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Immune-induced model of CFS - Interleukin-1 in brain may trigger fatigue (2014)

Discussion in 'Latest ME/CFS Research' started by Simon, Jul 11, 2014.

  1. Simon

    Simon

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    I recently blogged about theories that an initial immune problem could lead to in appropriate long-term activation of microglia (the brain's immune cells) and many of the symptoms of ME/CFS :Brain Cells Making us Sick? Messed up microglia could be driving symptoms This new paper is supporting evidence from a rat model:

    In a nutshell, it shows that poly-I:C - which activates the immune system (acts like a super-charged RNA virus), activates microglia long-term, and leads to them producing the cytokine Interleukin-!b. Importantly, their study indicates that Interleukin-1b then acts on astrocytes to trigger fatigue due to over-expression of serotonin transporters.

    Induction of interleukin-1β by activated microglia is a prerequisite for immunologically induced fatigue - Ifuku - 2014
    We previously reported* that an intraperitoneal (i.p.) injection of synthetic double-stranded RNA, polyriboinosinic:polyribocytidylic acid (poly-I:C), produced prolonged fatigue in rats, which might serve as a model for chronic fatigue syndrome.
    [poly-I:C provokes an immune response by mimicking dsRNA viruses.]

    The poly-I:C-induced fatigue was associated with serotonin transporter (5-HTT) overexpression in the prefrontal cortex (PFC), a brain region that has been suggested to be critical for fatigue sensation.

    In the present study, we demonstrated that microglial activation in the PFC was important for poly-I:C-induced fatigue in rats, as pretreatment with minocycline, an inhibitor of microglial activation, prevented the decrease in running wheel activity.

    Poly-I:C injection increased the microglial interleukin (IL)-1β expression in the PFC. An intracerebroventricular (i.c.v.) [ie into the brain] injection of IL-1β neutralising antibody limited the poly-I:C-induced decrease in activity, whereas IL-1β (i.c.v.) reduced the activity in a dose-dependent manner.

    5-HTT expression was enhanced by IL-1β in primary cultured astrocytes but not in microglia. Poly-I:C injection (i.p.) caused an increase in 5-HTT expression in astrocytes in the PFC of the rat, which was inhibited by pretreatment with minocycline (i.p.) and rat recombinant IL-1 receptor antagonist (i.c.v.).

    Poly-I:C injection (i.p.) led to a breakdown of the blood–brain barrier and enhanced Toll-like receptor 3 signaling in the brain. Furthermore, direct application of poly-I:C enhanced IL-1β expression in primary microglia.
    We therefore propose that poly-I:C-induced microglial activation, which may be at least partly caused by a direct action of poly-I:C, enhances IL-1β expression. Then, IL-1β induces 5-HTT expression in astrocytes, resulting in the immunologically induced fatigue.

    *Microglial Activation in Immunologically Induced Fatigue - 2013
    credit: paper posted on co-cure by Tate Mitchell
     
    Last edited: Jul 11, 2014
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  2. Firestormm

    Firestormm Guest

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    Thanks @Simon and nice to see you posting again :)

    Now then. This above refers to Interleukin B, but how or is it relevant to Interleukin A and perhaps this study from the MRC and Carmine Pariente: http://forums.phoenixrising.me/inde...nt-fatigue-induced-by-interferon-alpha.13799/

    What I mean to say is do the two Interleukin's - and their association with fatigue-induced symptoms - mean either could be responsible or be involved, and if not, then in what way do the two differ.

    Ha!

    Danke :)
     
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  3. Simon

    Simon

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    Good Q. It's actually interleukin-1beta in this study, Pariente's is using intereferon-alpha which is a different cytokine. However, both are cytokines that can induce fatigue. The Pariente approach has the advantage of looking at humans, and what makes it particularly interesting is that it looks at fatigue that develops after the IFN-a treatment. However, the Pariente study is putting a lot of emphasis on psychosocial indicators, and it isn't yet clear how in-depth it will examine biological factors. Also, rat models allow you to at what's happening in particular brain cells - though that's bad news for the rats.
     
    Last edited: Jul 11, 2014
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  4. Marco

    Marco Old blackguard

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    @Firestormm

    Excerpts only but see pages 225 and 228 re Poly IC induction of IL1-b; IFN-a and the effects on NK cell activity.

    Fatigue Science for Human Health
    edited by Y. Watanabe, B. Evengard, B.H. Natelson, L.A. Jason, H. Kuratsune

    http://books.google.co.uk/books?id=...UQ6AEwAA#v=onepage&q=5-HTT astrocytes&f=false

    I'd be interested to know if the mildly elevated pro-inflammatory cytokines (low grade inflammation inc IL1_b; IL6 and TNF-a) frequently found in PBMCs might be brain derived rather than a peripheral driver of glial activation.
     
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  5. IreneF

    IreneF Senior Member

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    Interesting but unconvincing, as much as I could understand it, since we don't know how those rats felt (were they depressed? were they fatigued? did they have upset stomachs?); we now have good evidence that cytokines and their ilk vary depending on the stage of the illness; and if 1/3 of CFS patients were able to return to work after taking an SSRI, it indicates that their illness was depression and not CFS.

    They may have elucidated part of the mechanism of sickness behavior.
     
  6. natasa778

    natasa778 Senior Member

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    Not necessarily. I wouldn't jump to that conclusion. SSRI may well be doing more than 'just' lifting depression. I have seen SSRIs - as well as 5-htp and tryptophan - improve various symptoms and conditions in people who were not even depressed to start with. Not trying to 'sell' the idea of taking them or anything :) just to say it is totally wrong imo to automatically equate SSRI effects with presence of depression (as in phycho/mental health issue)
     
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  7. IreneF

    IreneF Senior Member

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    SSRIs may be used for conditions other than depression, but one of the diagnostic issues of CFS is distinguishing it from depression; the fact that *so many* patients allegedly improved on Luvox tells me that the diagnostic criteria used by the author failed to distinguish between the two disorders. Also, I don't think anyone with what we have has ever improved with SSRIs. Correct me if I'm wrong.
     
  8. SOC

    SOC Senior Member

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    Some ME symptoms might improve with an SSRI. A cure from only using an SSRI should mean a misdiagnosis. MDD is an exclusionary condition for ME if treatment for depression relieves all symptoms, which is what appears to have happened in this case.
     
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  9. nandixon

    nandixon Senior Member

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    For other people passing by, in very simple terms, the model/theory being presented in the article of the original post is:

    Immunological insult--> activation of microglia--> production of interleukin 1β--> over-expression of serotonin transporters--> decreased serotonin availability-> fatigue

    (It's important to note that the decreased serotonin is occurring in the prefrontal cortex, "a brain region that has been suggested to be critical for fatigue sensation." So we're presumably not simply talking about depression here.)

    From a practical standpoint, this immunologically-induced fatigue theory might possibly explain why some people with ME/CFS feel better with chronic antibiotic use, particularly antibiotics of the tetracycline class (e.g., minocycline, doxycycline). These can inhibit activation of microglia, and possibly reduce fatigue as the article showed with minocycline.

    Thus, it might be worth trying minocycline if a person had previously found, for example, that SSRI's, 5-HTP or other drugs or substances that increase serotonin (or its effect), are energizing or otherwise helpful.

    The minocycline might address the potential problem further upstream, i.e., the inflammatory response, which may be better than trying to correct the lowered serotonin levels that occur later in response to the inflammation.

    However, my understanding is that most (or at least more) people with ME/CFS tend to feel worse when taking SSRI's, for example. I fall into this category, and in fact seem to feel worse with anything that increases serotonin.

    So the model/theory presented wouldn't seem to be a very good fit in the latter case. (It could be complicated, though, depending on which brain regions were experiencing higher or lower serotonin levels.) I may still try to see what happens with minocycline just to see if the inhibition of microglial activity might still be useful somehow.
     
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  10. adreno

    adreno Learned helplessness

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    SSRIs also inhibit microglial activation.
     
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  11. wastwater

    wastwater Senior Member

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    Maybe it would lead to a wired and tired type presentation
     
  12. nandixon

    nandixon Senior Member

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    Good observation. I do wonder if an SSRI would have worked as well as minocycline in the poly-I:C viral fatigue model that was used in the study.

    It seems SSRI's have mostly been used to inhibit activation of microglia in models using lipopolysaccharide (LPS) to induce the activation, i.e., a bacterial or neurodegenerative model (I think).

    So some questions might be: Do SSRI's also inhibit poly-I:C activation of microglia? If so, would the inhibition occur in the right location to prevent the fatigue, i.e., the prefrontal cortex? And would the inhibition be as effective as minocycline? (There's also a matter of side effects for one versus the other.)

    I might try to ask the authors if they know or can speculate whether an SSRI might work in their model.
     
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  13. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    Rat 'models' allow you to look at what's happening in particular rat brain cells.

    There is no reason to assume that the same things happen in human brain cells. There is an enormous number of differences between animal species at all levels, which is why animal 'models' have such poor predictive power for humans, as I have elucidated in several blogposts.

    A recent example relates to the decades of research on Alzheimer's disease using day-old chicks and rodents. Having looked at this research closely, I predicted years ago that the drugs developed and tested in these animals would not help humans, and this has indeed turned out to be the case. Millions of pounds/dollars have been poured into this research, including by charities, and hopes raised. Then, despite the drugs clearing beta-amyloid from the brains of sufferers, as in the animals, they have made not an iota of differences to their illness.

    Animal 'models' are a waste of money, time and lives, both human and otherwise.
     

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