Thursday, 15 December 2016

Best way to remyelinate is stop inflammation and allow the natural repair mechanisms to occur.

Psachoulia K, Chamberlain KA, Heo D, Davis SE, Paskus JD, Nanescu SE, Dupree JL, Wynn TA, Huang JK. IL4I1 augments CNS remyelination and axonal protection by modulating T cell driven inflammation. Brain. 2016; 139:3121-3136.

Myelin regeneration (remyelination) is a spontaneous process that occurs following central nervous system demyelination. However, for reasons that remain poorly understood, remyelination fails in the progressive phase of multiple sclerosis. Emerging evidence indicates that alternatively activated macrophages in central nervous system lesions are required for oligodendrocyte progenitor differentiation into remyelinating oligodendrocytes. Here, we show that an alternatively activated macrophage secreted enzyme, interleukin-four induced one (IL4I1), is upregulated at the onset of inflammation resolution and remyelination in mouse central nervous system lesions after lysolecithin-induced focal demyelination. Focal demyelination in mice lacking IL4I1 or interleukin 4 receptor alpha (IL4Rα) results in increased proinflammatory macrophage density, remyelination impairment, and axonal injury in central nervous system lesions. Conversely, recombinant IL4I1 administration into central nervous system lesions reduces proinflammatory macrophage density, enhances remyelination, and rescues remyelination impairment in IL4Rα deficient mice. We find that IL4I1 does not directly affect oligodendrocyte differentiation, but modulates inflammation by reducing interferon gamma and IL17 expression in lesioned central nervous system tissues, and in activated T cells from splenocyte cultures. Remarkably, intravenous injection of IL4I1 into mice with experimental autoimmune encephalomyelitis at disease onset significantly reversed disease severity, resulting in recovery from hindlimb paralysis. Analysis of post-mortem tissues reveals reduced axonal dystrophy in spinal cord, and decreased CD4+ T cell populations in spinal cord and spleen tissues. These results indicate that IL4I1 modulates inflammation by regulating T cell expansion, thereby permitting the formation of a favourable environment in the central nervous system tissue for remyelination. Therefore, IL4I1 is a potentially novel therapeutic for promoting central nervous system repair in multiple sclerosis.




What causes remyelination there is alot of interest in macrophages as they must clear up the debris of demyelination before remyelination can occur. In this study they find that a cytokine is more common in tissues about to repair than not repairing. However it does not make oligodendrocytes repair it simply blocks inflammation and if this is all it does then join the queue there are looks of things that block inflammation and many of them do it better. They find reduced clinical disease and surprise surprise then that they get less  nerve damage and less inflammation allowing repair to progresses. So the message is stop damage and all repair mechanisms to work

If we look at the EAE data, it all sounds fanastic but look at the data and the figures don't add up. The effect of the treatment is marginal (Figure A), now look at figure D and the effect is enormous so abit of cherry picking of the figures and this is supported by figure E where the SMI-32 is reduced by about 60% but not out of existence as suggested by figure D. Now go to figure C and the gates (lines) go right through a population of cells. 

Nice bit of reviewing:-(.

3 comments:

  1. Very sloppy reviewing. Interesting the last 2 days that clinical scores were measured there was as increase in score in the control group. The cynic in me immediately thinks it was to make the stats more significant.

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  2. Highly effective therapies stop inflammation so Brain get a chance to regenerate itself. Use it as early as possible! That's the message! Pres by Prof. Timothy Vollmer. I recommend highly his presentations (YouTube)

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  3. I'm confused.
    Should I use opioids and testosterone or not?
    I've already set up an appointment with my dealer!

    ReplyDelete

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