.008. [Epub ahead of print]

The therapeutic potential of glatiramer acetate (GA) in Multiple Sclerosis has been apparent for many years and has been proven effective in Experimental Allergic Encephalomyelitis, one of its animal models. The cuprizone (CPZ) model for the CNS de/remyelination has gained a renewed interest during the past decade. CPZ-induced demyelination is considered to be primarily an oligodendrocyte loss with participation of the inflammatory response. As the blood brain barrier remains intact, we found this model advantageous for studying GA effects on CNS remyelination with minimum influence of the peripheral immune cellular component. Our results show that GA, given one week before the CPZ treatment, had a maturational effect functional to remyelination. However, myelin was unorganized as compared to controls. When GA was concomitantly injected with CPZ, oligodendroglial precursor proliferation diminished in favour of maturation and myelin recovered an organized disposition. GA-treated animals also show microglial cell (MG) activation. In vitro assays demonstrated that GA-primed MG cultures had a significant increase in IL-10 and IL-4 secretion. GA-challenged MG-conditioned media induced oligodendrocyte proliferation and subsequent differentiation. Our results suggest that, in addition to its well-recognized immunoregulatory properties, GA also has an effect on resident immuno-response, which leads mature oligodendrocytes towards CPZ-induced demyelination repair.



Mixture of Amino acids in Glaterimer Acetate

Yesterday we took some stick for asking what doesn't glaterimer acetate (GA) do? OK that was a bit tounge in cheek, but the reality is that the mechanism of immunomodulation attributed to GA has been very varied throughout the years. 

I suppose as it is doing something positive in MS who cares?

Well if you want to improve the effectiveness this would help. Some people think that a different mixture of amino acids is better, others scratch their heads.


I am interested to see that in this new study it is claimed that GA helps promote remyelination. I think this is yet more evidence for saying that mechanism of action could be varied. 

You suggested some explanations......I wonder how the remyelination would be due to cross linking Ig and causing TRegitopes

Cuprizone is a copper containing substance that is toxic to oligodendrocytes in certain bits of the brain, when added to the diet of rodents. Once removed then remyelination occurs. This may be speeded up by addition of chemicals that promote remyelination. This study suggests that copaxone can do this. The suggestion is that coxpaxone stimulates microglia to produce growth factors that stimulate oligodendrocytes to mature. Does this occur in humans? It would be good if it does. Does glaterimer acetate get into the brain? If if does not would this be important? If it does could it be important?

This study on remyelination repeats something done in a different remyelinating model some time ago,it is suggested to have other functions in neurodegenerative diseases too. 

It is hard to get you head round it.......not to say that you can't..and importantly we do not know how many drugs really work.

7 comments:

  1. I guess this is a subject that I really havent been focused on. I am more interested in what can restore self-tolerance because I think this is the first step. Remeylination and repair of damage would be the second step in my view because if you do not restore self-tolerance the second step would be jumping the gun.

    It would be great if Copaxone would restore self tolerance as well as promote remylination, but I would be happy with just restoring self-tolerance as I don't expect my current accumulated disabilities to be reversed.

    Does Copaxone get into the brain? I don't know, but since it does not seem to effect the permeability of the blood brain barrier I would suspect it has some activity in the CNS.

    Here is an article that is quite old that suggests GA-specific t-cells are found in the CNS. I think this article was written before a lot was known about regulatory T-cells and FoxP3 (they are reffered to as suppressor cells), but I guess it does indicate that GA has influence in the CNS.

    http://www.pnas.org/content/100/24/14157.full.pdf

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    1. If you want to see some really good restoring self tolerance see
      http://www.ncbi.nlm.nih.gov/pubmed/15939483

      How does it work..multiple possibilities...however I can assure you it works.

      The individual components have all been tried in MS put the two approaches together....end of autoimmunity. Just have to work out how to get the two components translatable, working on this.

      You may be interested to read this
      http://www.ncbi.nlm.nih.gov/pubmed/16990994

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    2. As far as the first paper, I think once MS progresses to a neurdegnerative state, self tolerance may not be relevant anymore.

      I could visualize this if chronic demylination exposes the nerves and they begin to die after long periods of time. Reinstating self tolerance would do little at this point:

      http://www.jhasim.com/files/articlefiles/pdf/asm_9_2_p37_41.pdf

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    3. Maybe missing the point. It tells you how to reinduce tolerance. If you start you start too late in ms it is too late if you start too late in eae also.

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    4. I guess I don't get the point. However it seems you may be able to restore immune tolerance for autoimmune diseases by a bone marrow transplant.

      http://www.ncbi.nlm.nih.gov/m/pubmed/18256318/

      However it seems in the phase III trials at northwestern, they will not treat you if you are SPMS or PPMS.

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  2. Also, here is another paper (although quite old) that looked at GA antibodies in mice. It seems all people who take Copaxone develop antibodies against GA. It would be great if more research could be conducted on this subject in light of the recent hypothesis of Tregitopes:

    http://www.fasebj.org/content/16/10/1260?cited-by=yes&legid=fasebj;16/10/1260

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    1. Well as the work on Tregitomes was done by a company, they I suspect will be investigating this...papers of this nature either help small companies get air time that helps them get cash...or for big companies they do it for marketing to keep product in the air or the publish after the work is no longer interesting

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