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Monday 10 March 2014

Palmitoylethanolamide (PEA) vs flavonoids Luteolin, Quercetin and Rutin in Autism, Allergies and Arthritis

You might be wondering the relevance of arthritis to an autism blog. Rheumatoid arthritis is an inflammatory condition in which the body's own immune system starts to attack body tissues.  It is often co-morbid with inflammatory bowel disease (including Crohn's disease and ulcerative colitis).  IBD is comorbid with autism.  The study below shows how many autoimmune diseases, including arthritis are connected with autism. 

RESULTS: A total of 3325 children were diagnosed with ASDs, of which 1089 had an infantile autism diagnosis. Increased risk of ASDs was observed for children with a maternal history of rheumatoid arthritis and celiac disease. Also, increased risk of infantile autism was observed for children with a family history of type 1 diabetes.
CONCLUSIONS: Associations regarding family history of type 1 diabetes and infantile autism and maternal history of rheumatoid arthritis and ASDs were confirmed from previous studies. A significant association between maternal history of celiac disease and ASDs was observed for the first time. The observed associations between familial autoimmunity and ASDs/infantile autism are probably attributable to a combination of a common genetic background and a possible prenatal antibody exposure or alteration in fetal environment during pregnancy.

Note that in an earlier post on the vagus nerve, we saw how an implanted vagus nerve stimulator could reduce the inflammation in arthritis.  This is being developed as an alternative to the extremely expensive new drugs for arthritis that target IL-6 and TNF.
In earlier posts on Mast Cells we heard all about Dr Theoharides from Tufts University who is big on using naturally occurring flavonoids to stabilize mast cells and so treat all kinds of allergic reactions as in mastocytosis and in some types of autism.  See below for a reminder of the roll mast cells play in allergies:-

 

Source: Wikipedia
 

Luteolin is Theoharides’ favourite flavonoid because it is the most the most lipophilic and therefore more likely to enter the brain.  Mast cells are all over the body, including the brain.  In autism, he clearly is focused on the mast cells in the brain, but perhaps the mast cells elsewhere are equally problematic.  Indeed, perhaps the mast cells outside the brain are far more important, just because there are far more of them and the inflammatory mediators released by them will travel throughout the entire body.
 
The other two flavonoids know to effect mast cells and inflammation are Rutin and Quercetin. 

Arthritis Luteolin and Palmitoylethanolamide
I was quite surprised to find that research had been carried out on the anti-inflammatory effect of both Luteolin and Palmitoylethanolamide (PEA).  PEA is the substance I have been researching recently, it is not a flavonoid, but it is naturally occurring within the body and has some very interesting properties.

One of the inflammatory markers that is raised in autism is called IL-6.  The research was on arthritis in mice, but it did measure the effect of Luteolin and PEA on IL-6.  The result was interesting:-




 
PEA had the greater effect, but in combination with Luteolin the result improved further. 

This gives yet more reason to look into PEA for autism, but not to forget Luteolin.

The problem with Luteolin and Theoharides’ formulation called Neuroprotek is that it is really expensive in the suggested dosage.
 

What about Quercetin?
Quercetin is relatively cheap.

Unfortunately there is no direct comparison of Luteolin vs Quercetin in arthritis, but there is plenty of research showing that Quercetin is highly beneficial in arthritis. 
Abstract
Pentahydroxyflavone dihydrate, quercetin (QU) is one of common flavonols biosynthesized by plants and has been suggested to modulate inflammatory responses in various models. In the present study, we investigated in vivo effects of oral or intra-cutaneous QU in chronic rat adjuvant-induced arthritis (AA). Growth delay and arthritic scores were evaluated daily after AA induction in Lewis rats. Oral administration of QU (5 x 160 mg/kg) to arthritic rats resulted in a clear decrease of clinical signs compared to untreated controls. Intra-cutaneous injections of lower doses (5 x 60 mg/kg) of QU gave similar anti-arthritic effects, while 5 x 30 mg/kg concentrations were inefficient in this respect. Finally, injection of relatively low QU doses (5 x 30 mg/kg) prior to AA induction significantly reduced arthritis signs. As QU was suggested to inhibit macrophage-derived cytokines and nitric oxide (NO), we then analyzed macrophage response ex vivo. Anti-arthritic effects of QU correlated with significant decrease of inflammatory mediators produced by peritoneal macrophages, ex vivo and in vitro. These data indicate that QU is a potential anti-inflammatory therapeutic and preventive agent targeting the inflammatory response of macrophages. 

Here is a great paper summarizing the many and varied benefits of quercetin:-


An interesting point with all flavonoids is their bioavailability.  This means what proportion that you eat is actually absorbed.
Quercetin is present in apples, but the largest amount is in the peel and is highest in red apples.   Quercetin is found is lesser amounts in red wine, but it appears the bioavailability is much higher because of the alcohol.  So grape juice would not help much. 


Applications of Quercetin


Asthma

Quercetin is an effective bronchodilator and helps reduce the release of histamine and other allergic or inflammatory chemicals in the body.

Quercetin has demonstrated significant anti-inflammatory activity because of direct inhibition of several initial processes of inflammation.

Cancer

Laboratory studies have investigated Quercetin's potential for use in anti-cancer applications. The American Cancer Society says while quercetin "has been promoted as being effective against a wide variety of diseases, including cancer," and "some early lab results appear promising, as of yet there is no reliable clinical evidence that quercetin can prevent or treat cancer in humans."

Eczema

Serum IgE levels are highly elevated in eczema patients, and virtually all eczema patients are positive for allergy testing. Excessive histamine release can be minimized by the use of antioxidants. Quercetin has been shown to be effective in reducing IgE levels in rodent models.

Inflammation

Several laboratory studies show quercetin may have anti-inflammatory properties, and it is being investigated for a wide range of potential health benefits.

Quercetin has been reported to be of use in alleviating symptoms of pollinosis. An enzymatically modified derivative was found to alleviate ocular but not nasal symptoms of pollinosis.

Studies done in test tubes have shown quercetin may prevent immune cells from releasing histamines which might influence symptoms of allergies.

A study with rats showed that quercetin effectively reduced immediate-release niacin (vitamin B3) flush, in part by means of reducing prostaglandin D2 production. A pilot clinical study of four humans gave preliminary data supporting this.

Fibromyalgia

Quercetin may be effective in the treatment of fibromyalgia because of its potential anti-inflammatory or mast cell inhibitory properties shown in laboratory studies

Monoamine-oxidase inhibitor

Possibly an active component of heather, quercetin was suspected from a bioassay test on crude extracts to selectively inhibit monoamine oxidase, possibly indicating pharmacological properties.

Prostatitis

Quercetin has been found to provide significant symptomatic improvement in most men with chronic prostatitis, a condition also known as male chronic pelvic pain syndrome.


Luteolin
Luteolin is known to stabilize mast cells.  It has been studied in several preliminary in vitro scientific investigations. Proposed activities include antioxidant activity (i.e. scavenging of free radicals), promotion of carbohydrate metabolism, and immune system modulation. Other in vitro studies suggest luteolin has anti-inflammatory activity, and that it acts as a monoamine transporter activator, a phosphodiesterase inhibitor, and an interleukin 6 inhibitor. In vivo studies show luteolin affects xylazine/ketamine-induced anesthesia in mice. In vitro and in vivo experiments also suggest luteolin may inhibit the development of skin cancer.

In autism the ability to stabilize mast cells and inhibit IL-6 is very useful.
 

Luteolin, a flavonoid found in high concentrations in celery and green pepper, has been shown to reduce production of proinflammatory mediators in LPS-stimulated macrophages, fibroblasts, and intestinal epithelial cells. Because excessive production of proinflammatory cytokines by activated brain microglia can cause behavioral pathology and neurodegeneration, we sought to determine whether luteolin also regulates microglial cell production of a prototypic inflammatory cytokine, IL-6. Pretreatment of primary murine microlgia and BV-2 microglial cells with luteolin inhibited LPS-stimulated IL-6 production at both the mRNA and protein levels. To determine how luteolin inhibited IL-6 production in microglia, EMSAs were performed to establish the effects of luteolin on LPS-induced binding of transcription factors to the NF-κB and activator protein-1 (AP-1) sites on the IL-6 promoter. Whereas luteolin had no effect on the LPS-induced increase in NF-κB DNA binding activity, it markedly reduced AP-1 transcription factor binding activity. Consistent with this finding, luteolin did not inhibit LPS-induced degradation of IκB-α but inhibited JNK phosphorylation. To determine whether luteolin might have similar effects in vivo, mice were provided drinking water supplemented with luteolin for 21 days and then they were injected i.p. with LPS. Luteolin consumption reduced LPS-induced IL-6 in plasma 4 h after injection. Furthermore, luteolin decreased the induction of IL-6 mRNA by LPS in hippocampus but not in the cortex or cerebellum. Taken together, these data suggest luteolin inhibits LPS-induced IL-6 production in the brain by inhibiting the JNK signaling pathway and activation of AP-1 in microglia. Thus, luteolin may be useful for mitigating neuroinflammation.

Health effects of Rutin


While a body of evidence for the effects of rutin and quercetin is available in mice, rats, hamsters, and rabbits, as well as in vitro studies, no clinical studies directly demonstrate significant, positive effects of rutin as dietary supplement in humans.
  • Rutin inhibits platelet aggregation, as well as decreases capillary permeability, making the blood thinner and improving circulation.]
  • Rutin shows anti-inflammatory activity in some animal and in vitro models]
  • Rutin inhibits aldose reductase activity.
  • Recent studies show rutin could help prevent blood clots, so could be used to treat patients at risk of heart attacks and strokes.
  • Some evidence also shows rutin can be used to treat hemorrhoids, varicosis, and microangiopathy.
  • Rutin increases thyroid iodide uptake in rats without raising serum T3 or T4.
  • Rutin is also an antioxidant, compared to quercetin, acacetin, morin, hispidulin, hesperidin, and naringin, it was found to be the strongest. However, in other trials, the effects of rutin were lower or negligible compared to those of quercetin.
 

Vox Populi (from Amazon.com reviews)

Rutin   

Few comments

-    This works wonders for hemorrhoids”
 

Quercetin

Hundreds of positive comments for: Nasal allergy, eczema, sinusitis, prostatitis, joint pain etc.

Lifesaver for allergies”
“This really helps and works like Sudafed” 

Luteolin / Neuroprotek (main ingredient is Luteolin)
Few comments mainly:  mastocytosis, allergies, eczema, autism
Works for some people with autism and not for others:
“My son with autism stopped his aggressive behaviour in a day”
“Works for my fibromyalgia”
 
Conclusion
I do have a couple of jars of Neuroprotek, which I was going to try on Monty, aged 10 with ASD, when the pollen season returns in the summer.  Using it all year round would not be cheap and might have little effect.  I find Quercetin very interesting and worthy of investigation; but PEA remains my current favourite.
It does come down to the question of which mast cells de-granulating cause the problem in autism.  In some people it could be the ones in their digestive tract and in others the ones in their eyes and nose.  The ones in the brain may or may not be relevant; these are the ones Theoharides seems to focus on.
PEA, Quercetin and Luteolin seem to have many benefits unrelated to mast cells.  Since they cannot be patented, there is no incentive for Big Pharma to invest in developing their potential.  So even if they did had some remarkable property, like in cancer therapy, we would likely never find out.
If I was a mouse with arthritis, I would add PEA and Quercetin (or Luteolin) to my weekly shop.  Anyone who is a big user of H1 antihistamines should find Quercetin helpful.

24 comments:

  1. Hello,

    Have you tried Neuroprotek on your son? Did you get good results? Also, what't your take on this : http://scienceblogs.com/insolence/2013/07/30/autismfreebrain-selling-supplements-to-cure-autism/

    ReplyDelete
  2. I did try it and its "creator", Theoharides, is without doubt a clever guy. Verapamil is 100x better and works from the first pill. Neuroprotek is very expensive, you need a lot of it, and Theoharides says it takes months to show an effect. I do use Quercetin, which also has an immediate effect.

    I did write to tell Theoharides about Verapamil - but no reply.

    There is a vast amount of nonsense written about autism on the internet, it is much better to ignore it and just follow the science. Use Google scholar to find the science.

    Cromolyn Sodium, and even H1 antihistamines (some sold OTC) have an almost immediate effect on mast cells; but Verapamil is by far the most effective in my son.

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  3. It is said that luteolin supplements have wide applications and play an important role in our lives. From here: www.nfextracts.com/luteolin-supplements. Generally speaking, they are useful for the treatment of some diseases.

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  4. How do you give NeuroProtek? I bought the capsules but my son won't swallow pills. Do you let M chew them? Or do you open and empty them? We just made a mess of it this morning- HELP

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    1. You can open them and mix them in something like apple sauce. If you use omega 3 oil, you could mix it in that. You can also squeeze out the contents onto a small piece of toast.

      Delete
  5. I've read some articles recently where researchers caution against giving concentrated flavonoids (like those found in supplements) to kids as they can affect the endocrine system, and potentially cause harm. But we also know how valuable flavonoids are as mast cell blockers. What do you think of the risk/benefit approach to giving flavonoid supplements?

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    1. I tried Quercetin myself as well as giving it to my son. It did great things for me, but then after a while had less good effects. I looked into the science and found research showing how it could be both anti-oxidant and also pro-oxidant. Many natural substances can affect hormones, even eating a few grapefruit a day, as one reader told me, can increase progesterone levels. In my case I got tendonitis in my ankle, which is a frequent side effect of steroid use. I stopped the Quercetin and it went away. However the occasional use for sinusitis seems to be trouble free and highly effective in other family members. Summertime use in small doses (half a capsule) does seem to help my son with ASD. I do not give it year round.

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  6. I have been very interested in your writing on mast cells, as my daughter has randomly had a couple of mild allergic reactions (not seasonal) and suffers from chronic constipation which I have read could be a sign of food allergies/sensitivities. However, my daughter also suffers from frequent illnesses and is generally sick a lot (which I have also read is common with autism). Do you have an opinion about whether the use of mast cell stabilizers like those described in this article would interfere with the body's ability to respond to true infections? While I believe some type of immune process might be involved in my daughter's autism symptoms, I worry about using treatments that might further compromise her immune system's ability to keep her body healthy.

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    1. Some immunomodulating therapies used in autism, like steroids would indeed reduce the body's ability to react to harmful threats. I do not believe this occurs using mast cell stabilizers. My son with ASD is healthier than his brother. A wide mixture of flavonoids, as found in a diet full of berries and fruits, or in a few drops of propolis does have an effect on general health.

      I would see no harm in trying these interventions.

      Delete
  7. Hi I have PEA which I aquired to help with cannabis withdrawal(I know, I know, it doesn't exist ;) ) Anyways my son also has autism and I have tried the pea so many times due to all of the impressive research, and it literally makes him go apeshit. Verbal stimming goes through the roof, and his behavior becomes intolerable. So we have never made it through the adjustment period. It is not micronized, so I was wondering if this is the problem. I notice it can cause me intestinal issues when I take too much on an empty stomach. I am wondering how PEA is working out for you. It has some of the most promising evidence I have seen popping up of any ASD supplement, so it kills me not to use it. If it is working well for you, at what dosage does it? Was there any issues like mine? an adjustment period? For what its worth same reaction to luteolin, and I see they state increased irritability is a transient side effect of luteolin in 1/2 of the subjects for 1-8 weeks. How does anyone tolerate 8 weeks of increased irritability and in my case vocal stimming...

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    1. Mark, we tried PEA and it had no effect at all.

      If it has a negative effect, probably best not to use it.

      Delete
  8. Has anyone found a supplement that is a good source of luteolin (beyond Neuroprotek)?

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  9. I've been using a new product called MIRICA that contains both PEA and luteolin for neuropathy. It works so well for reducing pain and anxiety.

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  10. Peanuts and egg yolks (both food favorites of mine) contain PEA... I wonder why I never made the link... PEA being a GPR55 agonist and can modulate mesolimbic dopamine activity.

    Before I start buying PEA, Im struggling to find information regarding the amount of PEA present in peanuts/peanutbutter. It also seems present in soy lecithin (decent results in the past Ive had with this). Does anyone know how much PEA is present naturall in peanuts?

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  11. my daughter's autism symptoms always got worse in summer. We suspected allergies, but the doctor didn't believe us. I read here on your blog about allergies and autism and I tried all the over-the-counter anti-allergic drugs from the pharmacy without any effect.
    The most difficult period every year is between April and September.
    Last year I finally did an allergy test and my daughter is very allergic, so allergic we have to carry an epipen with us all the time. I asked the doctor about the treatment and she recommended the same anti-allergic drugs from pharmacies.
    In October last year, I tried neruporteck, but my daughter does not swallow pills and if I opened it because of the taste, she did not accept it. In January this year, I bought the same ingredients separately, much cheaper, and started slowly and with small doses. The first improvements appeared after about 3 months. We are in May and there is no sign of allergy, insomnia, violence or nervousness. I hope we keep it like this. Thank you for the book and the time you give to this blog.
    To our surprise, the first improvements were not on allergies but on autism symptoms.

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    1. I think Neuroprotek low phenols is now available in liquid (seems the same without the capsules), still is expensive.
      Is in my list to try next, from my research seems that takes 3-6 months to start to see the effects

      SB

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  12. Hi,

    You can find a cheap coultramicronized PEA and lutein formulation here: https://www.epitech.it/product/8060/en

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    1. Hi Daniel, did you ever get a chance to trial Valproate as it has the epigenetic effect that's helpful in Rett syndrome. My son has a rare mutation on GABRB2 and off late I've been seriously considering it. Though there are greater chances that it might not work, as it's a genetic mutation, but I also feel it might do something helpful.

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  13. Hi Janu! I did not tried Valproate with my Rett daughter but many Rett girls are treated with Valproate for epilepsy. What I heard from Rett parents is that their daughters improve a lot when they replace antiepleptics including Valporate for a Ketogenic diet. I am also experiencing a nice improvement with exogenous ketones. With 3 grams of salt based ketones my daghter is more relaxed and smarter. With 3 ml of ester ketones instead of salt ketones the improvement is even more clear.
    Ester ketones taste is horrible but I would defenitely give a try to it with DeltaG ketones. You might have a sence of what you can achive with the ketogenic diet without having to sacrifice many other benefits of a more standard diet.
    If you go this way, bear in mind to combine exogenouse ketones with a low glycemic index diet: no sugar, no pasta, no bread,...

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    Replies
    1. Thanks Daniel, for sharing valuable information about Ketones. It is definitely something for me to consider, though Ketogenic diet by itself is not a viable option for us, considering my son is a hyper picky eater and already on the low percentile for weight and height.

      From you mentioning ketones having a great effect, it all seems to boil down to addressing the Epigenetics. Circling back on the Valproate, it looks like there is a particular dose range in which only Valproate has the epigenetic effect. In this paper (1) it is mentioned that at 20 to 30 mg/kg is when it has a comparable effect with typical epigenetic drugs. In another paper (2) which used Valproate successfully in a Rett mouse model, in fact used a slightly higher dose which roughly translates to 40 mg/kg (for my son weight and surface area) of HED from mouse dose used.

      In our case, SSRI has worked miracles. It stopped the Ataxia, fixed mood issues, improved gross motors skills, improved awareness and receptive language and not the least put a smile on his face. Without it my son would have been wheelchair bound like some kids affected by this mutation. I’m longing for speech and more cognition.Recently I just read SSRIs also have epigenetic effects (3). SSRI escitalopram has been shown to inhibit DNMT and thus have epigenetic benefits. This is the only blog which discusses about Epigenetics and hats off to Peter for that.

      Now having read about Epigenetics for a while now, I think the Biomed world pushing strong methylation treatments could be a complete sham as it can turn off many good genes. Now I’m thinking that the hyper dosing of the B-Vitamins, Folate and B12, pushed into these kids can be causing more harm than help. Now it makes sense to me why Dr. Goldberg was strongly against using any Vitamin supplementation, even smaller doses. I wonder what Peter thinks about this.

      (1) https://www.embopress.org/doi/full/10.1093/emboj/20.24.6969
      (2) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4072629/
      (3) https://academic.oup.com/ijnp/article/15/5/669/647786

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    2. Janu, some people do seem to do well on specific B vitamins, but many people have a negative reaction. Some people have a good reaction to high dose biotin, for example, but this then turns into a negative effect, creating problems like self-injury.

      Care needs to be taken.

      What works wonders for one person may be completely inappropriate for someone else. The issue is mostly concerning B vitamins.

      Delete
    3. Hi Janu, how much the dose of valpore you used

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    4. Anonymous, I'm not using Valproic acid.

      Delete
  14. Hi Janu! Thank you for sharing your experience and the link to the valporate acid in a Rett mouse model.

    My feeling is that energetics play a role in regulating the neuronal excitability:

    Ketones for instance might signal the kinases that regulates the NKCC1/KCC2 balance: 10.3389/fnins.2020.00673

    Creatine kinases might also regulate NKCC1/KCC2 balance:
    10.1016/S0014-5793(04)00328-X

    Hyperglicemia might induce convulsions: 10.4103/ijri.IJRI_344_19

    Fluoxetine was able to activate the silenced MECP2 gene in a mouse model and improved motor function:
    10.1038/s41598-021-94156-x

    And yes, folic acid might downregulate MECP2 and MBD2: 10.1016/j.bbrep.2019.100681

    Kind regards!
    Daniel


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