International ME/CFS and FM Awareness Day Is On May 12, 2018
Thomas Hennessy, Jr., selected May 12th to be our international awareness day back in 1992. He knew that May 12th had also been the birthday of Florence Nightingale. She was the English army nurse who helped to found the Red Cross as well as the first school of nursing in the world.
Discuss the article on the Forums.

Could inhibition of Caspase-3 help for suspected herpesvirus-caused CFS?

Discussion in 'Antivirals, Antibiotics and Immune Modulators' started by Wonkmonk, Jun 13, 2018.

  1. Wonkmonk

    Wonkmonk Senior Member

    Messages:
    633
    Likes:
    830
    Germany
    I found this study, which says that latent herpesviruses (EBV, HHV6, KSV) can use apoptosis as a means to reactivate and replicate. That's probably a defence mechanism by the herpes virus to avoid being removed from the host via apoptosis. Once infected cells go into apoptosis, the other infected cells reactivate in order to stop the host from clearing the virus (my understanding).

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807386/

    There are other similar studies, e.g. for HSV-1.
    https://www.ncbi.nlm.nih.gov/pubmed/22908263/

    The fist study says that this mechanism of reactivation depends on caspase-3.

    Dr Lerner hypothesized that noncytolytic infection with herpesviruses destroys a lot of cells via apoptosis in herpesvirus-caused CFS. So every time that happens, it would be a signal for other herpesvirus infected cells to reactivate, which might play a role in sustaining the disease.

    So could these patients possibly benefit from inhibiting caspase-3?

    I found that Ibuprofen at higher doses is a caspase-3 inhibitor:

    https://www.sciencedirect.com/science/article/pii/S2451945617300338

    There are also some flavonoids (apigenin, luteolin) which seem to inhibit caspase-3.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3226999/

    Is any of this worth trying? (Ibu has possible adverse effects and the flavonoids are uncommon supplements and rather expensive)
     
    sb4 likes this.
  2. Runner5

    Runner5 Senior Member

    Messages:
    250
    Likes:
    390
    PNW
    Ibuprophen even in small doses is extremely toxic to the GI creating 'webbing' and damage farther down in the intestinal tract where it's not always easy to 'feel' or know that you're getting damage. (or at the very least it makes my stomach bleed and I can't use it ;-P)

    If you want to decrease inflammation ginger is very good. Most recommend Tumeric but I find both works well for me. I use Ginger to head off migraines when they come on and I'm two-month migraine free which is pretty spectacular. I use whole (peeled) root in smoothies or some Gin Gin candies.

    I eat blueberries, beets, wild rice of various colors and have a lot of flavonoids in my diet. I still have CFS but I have felt a little better -- not totally ruling out placebo effect though.
     
  3. Wonkmonk

    Wonkmonk Senior Member

    Messages:
    633
    Likes:
    830
    Germany
    I am actually not thinking so much about inflammation, but rather about how to control a noncytolytic chronic herpesvirus infection.

    For inflammation, all the things you mention are good, of course.

    But regarding flavonoids, some seem to increase caspase-3 activity while other (few) seem to have an inhibitory effect, so eating fruit probably won't do it, because they contain a broad spectrum of flavonoids. You'd probably need a very specific use of selected flavonoids.
     
  4. Hip

    Hip Senior Member

    Messages:
    10,677
    Likes:
    17,549
    @Wonkmonk, I think you may mean abortive herpesvirus infection, which is the type of infection Dr Lerner proposed causes ME/CFS; non-cytolytic infection applies to enteroviruses (although I did see one study suggesting EBV can create a non-cytolytic infection).
     
  5. Wonkmonk

    Wonkmonk Senior Member

    Messages:
    633
    Likes:
    830
    Germany
    Apologies if I am not precise, I have no science background. Yes, I am referring to Dr Lerners studies, and I think I remember he labels it "abortive", but I thought this is similar to non-cytolytic, because Dr Lerner posits that there is no lysis (destruction of the cell by the virus during replication) and that there is apoptosis instead ("voluntary" cell death triggered by the infection by the virus). So I thought that's also "non-cytolytic", but maybe that wasn't precise.

    But apart from that, I would love to hear your thoughts on the caspase idea.
     
  6. Hip

    Hip Senior Member

    Messages:
    10,677
    Likes:
    17,549
    I found this paper which observed caspase 3 inhibition also reduced influenza virus propagation. So it is possible caspase 3 inhibition might have some anti-herpesvirus effect.

    However, it's hard to predict the magnitude of the antiviral effect of a caspase 3 inhibitor like ibuprofen; there might be some antiviral effect, but it might be too weak to be of significance.
     
  7. Hip

    Hip Senior Member

    Messages:
    10,677
    Likes:
    17,549
    This paper says that:
    Note : I-IFN = type 1 interferons (like IFN-α and IFN-β).

    So elevated caspases could reduce the type I interferon response which is responsible for intracellular immunity.

    The paper also says:
    Well for non-cytolytic enterovirus infections, TLR3 is important, as TLR3 is the sensor which detects non-cytolytic enterovirus infection inside the cell (TLR3 senses the dsRNA of non-cytolytic enterovirus). When TLR3 senses dsRNA, it triggers the release of interferons which then activate the intracellular immune response.

    So if there were high levels of caspase-8, then this might inhibit the intracellular immune system in intracellular infections.

    However, that paper is complex and dense with numerous different biological pathways, so it is hard follow.



    Caspase is involved in the universal antiviral DRACO which is under development, which should work against more-or-less all viruses. Sadly, nobody seems to be funding DRACO, which is tragic, as it could well cure ME/CFS.
     
    sb4 and Sidny like this.
  8. Wonkmonk

    Wonkmonk Senior Member

    Messages:
    633
    Likes:
    830
    Germany
    Thanks for pointing this out. As with most treatments, there might be countervailing effects, and it would be a question if the positives outweigh the negatives (or the caspase thing might not work at all, which is actually the most likely thing).

    But I am wondering if there could be benefits if apoptosis of infected cells were stopped or limited. One might think it would be good to have apoptosis because it is one infected cell less, but if the reactivation hypothesis is correct, apoptosis might in fact propagate the disease and create a vicious cycle (apoptosis --> reactivations --> more apoptosis).

    I am also wondering if it might be possible that the virus spreads through apoptosis (i.e. spread the viral particles inside the cell into the blood stream and adjacent cells).

    So maybe apoptosis (at least on a larger scale) isn't such a good thing and is something that is to be prevented.
     
    Sidny and sb4 like this.
  9. Hip

    Hip Senior Member

    Messages:
    10,677
    Likes:
    17,549
    I think I remember reading that the immune system itself makes a carefully-weighed decision as to whether to fight a viral infection inside a cell (by activating the intracellular immune response), or to just kill off that virally-infected cell entirely (by activating apoptosis, the cell's built-in autodestruct mechanism).

    Obviously the immune system would like to save a cell if possible, so apoptosis is a last resort response if the infection starts getting out of hand.

    But I have seen studies in which drug treatments that reduced apoptosis in viral infection (eg heart muscle infection, myocarditis) proved beneficial. Obviously if there is a lot of apoptosis, that can be damaging to an organ.



    Intuitively, I would have guessed that apoptosis might be more of an issue in acute viral infection rather than in the chronic infection.

    Acute infection is a fierce battle between immune system and virus; whereas in chronic-long term infection, like the chronic non-cytolytic enterovirus infections that exist in chronic enterovirus myocarditis and in ME/CFS, this becomes a slow low-level infection.

    However, I just found this study on both acute and chronic coxsackievirus B myocarditis, and this contradicts my intuition: it found no apoptosis in acute infection, but found apoptosis in 1 out of 3 patients with chronic infection:
     
    sb4 and Wonkmonk like this.

See more popular forum discussions.

Share This Page