May 12, 2017 Is International ME/CFS and FM Awareness Day
International ME/CFS and FM Awareness Day is May 12th, 2017. Jody Smith shares some information about upcoming events and ways you can be heard ...
Discuss the article on the Forums.

Inflammation Is Controlled Differently in Brain and Other Tissues

Discussion in 'General ME/CFS News' started by aprilk1869, Oct 23, 2011.

  1. aprilk1869

    aprilk1869 Senior Member

    Messages:
    294
    Likes:
    72
    Scotland, UK
    ScienceDaily (Oct. 20, 2011) A team led by scientists from The Scripps Research Institute has identified a new metabolic pathway for controlling brain inflammation, suggesting strategies for treating it.

    The new report, which appears in the October 20, 2011 edition of Science Express, focuses on the type of inflammation normally treatable with non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin or ibuprofen. The study shows this type of inflammation is controlled by different enzymes in different parts of the body.

    "Our findings open up the possibility of anti-inflammatory drugs that are more tissue-specific and don't have NSAIDs' side effects," said the study's senior author Benjamin F. Cravatt, chair of the Department of Chemical Physiology and member of the Skaggs Institute for Chemical Biology and the Dorris Neuroscience Center at Scripps Research.

    A Serendipitous Discovery

    The serendipitous discovery originated with an attempt by Cravatt and his colleagues to develop a new kind of pain-relieving drug targeting an enzyme known as monoacylglycerol lipase (MAGL). This enzyme normally breaks down a natural pain-relieving neurotransmitter known as 2-AG, a "cannabinoid" molecule whose actions are mimicked by certain compounds within marijuana. To reduce the rate of 2-AG breakdown, allowing 2-AG levels to rise and provide more pain relief, the Cravatt lab developed a powerful and selective MAGL-inhibiting compound, which the scientists described in 2009 and are still investigating as a possible pain drug.

    In the course of this research, the scientists tested their MAGL inhibitor on mice and also engineered mice that genetically lack MAGL. "We noticed that the brains of the MAGL-inhibited mice showed reduced levels of arachidonic acid, a key precursor molecule for inflammatory lipids," said Daniel Nomura, a former member of the Cravatt lab who is currently assistant professor in the Department of Nutritional Science & Toxicology at the University of California, Berkeley. Nomura is the paper's co-corresponding author with Cravatt, and co-first author with Bradley E. Morrison of Scripps Research.

    Arachidonic acid had been thought to originate similarly throughout the body, from a process involving fat molecules and phospholipase A2 enzymes. To their surprise, the researchers found that in the brain, arachidonic acid production is controlled chiefly by MAGL.

    In effect, the enzyme takes pleasure-associated 2-AG, which is found in high concentrations in the brain, and turns it into arachidonic acid -- the precursor for pain- and inflammation-causing prostaglandin molecules. The researchers showed that blocking the activity of MAGL, or genetically eliminating it, shrinks the pool of arachidonic acid and prostaglandins in mouse brains, effectively limiting the possibility of brain inflammation.

    Providing a Protective Effect

    To further test this effect, the researchers set up two standard models of brain inflammation in lab mice. In one, they tried to induce inflammation with lipopolysaccharide, a highly pro-inflammatory molecule found in bacteria. In the other, they used the toxin MPTP, which induces brain inflammation and preferentially kills the same muscle-regulating neurons lost in Parkinson's disease.

    "In both models, reducing MAGL -- genetically or with our MAGL-inhibitor -provided the animals with protection from neuroinflammation," said Nomura, who is continuing to research the system at UC Berkeley.

    NSAIDs such as ibuprofen are already used to reduce the inflammation that originates from arachidonic acid. They work by inhibiting the cyclo-oxygenase enzymes that convert arachidonic acid into prostaglandins. But NSAIDs also inhibit cyclo-oxygenase enzymes that protect the lining of the gastrointestinal tract. They thus can cause gastrointestinal bleeding, among other adverse side effects. That greatly limits their potential usefulness. In the brain, where MAGL is the major controller of arachidonic acid levels, blocking the enzyme could be a better strategy. Alzheimer's disease, Parkinson's disease, multiple sclerosis, and traumatic brain injury all involve harmful but potentially treatable brain inflammation.

    "In principle, with a MAGL inhibitor we could avoid the gastrointestinal toxicity that's associated with NSAIDs while still maintaining the anti-inflammatory effect," said Nomura.

    Unexpected Elements

    The new findings also are important from a basic science perspective because they advance the understanding of prostaglandin-mediated inflammation. Phospholipase A2 enzymes have long been considered the dominant producers of arachidonic acid, and thus a major element in prostaglandin-mediated inflammation throughout the body. Nomura, Cravatt, and their colleagues confirmed in their experiments that phospholipase A2 enzymes play a major role in arachidonic acid production in the gut and spleen. However, in the brain, the MAGL enzyme was the principal regulator, with phospholipase A2 enzymes making a more limited contribution. MAGL also regulated arachidonic acid and prostaglandins in liver and lungs.

    "Biological pathways that we think we understand sometimes turn out to have these unexpected, tissue- or context-specific elements, which is why it's so important to follow up on clues such as the ones we found," Cravatt said.

    In addition to Cravatt, Nomura, and Morrison, authors of the paper "Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation" are Jacqueline L. Blankman,Jonathan Z. Long, Maria Cecilia G. Marcondes, Anna M. Ward, and Bruno Conti of Scripps Research; and Steven G. Kinsey, Yun Kyung Hahn, and Aron H. Lichtman of the Lichtman lab at Virginia Commonwealth University.

    The research was supported by the National Institutes of Health, the Institute for Drug and Alcohol Studies at Virginia Commonwealth University, the Ellison Medical Foundation, and the Skaggs Institute for Chemical Biology at Scripps Research Institute.

    http://www.sciencedaily.com/releases/2011/10/111020084810.htm
     
  2. Tristen

    Tristen Senior Member

    Messages:
    624
    Likes:
    480
    Northern Ca. USA
    I do get some relief of symptoms, especially cognitive symptoms, with NSAIDS. It would be much better for obvious reasons to target brain inflammation specifically. I just wish they had shared some ideas for natural MAGL enzyme inhibitors, that I could get hold of now (other than pot). The pharmaceuticals won't be out for years. But this is great news. Thanks for sharing.
     
  3. alex3619

    alex3619 Senior Member

    Messages:
    12,394
    Likes:
    34,729
    Logan, Queensland, Australia
    Hi AprilK1869, adjusting arachidonic acid levels to treat CFS goes back to the 80s! I learnt of it in 1993. I was treated by a dietary strategy to do this and improved, as do 90% of patients. However, as is often the case, the doctor who was doing this was prosecuted because there is no treatment for CFS! This was Brisbane, Australia, and the doctor was Dr. Andriya Martinovic. He has one paper on PubMed by Gray and Martinovic:

    Med Hypotheses. 1994 Jul;43(1):31-42.
    Eicosanoids and essential fatty acid modulation in chronic disease and the chronic fatigue syndrome.
    Gray JB, Martinovic AM.
    Erratum in

    Med Hypotheses 1995 Aug;45(2):219.

    Abstract

    Abnormalities of Essential Fatty Acid (EFA) incorporation into phospholipid are found in chronic diseases. More recently changes in circulating EFA metabolites (EFAM) together with EFAM hypo-responsiveness of immune cells and EFAM production from cells have been found associated with disease. We hypothesize that changes in ratio of EFAMs are the normal physiological responses to stressors, but when stressors are excessive or prolonged, EFAM systems may become unpredictably hypo-responsive owing to factors such as receptor down regulation and substrate depletion. In time, many homeostatic system become deranged and held in that state by minor stressors. Literature review of chronic fatigue syndrome (CFS) shows hyper and hypo-responsiveness in immune function, several Hypothalamo-Pituitary (HP) axes and sympathetic nervous system, all relatable to dysfunctional changes in EFA metabolism. For the first time, we explain chronic immune system activation and hypo-responsive immune function in CFS; through EFAMs. Dietary EFA modulation (DEFA) can alter ratios of both membrane EFAs and produced EFAMs, and if maintained can restore hypo-responsive function. We discuss dietary strategies and relevance in CFS, and a case series of CFS patients applying DEFA with other titrated published managements which saw 90% gaining improvement within 3 months and more than 2/3 fit for full time duties. This hypothesis and DEFA may have relevance in other chronic conditions.

    PMID: 7968718

    I was a patient of his, and have been writing about eicosanoid modulation via arachidonic acid based dietary strategies since 1993. Currently I recommend high grade fish oil, fresh extra virgin olive oil and fruit (if tolerated) as a simple measure. The approach used by Martinovic was complicated, and not possible to do easily based on written descriptions. He was researching this for over a decade on an almost zero budget.

    Bye
    Alex
     
    cigana likes this.
  4. Tristen

    Tristen Senior Member

    Messages:
    624
    Likes:
    480
    Northern Ca. USA
    I did a comprehensive panel with Metametrix back in the 90's that included just about everything on their menu. It was one of my first tests attempting to determine why I had become so ill. I remember that fatty acids were most deficient, and arachidonic acids abnormal. I've been on the best EPA's for years and have never noticed that it does anything for inflammation. But I do love good olive oil, and maybe that's why.
     
  5. alex3619

    alex3619 Senior Member

    Messages:
    12,394
    Likes:
    34,729
    Logan, Queensland, Australia
    Hi Tristen, low omega-6 EFA (essential fatty acid) is very common in ME and CFS. We probably hyperutilize arachidonic acid, we certainly have a number of biochemical issues that drive increased arachidonic acid metabolism. Arachidonate also promotes massive oxidative stress via an unknown mechanism (unknown a decade ago, I have not researched this recently). We also have issues with synthesis, if for no other reason than low levels of gluthathione leads to inhibition of arachidonic acid synthesis. So we make too little to keep up the the high demand - but that demand is pushing inflammation and oxidative stress. Its what makes it so hard to treat - we simultaneously have too muich and are deficient. If we can increase levels but not use them to drive inflammation, then that would be ideal - but nobody has worked out how to do that.

    The Zone diet by Barry Sears was developed to control these pathways. It worked only marginally for me so I stopped doing it.

    Bye
    Alex
     
  6. heapsreal

    heapsreal iherb 10% discount code OPA989,

    Messages:
    8,831
    Likes:
    8,095
    australia (brisbane)
    Can i say that alot of inflammation is controlled by hormones and in cfs ours are out of whach to say the least. A common sign is high LDL cholesterol which normally our body would use to make the hormones it needs, for some reason this isnt occurring and then our LDL is driven up. We all know cortisol controls inflammation but dhea also controls IL6 and inflammatory cytokine which is shown to be high in cfs/me people and cause alot of sleep disturbances. I think even when we supply the essential fatty acids our body isnt using them to make the correct hormones etc to control inflammation, so secondary things occur like increases in uric acid which have antioxidant effects with LDL cholesterol to try and control inflammation. Also i think its not about just controlling inflammation but the repair phase that is suppose to happen afterwards which again is accomplished by hormones like testostrone and growth hormone, as you can see it gets into a viscious circle because we cant sleep properly to make growth hormone etc etc we always seem to be chasing our tale.

    I believe we should cut out the middle man and add the hormones we need which will then help us to control inflammation as well as growth and repair. Thats my 2 cents worth anyway.

    cheers!!!
     
  7. mellster

    mellster Marco

    Messages:
    804
    Likes:
    189
    San Francisco
    This is interesting and I agree we need to look at all our hormones, all of them not just t3, tsh etc. I remember having elevated LDL (130 I think) during and after the viral onset while I was still very fit from 3-4 x weekly kickboxing sessions, and maybe it will become a useful element to watch in CFS (so far I do not buy into cholesterol as a useful predictor for anything as heaps mentioned it is actually needed by our body and varies very much from individual to individual). cheers

     
  8. she

    she Practically perfect

    Messages:
    12
    Likes:
    8
    The Netherlands
    I cannot follow the medical discussion - I really cannot figure out what's what ;
    and more even - cannot control any of the proclamation made.
    but is the bottom line: take 1 aspirine a day and don't swallow it but let it melt in the mouth ?

    Cheers!
     
  9. heapsreal

    heapsreal iherb 10% discount code OPA989,

    Messages:
    8,831
    Likes:
    8,095
    australia (brisbane)
    If it was as easy as taking an asprin , this thread wouldnt exist, there seems to be many mechanisms involved in inflammation.

    cheer!!!
     
  10. Daisymay

    Daisymay Senior Member

    Messages:
    726
    Likes:
    3,955
    Thanks for posting, very interesting, goes to show how little we know yet the medical profession usually assume they know everything.....
     
  11. Tristen

    Tristen Senior Member

    Messages:
    624
    Likes:
    480
    Northern Ca. USA
    Thanks Alex
     
  12. Tristen

    Tristen Senior Member

    Messages:
    624
    Likes:
    480
    Northern Ca. USA
    I have high Uric acid, and it may be contributing to joint problems. I've been reluctant to take drugs to reduce it because of suspecting it has a positive affect on the excessive oxidative stress we deal with. I'm actually right in the middle of looking closer at this because the joint problems are progressing.

    I actually have low-normal LDL with slightly low HDL. I would expect this to be more common with viral infections since they use cholesterol for replication. But I do hear of many PwME beign low. Very complex stuff. I test low for HGH and DHEA. I do supplement DHEA in spite of the warning. T3&4 are normal, but RT3 was quite high, but we brought it back into normal taking T3. I test high for Testosterone. My doc thinks I always have.
     
  13. heapsreal

    heapsreal iherb 10% discount code OPA989,

    Messages:
    8,831
    Likes:
    8,095
    australia (brisbane)
    Cool tristen, whats the go with the warnings about dhea?? You have tested low so supplementing to get to normal levels is the right thing to do. You sound similar to me in that you test high for testosterone but low in dhea etc. Do u get E2 tested? How did u fix reverse t3 problems? i have heard some take more t3 but ??? Pregnenolone can help with cortisol levels which then help thyroid function too.

    Have you found overall that treating your hormones has helped things like joint pain etc as well as other symptoms? Sounds like you have a forward thinking doc which is good.

    cheers!!!
     
  14. Tristen

    Tristen Senior Member

    Messages:
    624
    Likes:
    480
    Northern Ca. USA
    Oh the DHEA warning thing was just about not messing with raising downstream hormones like Cortisol, back with the xmrv thriving on cortisol issue. But even if that were valid, I would think supplementing is good if deficient. I just started taking it again the last few months. 15mg per day. I did notice a positive difference.

    I took compounded T3 for 1 month and it brought the RT3 back to normal. I found the compounded T3 to be much smoother than Cytomel.

    Yes, I thought of trying pregnenolone. I should ask my GP about that next visit. She is forward thinking, basically she's an LLMD. E2?
     
  15. heapsreal

    heapsreal iherb 10% discount code OPA989,

    Messages:
    8,831
    Likes:
    8,095
    australia (brisbane)
    E2 is estrogen, sometimes people have too much of an enzyme which can convert dhea and testosterone to estrogen(E2), so these levels of dhea and testosterone can be nice and high and u still feel like crap, sometimes this can be because its converting to E2. Meds like arimidex are used to help control E2, but once again u dont wont to lower it too far but get it to just the right level as being too low can cause problems as well.
    I think if the retrovirus stuff is valid, the whole hormone stuff doesnt sit right with me, i still think we need our hormone levels at the optimum level for our immune systems to function properly. It doesnt make sense to keep our hormones low and thus our immune system low to then try and fight a viruses??? but i can understand going too high, but have hormones monitored with proper testing should sort all this though.

    cheers!!!
     
  16. rydra_wong

    rydra_wong Guest

    Messages:
    514
    Likes:
    43
    I would not refer to this as an effect of arachadonic acid because it can be misunderstood to be that u r saying we need more of that. The "fix" is MORE OMEGA-3. This was written up a long time ago in Dr. Barry Sears' book Omega-Rx Zone (he has a PhD in lipid science). He said that 9g/day omega-3 will STOP the arachadonic pathway because the omega-3's use the same enzymes used to digest arachodonic acid and they get priority so a large dose of omega-3 depletes these enzymes. It works for me for allergies and mine are the worst my allergist has ever seen in 20 years of practice. (I am not saying it works perfectly - I developed a new allergy to cold, dry air this year which it does not seem to touch). It works great though - it takes me from 8 boxes of kleenex a day to 6 or less and I canbreath and my face is not swollen. I read this inhibits NF-kB and also another one (I forget which one because I already have that one inhibited by DHEA).

    (I was replying to somebody - seems like this should indicate the name you are replying to when you hit reply. It is too many pages to scroll back and figure it out...!
     
  17. Jenny

    Jenny Senior Member

    Messages:
    1,349
    Likes:
    478
    London
    9 grams a day! That's a huge amount - 10 times more than what I've been taking and I thought I was taking a lot.

    Jenny
     
  18. Dreambirdie

    Dreambirdie work in progress

    Messages:
    5,328
    Likes:
    4,047
    N. California
    Rydra--What form of Omega-3 do you take, and how many capsules is that?

    I am currently taking the Nordic Naturals Ultimate Omega at 4 capsules/day, which is about 2500 mg/day.

    Also: Doesn't it thin your blood if taken in excess?
     
  19. redo

    redo Senior Member

    Messages:
    837
    Likes:
    102
    Thanks for posting. Fascinating.
     
  20. alex3619

    alex3619 Senior Member

    Messages:
    12,394
    Likes:
    34,729
    Logan, Queensland, Australia
    Hi Rydra_Wong and Dreambirdie.

    First to Dreambirdie's question: yes omega-3 (fish oil derived) can thin the blood. That could be an issue with some of us, but in very high doses it can treat many neurological disorders.

    To Rydra_Wong's comment, Barry Sears could not get Omega_3 to work properly, which he has admitted. Yes, it helps. Its not perfect as you note. Its why he prefers combining it with the Zone diet, to regulate the enzymes that lead to production of arachidonic acid, enzymes which are under huge stress in CFS and ME (their function is proportional to levels of reduced glutathione).

    I use three methods. First, I reduce the total amount of omega-6 in my diet, especially long chain such as arachidonic acid. Arachidonic acid is high in animal fat, organ meats, tropical coastal seafood, egg yolks and dairy fat (its primarily an animal fat after all). Reduce it too low and it will damage health though. Its an essential fatty acid.

    Second, I take omega-3 (fish oil). High EPA oil is better than high DHA oil for this purpose. Go for quality - the cheaper oils are not even close to pure.

    Third, I use extra virgin olive oil. The biologically active chemicals in it are anti-inflammatory and anti-allergy. That is not the main reason however - in fact there are two. With such high oxidative stress in our diet, much of the omega-6 and omega-3 is damaged, and leads to incorporation into the eicosanoids (hormones) which might, and this is not proven, lead to reduced activity hormones or even inactive hormones. Thats not good. It does not matter if monounsaturated fats in olive oil are attacked by oxidative stress - we don't make hormones from them. The second reason it to do with arachidonic acid. Omega-3 competes by competitive inhibition, that is the enzyme (cycho-oxygenase, COX for short - no snickers please :) that converts arachidonic acid binds to omega-3 in preference to omega-6, and when bound to one it can't bind to the other. Olive oil is an eating oil, you can take it in quantity. It is mostly monounsaturated. Monounsaturates also bind to cyclo-oxygenase, but the affinity is low. However the olive oil intake can be high and constant. So it competes with omega-6 by a process called mass action, in which the sheer volume of low affinity substrate out competes the omega-6. Both fish oil and extra virgin olive oil compete with arachidonic acid conversion, and both slow its effects. My hypothesis is that the combination is more effective together than separately.

    In addition we don't understand enough about arachidonic acid release. Alcohol triggers its release in a dose dependent fashion, and I think this is the closest match to why alcohol can kill people. When arachidonic acid release is blocked by drugs, alcohol poisoning is non-fatal, when its not and the alcohol levels are high enough, death results. Arachidonic acid also causes a massive oxidative burst in the mitochondria, mechanism unknown. Both olive oil and fish oil wont have any effect on this mechanism if present. Its not just that arachidonic acid can make pro-inflammatory hormones (and at least one anti-inflammatory I think) but that it causes oxidative mitochondrial bursts. That is fatal in reperfusion events. I have identified a number of pathways over the years that might be causing arachidonate to be released, leading to rapid conversion to hormones via cyclo-oxygenase. One is our lower than normal cortisol, but our circadian problem with coritisol will also have an effect. Cortisol suppresses arachidonic acid release. The other is nitric oxide - nitrosative stress increases arachidonic acid release. I have found others but I would have to research them again - I did this lit search a decade ago. So our brake doesn't work (cortisol) and our accelerator is stuck on (nitrosative stress). As a result of this more arachidonic acid is released than should be, particularly if we consume alcohol (a really really bad idea in CFS or ME). I think NFkB also induces arachidonic acid release, but I am having a bad memory day and don't have the time to check - take this as a possibility only. From memory, which as I said is bad today, the other drivers of arachidonic acid release are also inflammatory chemicals.

    High omega-3 or the Zone diet improve me a little - but I expend more energy on the Zone diet than I get back from it so I abandoned this approach. High omega-3 is only advisable if you can get hold of high quality oil, or the impurities in the regular stuff will make you sick. I have difficulty getting hold of the better oil. It most likely will be a liquid, and so vulnerable to oxidation, so its handling and storage is critical. Don't buy it if its been sitting in a warehouse or has spent weeks travelling overseas by ship.

    Aspirin is a suicide inhibitor of arachidonic acid. So its tempting to use it. I don't because we need the enzyme cyclo-oxygenase functioning well. Its essential to health. I would prefer to regulate it, not destroy it.

    Bye
    Alex
     

See more popular forum discussions.

Share This Page