1. Patients launch $1.27 million crowdfunding campaign for ME/CFS gut microbiome study.
    Check out the website, Facebook and Twitter. Join in donate and spread the word!
First Direct Evidence of Neuroinflammation - 'Encephalitis' - in ME/CFS
A small study with just nine patients has captured the attention of patients and researchers alike after reporting direct evidence of inflammation in the brain of ME/CFS patients. The finding was one of the highlights picked out by Professor Anthony Komaroff in his IACFS/ME...
Discuss the article on the Forums.
  1. AACox2


    For those of us with viral involvement (as defined by all herpes viruses, HHV6, CMV, etc and enteroviruses EV71, Coxsackie B3, etc.), it is my belief that part of what might help us lies in understanding COX-2. I dropped my enormously elevated HHV6 titer by 2/3 and CMV Igg and Igm to negative. I accomplished this, in part, through the use of a COX-2 inhibitor and and ARB.

    I think the confusion in the literature about the role of COX2 in immunity is because it differentially affects different wings of the immune system. COX2 is an activator of TH2 immunity, its actually required for generation of antibodies through endosomal TLR9. On the other hand, it cripples TH1 immunity through the immunosuppressive prostanoid PGE2 (endoperoxidase, ie COX, catalyzes the conversion of arachidonic acid to PGE2) which, interestingly, is the prostanoid that biases the NK cells (and other effector cells) from an aggressive to tolerant phenotype in mammalian pregnancy (sound familiar?). It is secretory and signals in a paracrine manner.​

    Tumors secrete massive amounts of PGE2 which is one of the ways that cancers lead to systemic immune suppression via COX2/PGE2/PKA, etc. ultimately leading to expression of indoleamine 2,3 dioxygenase (IDO), tryptophan catabolism into kynurenine, which was just discovered to be the endogenous ligand for the aryl hydrocarbon receptor, the activation of which results in the robust generation of Regulatory T cells (again, sound familiar?) which leads to a self sustaining loop of immune tolerance (suppression). I can tie most of the other white cell subsets into this loop, but basically, the alternatively activated phagocytes and Tregs can influence most effector subsets. They are good in tissue healing, graft acceptance and pregnancy but bad in cancer, etc.​

    Diseases where this robust increase in Tregs and general immune suppression becomes highly problematic include cancer, HIV and CFS, all of which have massive increases in Treg suppressiveness and numbers and significantly inhibited NK cell cytotoxicity (not dissimilar to pregnancy). In these conditions, I believe this tolerance must be broken. Celebrex, for example, is impressive in several types of cancer, but its early days. You can see how infected phagocytes can cripple other aspects of the immune system in a paracrine manner. Its interesting to note that less than 1 in 100,000 white cells are actually infected in AIDs patients, but they have huge amounts of circulating PGE2 and IDO.​

    Also of note, PGE2 is involved in pain nociception. Minocycline is a PGE synthase inhibitor, which is why I suspect it reduces symptoms for some people. On the other hand, because it is a PGE synthase inhibitor, there could be some restoration of effector function, which may lead to an increase in symptoms. Interestingly, both minocycline and celebrex improve DHT reactions in AIDs patients.​
    The literature indicates the following data in humans: COX-2 is hyper activated in white cells of CFS patients. Circulating TRegs are increased. Natural killer cell numbers and cytotoxicity are reduced. Anti-body production is amplified. All can be reduced by inhibition of COX-2, but most of the tools used for this purpose are blunt and have side effects.​
    Virtually all herpes viruses induce COX-2 (as does HIV) generating PGE2. PGE2 signals in an endocrine/paracrine manner and has broad based blunting effects on innate immunity through binding of the EP2 and EP4 receptors, activation of adenlyl cyclase and increases in cyclic AMP through PKA. Interestingly, catecholamines do the same thing through the beta adrenergic receptors. Interesting that stress increases herpes breakouts. PGE2 is actually being used in allogenic stem cell transplants to block the immune response (primarily NK cells) to donor cells.​
    In the lab, CMV replication can be reduced by 100 fold with selective COX-2 inhibitors. Addition of PGE2 to HHV6 cell culture dramatically increases its replication in a cAMP dependent manner. COX-2 inhibitors also inhibit the expansion of EBV positive and KSHV infected lymphoblastoid cells and regress CMV positive tumors in mice. EV71 is also dependent upon COX-2 activity to replicate, etc.​
    There was a recent patent which indicated that vioxx and other COX-2 inhibitors may have caused a reactivation or immune response to latent herpes (CMV) infection in the vasculature, namely the heart. There are also papers which mention targeting this enzyme in lieu of typical anti-viral meds.​
    I used a pulsed approach of celebrex (alternate days) along with and angiotensin receptor blocker to dampen excessive inflammation. I believe that breaking immune tolerance to pathogens should be done gradually. Initially, I felt feverish, achy, super tired, etc. Eventually, I felt stronger and my blood work showed improvement after showing no improvement for years.​
    Tissue damage increases COX-2 which increases the replication of many viruses, which increases tissue damage, etc. etc. I suspect this is what happens in chronic enterovirus infections in the gut.​
    Of course, we all know that there can be bad side effects to inhibiting this pathway. Just sharing my intro thoughts.​
    More later. Thanks for this great forum, btw.​
    NOTE: I am not a professional nor am I providing any type of medical advice nor advocating the use of any kind of drug. Just sharing my thought on research and personal experiences.​
    Emootje and dece like this.
  2. maryb

    maryb iherb code TAK122

    AACox2 - were you under a doctor whilst on these drugs? I have an interest having tested several times positive for EBV active infection over the past few years
  3. AACox2


    You must be under a doctor's care. This is anecdotal evidence from a sample size of 1. These drugs carry risks so you need a doc.

    I tried everything under the sun as most have. When I went off the combo I relapsed some months later. Starting again now so I'll let you know how it goes.

    I will post a bunch of papers about this pathway to stimulate some conversation.
  4. lansbergen

    lansbergen Senior Member


    Levamisole modulates prostaglandin E2 production and cyclooxygenase II gene expression in human colonic cancer cells.


    Colon 205 cells produced significantly more PGE(2) when stimulated by LPS. Levamisole inhibited PGE(2) production by LPS-stimulated colon 205 cells in a dose-dependent fashion. In addition, COX-2 mRNA expression and COX-2 protein induced by LPS were also reduced by levamisole. Finally, NF-kappaB activation of LPS-stimulated colon cells was inhibited by levamisole.


    Levamisole inhibits PGE(2) production by LPS-stimulated colon 205 cells. The inhibition of levamisole occurs at the transcription level of COX-2 gene and is regulated through NF-kappaB activation.
    Emootje likes this.
  5. Hip

    Hip Senior Member

    You can also take COX-2 inhibiting supplements, some of which come close to the potency of COX-2 inhibitors drugs like celecoxib (Celebrex), but without the risks. Taking two or three of the more potent supplements together will probably give you similar results to celecoxib.

    Potent COX-2 inhibitor herbs:

    Rhodiola rosea 500 mg
    Rosemary (rosmanol) 1000 mg
    Curcumin 1000 mg
    Holy Basil (Tulsi) 1000 mg
    Propolis 4000 mg
    Terminalia Chebula 1000 mg
    EGCG Green Tea Extract 300 mg
    Boswellia Serrata Extract 300 mg

    Potent COX-2 inhibitor essential oils:

    Thyme 2 drops
    Clove 2 drops
    Oregano 2 drops
    Rose 2 drops
    Fennel 2 drops
    Bergamot 2 drops

    Other COX-2 inhibitor herbs:

    Sulforaphane 400 mcg
    Reishi 1000 mg
    Ginger 1000 mg
    Nettle 1000 mg
    Milk Thistle 1000 mg
    Lemon Balm 1000 mg
    Ashwagandha 1000 mg
    American Ginseng 500 mg
    Bromelain 500 GDU
    Feverfew 500 mg
    Hops 500 mg
    Quercetin 250 mg
    Berberine 50 mg
    Evening Primrose Oil 2000 mg
    Fish Oil 1000 mg
    Baikal Skullcap 500 mg
    Emootje likes this.
  6. alex3619

    alex3619 Senior Member

    Logan, Queensland, Australia
    The COX model of CFS goes back to the late 1980s, I was in a participant (guinea pig?) in this research in Australia in 1993. The only easily accessible reference is on PubMed in about 1995 - I used to find it using a PubMed search on Martinovic and CFS, but today that is not working for some reason - it was published in Medical Hypotheses I think.

    COX-2 inhibitors are very dangerous. I have been working on controlling COX-2 for most of 19 years now. There are dietary methods, drugs are quick and easy but have too many problems. The longer drug therapy is used, the more dangerous it becomes. COX-2 is necessary to the synthesis of a wide range of essential hormones. If these are shut down too much you are potentially a ticking time bomb. This is why I predicted Vioxx would be dangerous a year before that information went public. It was no surprise to me.

    Evening primrose oil pushes arachidonic acid synthesis, one substrate for COX-2. Fish oil (EPA) slows it down. Bioflavinoids are suspected of having a beneficial effect. Mass action effects can slow COX-2 by consuming large quantiites of short chain monounsaturated fats. I use extra virgin olive oil. Free cellular arachidonic acid drives increased mitochondrial oxidative stress ( I do not know the mechanism, this is an empirical observation) and alcohol is one thing that triggers arachidonic acid release. Cortisol is also beneficial in low doses, and low cortisol can drive COX-2 activity.

    I am aware that some people have made a full recovery using this model. Most make a partial recovery but only while treatment persists - which means for life. About ten percent get worse.

    Now without giving anything away, one of those substances listed earlier in this thread completely restored my energy, and I mean completely, but did not touch fatigue. I don't mention what it is because I regard it as dangerous, even if natural. Every three days the effect wore off and I had to double the dosage, and I repeated this several times. In the end I was eating a pound (over 400g) of the substance every day and at that point I stopped taking it, then crashed badly. In my case at least shutting down COX-2 aggressively drives the illness or at least a component of it. This requires a softly-softly approach in my opinion.

    Bye, Alex
    Emootje, SOC and dece like this.
  7. knackers323

    knackers323 Senior Member

    Have you learnt any more about cox2 Alex?
  8. alex3619

    alex3619 Senior Member

    Logan, Queensland, Australia
    Cox-2 (and Cox-1 etc.) are gateways to the class of hormones known as eicosanoids. These can be affected by diet, though imperfectly. There is no known reliable way to regulate them, though they can be imperfectly influenced.

    Eicosanoids are typically essential hormones. Shut 'em down too much, or increase them too much, and they can kill. There is an optimal range for these hormones, but because there are hundreds of them, with complex interactions with each other, metabolism, and just about every other cell function, its very hard to predict anything they will do. Worse, as we keep learning new things about them all the time, our understanding keeps changing.

    What we knew about these in the early 1980s would have filled a small book. Now there are huge numbers of journals, books and papers, and its really baffling stuff. To really speak about eicosanoids requires an expert. Alas, though I know some, I am not an expert.

    Barry Sear's the Zone Diet was intended to regulate eicosanoids. Later he added omega-3 fats to the regulation process. These hormones are under profound influence by many body processes. I don't think we know enough to reliably do much with them, which is why I emphasize being careful.

    One thing I can say though. Starve your body of polyunsaturated fats and you will die. Consume or release a megadose of free arachidonic acid (the fat COX works on) and you will die. This is the probable mechanism for alcohol poisoning. It releases much of the stored arachidonic acid, creating both oxidative stress in the mitochondria and a hormone surge. Those hormones regulate essential metabolic function. Death can result from too much of this. Blocking arachidonic acid metabolism with drugs prevents death from alcohol poisoning ... not that you will feel good afterwood.

    This is a deep topic. I have forgotten much much more than I currently recall on this subject.
    Emootje, Snowdrop and SOC like this.

See more popular forum discussions.

Share This Page