Thursday, 12 January 2017

Mechanism of GA

Christiansen SH, Zhang X, Juul-Madsen K, Hvam ML, Vad BS, Behrens MA, Thygesen IL, Jalilian B, Pedersen JS, Howard KA, Otzen DE, Vorup-Jensen T. The random co-polymer glatiramer acetate rapidly kills primary human leukocytes through sialic-acid-dependent cell membrane damage. Biochim Biophys Acta. 2017 Jan. pii: S0005-2736(17)30001-9.

The formulation glatiramer acetate (GA) is widely used in therapy of multiple sclerosis. GA consists of random copolymers of four amino acids, in ratios that produce a predominantly positive charge and an amphipathic character. With the extraordinary complexity of the drug, several pharmacological modes-of-action were suggested, but so far none, which rationalizes the cationicity and amphipathicity as part of the mode-of-action. Here, we report that GA rapidly kills primary human T lymphocytes and, less actively, monocytes. LL-37 is a cleavage product of human cathelicidin with important roles in innate immunity. It shares the positive charge and amphipathic character of GA, and, as shown here, also the ability to kill human leucocyte. The cytotoxicity of both compounds depends on sialic acid in the cell membrane. The killing was associated with the generation of CD45+ debris, derived from cell membrane deformation. Nanoparticle tracking analysis confirmed the formation of such debris, even at low GA concentrations. Electric cell-substrate impedance sensing measurements also recorded stable alterations in T lymphocytes following such treatment. LL-37 forms oligomers through weak hydrophobic contacts, which is critical for the lytic properties. In our study, SAXS showed that GA also forms this type of contacts. Taken together, our study offers new insight on the immunomodulatory mode-of-action of positively charged co-polymers. The comparison of LL-37 and GA highlights a consistent requirement of certain oligomeric and chemical properties to support cytotoxic effects of cationic polymers targeting human leucocytes.


So the first new mechanism for GA for 2017, its a cell killer.

9 comments:

  1. LL37 is also made by vitamin D if the vitamin D level in blood is high enough.

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  2. ..........most efficacious, in every way ;-)
    https://www.youtube.com/watch?v=2x8D4T--0v4

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    1. MD2 I cannot believe I clicked on that ;-)

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    2. A little light relief. I always think of GA as Medicinal Compound ;-)

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    3. I suppose better name than snake oil:-), but seriously maybe we can do a poll of themechanisms and pick one..I know my current favourite.

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    4. First time Lily Pinkers can follow the words here https://www.youtube.com/watch?v=u7pHDoJrrzA

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  3. Still doesn't put the kettle on though? Must be coming soon...

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  4. The newcomer who reads this will think as soon as GA is a "multipurpose" remedy, the miracle remedy for everything, it soon has action even against mycoses in the foot. But I use GA (fortunately or unfortunately, NHS scheduling criteria here in Brazil) and I hope he's at least actually doing something, because figuring out that you get inject every day with something that's almost a "placebo" isn't not cool.

    But what I have realized is that really since I started using GA it almost 2 years ago and 6 months I catch the flu very, very easy.
    It seems that my immunity isn't longer the same, before it hardly gripped, and it looks like I take Vitamin D3 and Vitamin C every day.

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  5. My sister progressed continously when she shooted it day by day (for 15 months). She had ponto-cerebellar lesions and atrophy too. She started Gilenya (fingolimod) in last february. Her EDSS imporved by 0,5 points (from 3,5-3,0 to 3,0-2,5), she feels better in the morning, and worse by evening. Her MRI stable with some sign of remyelination. She absolutely loves it!
    Copaxone means for her: waste of precious time.

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