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. 

Association of Family History of Autoimmune Diseases and Autism Spectrum Disorders

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. 

Palmitoylethanolamide and luteolin ameliorate development of arthritis caused by injection of collagentype II in mice

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. 

Therapeutic and preventive properties of quercetin in experimental arthritis correlate with decreased macrophage inflammatory mediators 

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:-

QUERCETIN: A VERSATILE FLAVONOID

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 reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1

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.

Vitamin P may be good for you!

Now if the tittle makes sense to you, either you are a Prozac fan, or you were around in the 1940s and 50s when there actually was a vitamin P.

This blog is about autism, and in the US lots of such kids are prescribed the powerful antidepressant Prozac. We are more interested in the other vitamin P; these days they are called flavonoids.  This post will meander into other health problems but will return to ASD later on.

Flavonoids are found in plants and there are 5,000 of them.  In plants they have various functions, one of which is to provide colour (usually yellow, red and blue); in humans it is proposed that certain flavonoids may account for the beneficial properties of certain foods, ranging from chocolate to red wine.

There are many food supplements sold that contain flavonoids, three of the popular ones seem to be:-
 

·         Rutin

·         Quercetin

·         Luteolin

There is even a special mix made for autistic people called NeuroProtek.

 

In Vitro or in Vivo?

Some things work well in the test tube but not so well in us humans.  In vitro means in the glass and in vivo means in us living creatures.

Well, flavonoids have wonderful antioxidant properties, but it seems that is in only true in the test tube.  In vivo they are rather a flop.  Yet, if you read all the advertising for these flavonoid supplements, they rave about the antioxidant properties.

 

A great discussion of flavonoids is presented by the Linus Pauling Institute at Oregon State University. I have summarized much of it here and added the autism part.

 

Some flavonoids are good for you, but not as antioxidants

If flavonoids are not good antioxidants, why are they supposed to be good for you?  It seems that they have an entirely different role as signalling molecules.

Concentrations of flavonoids required to affect cell-signaling pathways are considerably lower than those required to affect cellular antioxidant capacity. Flavonoid metabolites may retain their ability to interact with cell-signaling proteins even if their antioxidant activity is diminished. Effective signal transduction requires proteins known as kinases that catalyse the phosphorylation (transferring a phosphate group (-PO₄)) of target proteins at specific sites.

The results of numerous studies in cell culture suggest that flavonoids may affect chronic disease by selectively inhibiting kinases.

Cell growth and proliferation are also regulated by growth factors that initiate cell-signaling cascades by binding to specific receptors in cell membranes. Flavonoids may alter growth factor signaling by inhibiting receptor phosphorylation or blocking receptor binding by growth factors.

All this leads naturally to think that modulation of cell-signaling pathways by flavonoids could help prevent cancer.  Mechanisms proposed include:-

Stimulating phase II detoxification enzyme activity: Phase II detoxification enzymes catalyse that promote the excretion of potentially toxic or carcinogenic chemicals.

Preserving normal cell cycle regulation: Once a cell divides, it passes through a sequence of stages collectively known as the cell cycle before it divides again. Following DNA damage, the cell cycle can be transiently arrested at damage checkpoints, which allows for DNA repair or activation of pathways leading to cell death if the damage is irreparable. Defective cell cycle regulation may result in the propagation of mutations that contribute to the development of cancer.

Inhibiting proliferation and inducing apoptosis (cell death): Unlike normal cells, cancer cells proliferate rapidly and lose the ability to respond to cell death signals that initiate apoptosis.

Inhibiting tumor invasion and angiogenesis: Cancerous cells invade normal tissue aided by enzymes called matrix-metalloproteinases. To fuel their rapid growth, invasive tumors must develop new blood vessels by a process known as angiogenesis.

Decreasing inflammation: Inflammation can result in locally increased production of free radicals by inflammatory enzymes, as well as the release of inflammatory mediators that promote cell proliferation and angiogenesis (creation of new blood vessels) and inhibit apoptosis (beneficial cell death).

Modulation of cell-signaling pathways by flavonoids could help prevent cardiovascular disease by:

Decreasing inflammation: Atherosclerosis is now recognized as an inflammatory disease, and several measures of inflammation are associated with increased risk of heart attack.

Decreasing vascular cell adhesion molecule expression: One of the earliest events in the development of atherosclerosis is the recruitment of inflammatory white blood cells from the blood to the arterial wall.

Increasing endothelial nitric oxide synthase (eNOS) activity: eNOS is the enzyme that catalyzes the formation of nitric oxide by vascular endothelial cells. Nitric oxide is needed to maintain arterial relaxation. Impaired nitric oxide-dependent vasodilation is associated with increased risk of  cardiovascular disease.

Decreasing platelet aggregation: Platelet aggregation is one of the first steps in the formation of a blood clot that can occlude a coronary or cerebral artery, resulting in myocardial infarction or stroke, respectively. Inhibiting platelet aggregation is considered an important strategy in the primary and secondary prevention of cardiovascular disease.

 

Green tea and even red wine were supposed to have wonderful antioxidant properties; apparently this is not true after all.  They do seem to be good for you, but for completely different reasons.

People who consume larger amounts of flavonoids do seem to be healthier; but sadly that does not prove that eating flavonoids makes you healthy.  It might just be that a healthy diet just happens to be flavonoid-rich.

There is on-going research and multiple clinical trials into the possible benefits of flavonoids in these areas:-

Cardiovascular Disease

The results of some controlled clinical trials suggest that relatively high intakes of some flavonoid-rich foods and beverages, including black tea, purple grape juice, and cocoa (dark chocolate) has health benefits.

Cancer

The research is ongoing, it seems to show that those people with a diet rich in flavonoids have a lower risk of certain cancers; but it seems that tea consumption has no benefit here.

Neurodegenerative Disease

It is not clear to what extent flavonoids can cross into the brain thought the BBB (blood brain barrier).  Research is ongoing to see whether Parkinson’s disease, Alzheimer’s and dementia are correlated to flavonoids in the diet.  With 5,000 flavonoids this will take some time!

 

Flavonoid Content in Food

 

There are 5 principal types of flavonoids

1.    ANTHOCYANIDINS

Examples:- Cyanidin, Delphinidin, Malvidin, Pelargonidin, Peonidin, Petunidin

Supplements available include: Bilberry, elderberry, black currant, blueberry, red grape, and mixed berry extracts.  Don’t forget the red wine.

 

2.    FLAVONOLS

Examples:- Quercetin, Kaempferol, Myricetin, Isorhamnetin

The flavonol aglycone, quercetin, and its glycoside rutin are available as dietary supplements without a prescription in the U.S. Other names for rutin include rutinoside, quercetin-3-rutinoside, and sophorin. Citrus bioflavonoid supplements may also contain quercetin or rutin.

Flavonols are found in yellow onions, scallions, kale, broccoli, apples, berries and teas.

3.    FLAVONES

Examples:-  Luteolin, Apigenin

The peels of citrus fruits are rich in polymethoxylated flavones: tangeretin, nobiletin, and sinensetin. Although dietary intakes of these naturally occurring flavones are generally low, they are often present in citrus bioflavonoid supplements.

Flavones are found in parsley, thyme, celery, hot peppers, and chamomile

4.     LAVANONES

Examples:- Hesperetin, Naringenin, Eriodictyol

Citrus bioflavonoid supplements may contain glycosides of hesperetin (hesperidin), naringenin (naringin), and eriodictyol (eriocitrin). Hesperidin is also available in hesperidin-complex supplements

Lavanones are found in citrus fruits and juices, e.g., oranges, grapefruits, lemons

5.    FLAVANOLS 

A.    Monomers (Catechins)

examples:- Catechin, Epicatechin, Epigallocatechin Epicatechin gallate, Epigallocatechin gallate

B.    Dimers and Polymers:
examples:-  Theaflavins,  Thearubigins, Proanthocyanidins

Here is where to find them:-

Catechins: Teas (particularly green and white), chocolate, grapes, berries, apples
Theaflavins, Thearubigins: Teas (particularly black and oolong)
Proanthocyanidins: Chocolate, apples, berries, red grapes, red wine

 

USDA Database for the Flavonoid Content of Selected Foods

If you want to know which food contains how much of each flavonoid, just click on the link to go to a large database held by the US Department of Agriculture.

 

USDA Database for the Flavonoid Content of Selected Foods

 

Another flurry of Patents

Not for the first time, I have noted that a flurry of patents have been filed in connection with autism.  This time it’s a couple of guys from the University of South Florida who see promise in the flavonoids :-  luteolin, diosmin, and diosmin's aglycone form, diosmetin.

 

The more prolific publisher is Theoharis Theoharides.  Here is an excerpt, from his patent:-

  

 

Theoharides is a big believer the benefit of luteolin.  Here is his main hypothesis Neuro-inflammation, blood-brain barrier, seizures and autism.

A more recent paper, again about luteolin is:- Corticotropin-releasing hormone and extracellular mitochondria augment IgE-stimulated human mast-cell vascular endothelial growth factor release,which is inhibited by luteolin

I like the fact that he is questioning the permeability of the BBB (blood brain barrier) in autism.  It seems entirely plausible and would account for many things.

  

Conclusion

 

Well I was already convinced that red wine was good for me.  Now I just have add the right vitamin P.

Time for a cup of tea, better make it chamomile (for the luteolin) and some dark chocolate.

Monty is still rather young for the red wine.  If he was French, though ….