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Activation of the NLRP3 inflammasome in LPS-induced mouse fatigue and its relevance to CFS

Discussion in 'Latest ME/CFS Research' started by JaimeS, Apr 9, 2016.

  1. JaimeS

    JaimeS Senior Member

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    Activation of the NLRP3 inflammasome in lipopolysaccharide-induced mouse fatigue and its relevance to chronic fatigue syndrome
    • Zi-Teng Zhang†,
    • Xiu-Ming Du†,
    • Xiu-Juan Ma†,
    • Ying Zong,
    • Ji-Kuai Chen,
    • Chen-Lin Yu,
    • Yan-Gang Liu,
    • Yong-Chun Chen,
    • Li-Jun Zhao
    • Guo-Cai Lu
    †Contributed equally
    Journal of Neuroinflammation201613:71
    DOI: 10.1186/s12974-016-0539-1

    © Zhang et al. 2016

    Received: 5 January 2016

    Accepted: 31 March 2016

    Published: 5 April 2016

    Abstract
    Background
    The NLRP3 inflammasome (NOD-like receptor family, pyrin domain containing 3) is an intracellular protein complex that plays an important role in innate immune sensing. Its activation leads to the maturation of caspase-1 and regulates the cleavage of interleukin (IL)-1β and IL-18. Various studies have shown that activation of the immune system plays a pivotal role in the development of fatigue. However, the mechanisms underlying the association between immune activation and fatigue remained elusive, and few reports have described the involvement of NLRP3 inflammasome activation in fatigue.

    Methods
    We established a mouse fatigue model with lipopolysaccharide (LPS, 3 mg/kg) challenge combined with swim stress. Both behavioural and biochemical parameters were measured to illustrate the characteristics of this model. We also assessed NLRP3 inflammasome activation in the mouse diencephalon, which is the brain region that has been suggested to be responsible for fatigue sensation. To further identify the role of NLRP3 inflammasome activation in the pathogenesis of chronic fatigue syndrome (CFS), NLRP3 KO mice were also subjected to LPS treatment and swim stress, and the same parameters were evaluated.

    Results
    Mice challenged with LPS and subjected to the swim stress test showed decreased locomotor activity, decreased fall-off time in a rota-rod test and increased serum levels of IL-1β and IL-6 compared with untreated mice. Serum levels of lactic acid and malondialdehyde (MDA) were not significantly altered in the treated mice. We demonstrated increased NLRP3 expression, IL-1β production and caspase-1 activation in the diencephalons of the treated mice. In NLRP3 KO mice, we found remarkably increased locomotor activity with longer fall-off times and decreased serum IL-1β levels compared with those of wild-type (WT) mice after LPS challenge and the swim stress test. IL-1β levels in the diencephalon were also significantly decreased in the NLRP3 KO mice. By contrast, IL-6 levels were not significantly altered.

    Conclusions
    These findings suggest that LPS-induced fatigue is an IL-1β-dependent process and that the NLRP3/caspase-1 pathway is involved in the mechanisms of LPS-induced fatigue behaviours. NLRP3/caspase-1 inhibition may be a promising therapy for fatigue treatment.

    Keywords
    NLRP3 inflammasome LPS Chronic fatigue syndrome NLRP3 knockout mice IL-1β


    More here.

    -J
     
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  2. Valentijn

    Valentijn The Diabolic Logic

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    ... CFS is still seen as similar to being exhausted after forced swimming? :bang-head:

    And nice to know they aren't bothered about minor details like disease criteria:
    I'm glad they're looking into biological pathology, but they need to stop getting their background information about the disease from quacks. Proper criteria and a basic understanding of the core symptoms might provide them with a much better starting point in where to look for abnormalities.
     
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  3. JaimeS

    JaimeS Senior Member

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    Yeah, first citation is not promising!
     
  4. alex3619

    alex3619 Senior Member

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    Also note the low lactate.
     
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  5. Marco

    Marco Grrrrrrr!

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    They're not actually saying that. They identify infection and exercise as two out of four fatiguing stressors and the finding that exercise may augment fatigue due to bacterial infection sounds a plausible model for PEM.

    This strikes me as a very well designed study given the limitations of animal models.
     
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  6. Gijs

    Gijs Senior Member

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    You can also block IL1 like they try in the Netherlands.
     
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  7. Rrrr

    Rrrr Senior Member

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    The paper's conclusion is saying "NLRP3/caspase-1 inhibition may be a promising therapy for fatigue treatment."

    So I looked up "NLRP3/caspase-1 inhibition" and found this paper
    http://journal.frontiersin.org/article/10.3389/fphar.2015.00262/full

    It lists a few things that inhibit NLRP3/caspase-1, and one of them is resveratrol, an over the counter supplement any of us can buy. I have seen its name often over the years but never tried it. Have others?
     
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  8. JaimeS

    JaimeS Senior Member

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    Arglabin is another one that seems to have been effective as a NLRP3 inhibitor, and it's synthesized from Artemisia glabella. I wonder if it's in the other (more common!) artemisias.

    I have tried resveratrol -- a somewhat drying effect, nothing dramatic, but I was very sick when I tried it. Unless it caused a profound change, I might not have noticed anything at all.

    -J
     
  9. JaimeS

    JaimeS Senior Member

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    It also looks like cannabinoid receptor 2 agonists do the same. I just got cannabis oil recommended to me by my local nutritionist, with the whole, "...it's not like smoking pot, it won't do anything to you that way" speech. ;)

    Maybe I will try some, in that case...

    -J
     
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  10. alex3619

    alex3619 Senior Member

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    What about low dose cannabis oil and pulsed dose resveratrol. Sounds interesting. Cannabis oil is in the process of having restricted access legalized in Australia.
     
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  11. Valentijn

    Valentijn The Diabolic Logic

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    It made me feel quite a bit worse when I tried it a couple years ago. I don't remember my exact reaction (headache?), but it was not tolerable.
     
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  12. ScottTriGuy

    ScottTriGuy Stop the harm. Start the research and treatment.

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    Curious - why pulsed?

    I just added resveratrol last week and note the bottle directions say not for long term use.
     
    Last edited: Apr 10, 2016
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  13. alex3619

    alex3619 Senior Member

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    I used pulsed dosage because based on my testing I got the best result for the least cost. The standard dose did nothing for me. At 600mg I got a result. It lasts three to four days. So I do not need another dose for at least four days unless I eat a lot of wheat. Resveratrol greatly reduces my intolerance to wheat.

    I think the usual dose is 300mg/day. I have no response at that dose even if I take it for weeks.

    Resveratrol has some powerful chemistry going for it. I am cautious about taking too much, so the minimal dose that works is best in my view. Its also cheaper.

    I am not sure why they say its not for long term use. This supplement has been used by a great many people continuously for years. It is perhaps the most researched supplement there is since drug companies want to turn it into a drug, but much of that research would not be published. This is one of the very very few, and the most tested, anti-aging supplements. Its a PDE4 (phosphodiesterase) inhibitor, which means it alters the cAMP/Ca++ balance. If I recall correctly, its been a while since I investigated this, it works by decreasing the degradation of cAMP.
     
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  14. JaimeS

    JaimeS Senior Member

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    I was looking at cAMP and Ca2+ literally just last night and thinking that cAMP would be an intriguing therapeutic target. Interesting. Maybe I'll dig mine out -- I tried it when I was first ill, as I mentioned, and my system has really altered since then. Worth a second go.

    -J
     
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  15. Snow Leopard

    Snow Leopard Hibernating

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    The argument is that the difference (decrease) in performance is due to NLRP3 being involved in fatigue sensation somehow (either peripherally, or centrally). The problem is that you can't ask a mouse how they feel.

    A lot of animal models are or dubious validity as they are very different from the disease they are trying to study.
     
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  16. alex3619

    alex3619 Senior Member

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    In this case I think that applies. Since we have no idea what causes the fatigue and energy loss in ME and CFS we have no idea about whether or not this model is valid. Unless they find very elevated lactic acid its not likely to be relevant.
     
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  17. msf

    msf Senior Member

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    I knew that rats can tolerate higher levels of LPS than humans, so I was curious to know what the equivalent dose would be in humans. According to the paper below, 3mg/kg in rats is roughly equivalent to 3ng/kg in humans, which is 1/1000 000th the dose!

    So, the obvious solution to our problems is: become a rat!

    More seriously, I think the dose was too high even for rats, as it causes a SIRS-like syndrome in them at this level, which is not what we are looking at in ME.

    https://circ.ahajournals.org/content/suppl/2009/02/13/CIRCULATIONAHA.108.810721.DC1/CI191998.DS.pd
     
  18. rosie26

    rosie26 Senior Member

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    This word keeps being read as apples to me. Third time it has happened. :aghhh::D
     
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  19. Justin30

    Justin30 Senior Member

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    So do the bottes for Acetyl L Carnitine if you take it....
     
  20. Mij

    Mij Senior Member

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    I thought I was the only one
     
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