Minimizing Summertime Autism Flare-ups in 2015

When I first connected histamine to autism, I did not realize that this might be a common problem.  The most frequently viewed post on this blog is one on histamine and autism; so at least 10,000 people out there have googled “autism and histamine”.

Two years later, the therapy is still evolving and it should be said that, what works best for one person may not help in another person.  The main point is that in some people with autism, they face a summertime regression due to the effect of allergy.  So bad behaviours and aggression increase and good behaviours and indeed cognitive function decrease.  This appears to be the result of histamine and a pro-inflammatory cytokine called IL-6.

For the 2015 pollen season, which started early where we live, this is what we are using:-

Azelastine nasal spray, this is an H1 antihistamine that is also inhibits mast cells from “degranulating” and emptying their load of pro-inflammatory substances.  Once a day.

Quercetin is a cheap flavonoid that has numerous actions including on histamine H1 receptors, mast cells, and inflammation. 125mg two or three times a day.

Verapamil is an L-type calcium channel blocker and also a mast cell stabilizer. 40mg three times a day

Fluticasone propionate 50 µg (micrograms) – see below.  It is a steroid that has recently been shown to have some unexpected effects on mast cells.  

I have found that oral antihistamines were effective for only a couple of hours, but their effect varies widely from person to person.

In theory, Rupatadine should be the most effective anti-histamine, since it is also a potent mast cell stabilizer.  The old first generation antihistamines (that make you drowsy) could in theory be better than the new ones like Claritin, Zyrtec, since they can also cross the blood brain barrier (BBB).

Ketotifen and cromolyn sodium should also be useful, but if the allergy is pollen related, you really need the nasal spray (nasalcrom etc) to get the most effect.  In some countries they sell eye drops and not the nasal spray.  Usually the eye drops are more diluted than the nasal spray.  For example, the Azelastine eye drops contain 50% less Azelastine than the nasal spray, but are otherwise the same.  Where we live they have run out of the nasal spray but not the eye drops, so you could refill the spray with eye drops and double the number of sprays to get the same dose.

Drugs like Claritin and Zyrtec are H1 antihistamines and also partial mast cell stabilizers; they have a positive behavioral effect in some people with ASD, who are apparently allergy free.

New for 2015

I expect that two recent anti-inflammatory therapies, the Tangeretin flavonoid and the Miyairi 588 bacteria/probiotic may have a beneficial, indirect, effect on our usual summertime regression.

A more convention approach is to add fluticasone propionate to reduce the inflammation caused by allergy.  This drug is a steroid and widely used either as an inhaler to control asthma and COPD, or as a nasal spray to treat allergies.

As Flixotide inhaler, Monty, aged 11 with ASD and asthma, has already been taking fluticasone propionate for a few years.  We now use a tiny dose (50 µg), since his autism therapies have greatly reduced any asthma tendencies.

Fluticasone propionate nasal spray (Flixonase, Flonase etc) is widely sold as a treatment for hay fever and rhinitis and was recently combined with Azelastine (see above) as a treatment for moderate to severe allergies in a product call Dymista.

The combination of H1 antihistamine, mast cell stabilizer and anti-inflammatory all in one spray does seem a good idea.  The steroid dose using Dymista is actually lower than the usual dose of steroid when using Fluticasone propionate nasal spray alone.  You want to minimize the amount of steroid absorbed in the blood. When used as a spray/inhaler the amount is tiny, but still should be considered.

Dymista (Azelastine + Fluticasone propionate) does indeed work better than Azelastine alone.  There is no sign of allergy at all (no red eyes, sneezing, itchy nose), with Azelastine you still have an itchy nose.

In our case, the allergy symptoms, even minors ones, do correlate with the change in behaviour and cognitive function; so the target is no allergy symptoms at all.

If anyone has other therapies for summertime flare ups, feel free to share them.

Inflammation Leading to Cognitive Dysfunction

Today’s post highlights a paper with some very concise insights into how microglial cells become “activated” resulting in the “exaggerated inflammatory response” that many people with autism experience on a daily basis.  

This is very relevant to treatment, which is not usually the objective of much autism research.

I recall reading a comment from John’s Hopkins about neuroinflammation/activated microglia in autism; they commented that no known therapy currently exists and that, of course, common NSAIDs like ibuprofen will not be effective.  But NSAIDs are effective.

As we see in today’s paper, there a least 4 indirect cytokine-dependent pathways leading to the microglia, plus one direct one.

NSAIDs most definitely can reduce cytokine signaling and thus, indirectly, reduce microglial activation.

The ideal therapy would act directly at the microglia, and as Johns Hopkins pointed out, that does not yet exist with today's drugs.  If you read the research on various natural flavonoids you will see that “in vitro” there are known substances with anti-neuroinflammatory effects on microglial activation.  The recurring “problem” with such substances is low bioavailability and inability to cross the blood brain barrier.

Back to Today’s Paper

It was a conference paper at the 114th Abbott Nutrition Research Conference - Cognition and Nutrition

The full conference proceedings can be downloaded

The paper is not about autism, it is about more general cognitive dysfunction.  It is from mainstream science (I checked).

It explains how inflammation anywhere in the body can be translated across the BBB (Blood Brain Barrier) to activate the microglia.  This of course allows you to think of ways to counter these mechanisms.

It also raises the issue of whether or not anti-inflammatory agents really need to cross the BBB.  While you might think that ability to cross the BBB is a perquisite to mitigate the activated microglia, this may not be the case.  Much can be achieved outside the BBB, and we should not rule out substances that cannot cross the BBB.

Very many known anti-inflammatory substances do not cross the BBB.   

  

From Inflammation to Sickness and Cognitive Dysfunction: When the Immune System Subjugates the Brain

extracts from the above paper ...

Example – Influenza and Cognition

Neurological and cognitive effects associated with influenza infection have been reported throughout history.

The simplest explanation for these neurocognitive effects is that influenza virus makes its way to the brain, where it is detected by neurons.

However, most influenza strains, including those responsible for pandemics, are considered non-neurotropic, neurological symptoms associated with influenza infection are not a result of direct viral invasion into the CNS.

Moreover, neurons do not have receptors to detect viruses (or other pathogens) directly.

Cells of the immune system do, however, as the immune system’s primary responsibility is to recognize infectious pathogens and contend with them. For example, sentinel immune cells such as monocytes and macrophages are equipped with toll-like receptors (TLR) that recognize unique molecules associated with groups of pathogens (i.e., pathogen-associated molecular patterns). Stimulation of TLRs that recognize viruses (TLR3 and TLR7) and bacteria (TLR4) on immune sentinel cells can have profound neurological and cognitive effects, suggesting the immune system conveys a message to the brain after detecting an infectious agent. This message is cytokine based.

Macrophages and monocytes produce inflammatory cytokines (e.g., interleukin [IL]-1β, IL-6, and tumor necrosis factor-α [TNF-α]) that facilitate communication between the periphery and brain.

Cytokine-dependent Pathways to the Brain

Several cytokine-dependent pathways that enable the peripheral immune system to transcend the blood-brain barrier have been dissected.

Inflammatory cytokines present in blood can be actively transported into the brain.

But there are also four indirect pathways:-

1.     Cytokines produced in the periphery need not enter the brain to elicit neurocognitive changes. This is because inflammatory stimuli in the periphery can induce microglial cells to produce a similar repertoire of inflammatory cytokines. Thus, brain microglia recapitulates the message from the peripheral immune system.

2.     in a second pathway, inflammatory cytokines in the periphery can bind receptors on blood-brain barrier endothelial cells and induce perivascular microglia or macrophages to express cytokines that are released into the brain

3.     In a third pathway, cytokines in the periphery convey a message to the brain via the vagus nerve. After immune challenge, dendritic cells and macrophages that are closely associated with the abdominal vagus have been shown to express IL-1β protein; IL-1 binding sites have been identified in several regions of the vagus as well. When activated by cytokines, the vagus can activate specific neural pathways that are involved in neurocognitive behavior. However, activation of the vagus also stimulates microglia in the brain to produce cytokines via the central adrenergic system 

4.     A fourth pathway provides a slower immune-to-brain signaling mechanism based on volume transmission.  In this method of immune-to-brain communication, production of IL-1β by the brain first occurs in the choroid plexus and circumventricular organs—brain areas devoid of an intact blood-brain barrier. The cytokines then slowly diffuse throughout the brain by volume transmission, along the way activating microglia, neurons, and neural pathways that induce sickness behavior and inhibit cognition.

Can Flavonoids Reduce Neuroinflammation and Inhibit Cognitive Aging?

Flavonoids are naturally occurring polyphenolic compounds present in plants. The major sources of flavonoids in the human diet include fruits, vegetables, tea, wine, and cocoa.  Significant evidence has emerged to indicate that consuming a diet rich in flavonoids may inhibit or reverse cognitive aging

Flavonoids may improve cognition in the aged through a number of physiological mechanisms, including scavenging of reactive oxygen and nitrogen species and interactions with intracellular signaling pathways. Through these physiological mechanisms, flavonoids also impart an anti-inflammatory effect that may improve cognition. This seems likely for the flavone luteolin, which is most prominent in parsley, celery, and green peppers.

Whereas luteolin inhibits several transcription factors that mediate inflammatory genes (e.g., nuclear factor kappa B [NF-κB]and activator protein 1 [AP-1]), it is a potent activator of nuclear factor erythroid 2-related factor 2 (Nrf2), which induces the expression of genes encoding antioxidant enzymes. A recent study of old healthy mice found improved learning and memory and reduced expression of inflammatory genes in the hippocampus when luteolin was included in the diet. Thus, dietary luteolin may improve cognitive function in the aged by reducing brain microglial cell activity.

Hence, the flavonoid luteolin is a naturally occurring immune modulator that may be effective in reducing inflammatory microglia in the senescent brain.

Conclusion

In light of the recent evidence suggesting microglial cells become dysregulated due to aging and cause neuroinflammation, which can disrupt neural structure and function, it is an interesting prospect to think dietary flavonoids and other bioactives can be used to constrain microglia. But how can flavonoids impart this anti-inflammatory effect? Although in vitro studies clearly indicate that several flavonoids can act directly on microglial cells to restrict the inflammatory response, results from in vivo studies thus far do not prove that dietary flavonoids access the brain to interact with microglia in a meaningful way. This is a complicated question to dissect because flavonoids reduce inflammation in the periphery and microglia seem to act like an “immunostat,” detecting and responding to signals emerging from immune-to-brain signaling pathways. Thus, whether dietary flavonoids enter the brain and impart an anti-inflammatory effect on microglia is an interesting question but one that is more theoretical than practical because what is most important is how the immunostat is adjusted, whether that is via a direct or indirect route. However, because flavonoids are detectable in the brain they most likely affect microglia both directly and by dampening immune-to-brain signaling.

Interesting Natural Substances

In no particular order, these are several very interesting flavonoids/carotenoids.  In the lab, they all do some remarkable things.

In humans, they also do some interesting things; how helpful they might be in autism remains to be seen.

Being “natural” does not mean they are good for you and have no side-effects.

Some of the following are very widely used and so you can establish if there are issues with long term use.  It also makes them accessible.

Quercetin (found in many fruits, numerous interesting effects)

and two Quercetin-related flavonoids:-

Kaempferol (widely used in traditional medicine)

Myricetin (has good and bad effects)

Lycopene  (from tomatoes, potent anti-cancer, does not cross the BBB)

  

Luteolin(in many vegetables, like broccoli) 

Apigenin (from chamomile, stimulates neurogenesis, PAM of GABA_A, block NDMA receptors, antagonist of opioid receptors …)

Tangeretin (from tangerines, does cross the BBB, has potent effects in vitro)

Nobiletin (from tangerines)

Hesperidin (from tangerines)

Naringin (from Grapefruit, contraindicated with many prescription drugs)

Epicatechin/Catechin  (the chocolate/cocoa flavonoids, do cross the BBB, well researched)

Summertime Raging in Autism – H1 Anti-histamine Effect on Histamine Levels and IL-6

Last summer, I wrote a lot about autism getting much worse in that time of the year and how I found that common “24 hour” anti-histamine drugs seemed to have a magical effect; but one that lasted only 2-3 hours. There were only visible signs of a mild allergy, which could indeed easily be overlooked.

I did later receive a message from a reader who noticed his child’s ASD behaviours were greatly improved by Zrtec and his doctor agreed to prescribe this H1 antihistamine all year round.

Recently, I stumbled upon a blog, rich with many comments of parents of kids with severer types of autism.  Here I noted some parents referring to “summertime raging”, and I thought to myself, I know what they mean.  Fortunately, I found out how to make it go away.

Ant-histamine drugs

The two most common antihistamine drugs are Claritin (Loratadine), its active derivative Aerius (Desloratadine) and Zrtec (Ceterizine) and its active derivative Xyzal (levocetirizine).

The main action of an antihistamine is not actually to reduce the amount of histamine in your blood, rather it is to block the effect of histamine on the H1 receptors.

An H2 antihistamine blocks H2 receptors that are mainly in your intestines, and is used to reduce the amount of acid in the stomach.

This led me on a quest for substances that actually stop the increase in histamine, rather than just blocking some effects.  The only thing that does this is something that can stop so-called mast cells from degranulating and spilling their load of histamine, serotonin, nerve growth factor and cytokines, including IL-6, into the blood; from where, all except serotonin, are free to travel to the brain, across the blood brain barrier (BBB).  Serotonin cannot cross the BBB.

According to the mast cell specialist Theoharides, conventional drugs are not genuine mast cell stabilizers.  There are some partial ones, like Ketotifen, Cromalin, Rupatadine and Azelastine, but Theoharides thinks naturally occurring flavonoids like Luteolin and Quercetin work best.

Last summer in this blog I looked at newly discovered histamine receptors types H3 and H4 which are known to be present in the brain.

So how is it that Claritin and Zrtec can reduce autistic behaviours ?

I did note that both the above drugs did reduce summertime raging and also the Theoharides' research that showed they probably should not, since they are not mast cell stabilizers. 

Since my blog reader also found Zrtec helpful, so much so he gives it to his kid year round and it now seems summertime raging is not an unusual phenomenon in autism, I did some more checking.

In spite of what Theoharides tells us, it turns out that both Claritin and Zrtec do indeed reduce the amount of histamine in the blood.

Also, it turns out that not only is the pro-inflammatory cytokine IL-6 released from mast cells but it is also released from another type of cell, called the endothelial cell.

The endothelium is the thin layer of cells that lines the interior surface of blood vessels and lymphatic vessels, forming an interface between circulating blood or lymph in the lumen and the rest of the vessel wall. The cells that form the endothelium are called endothelial cells. Endothelial cells in direct contact with blood are called vascular endothelial cells, whereas those in direct contact with lymph are known as lymphatic endothelial cells.

And what prompts endothelial cells to release IL-6? Histamine does.

Indeed we have studies showing how Claritin (loratadine) and  Zrtec (Ceterizine) reduce histamine and IL-6; it is the IL-6 from the endothelial cells.

Inhibitory activity of loratadine and descarboxyethoxyloratadine on histamine-induced activation of endothelial cells.

"CONCLUSION:

These results demonstrate that both L and DCL are active to reduce the histamine-induced activation of EC. Interestingly, DCL seems to be effective at lesser concentrations especially to inhibit cytokine secretion."

The above study would suggest that Aerius (DCL) should be more effective than Claritin (L) its predecessor.

Human Mast Cells(HMC-1 5C6) Enhance Interleukin-6 Production by Quiescent and Lipopolysaccharide-Stimulated Human Coronary Artery Endothelial Cells

"Histamine is a major constituent of the mast cell. The effect of histamine on endothelial cells is primarily mediated through H1R

Collectively, our results suggest that mast cell-derived histamine and proteases play an important role in vascular inflammation and calcification in addition to their well-recognized participation in allergic diseases."

This study, and others like it, show how mast cell degranulation contributes to heart disease.  This would suggest that mast cell stabilizers have a much wider role in human health than is realized.  Another example of how a red apple a day (with the skin) may indeed help keep the doctor away and a glass of red wine will do the same.  Both are rich sources of the mast stabilizer Quercetin.  The alcohol increases the bio-availability.

Cetirizinea histamine H1 receptor antagonist improves viral myocarditis

"Conclusion

These results suggest that cetirizine exerts its beneficial effects on viral myocarditis by suppressing expression of pro-inflammatory cytokines, genes related to cardiac remodeling in the hearts of mice."

So how do Claritin and Zrtec reduce summertime/year round raging in autism?  Well it could be histamine or it could be IL-6, we cannot know for sure.  The science tells us that the brain has many H3 and H4 receptors, so they are possibly to be implicated.  Or, it may just be IL-6;  histamine’s involvement could be just provoking the endothelial cells to release more IL-6.

Conclusion

Claritin/Zrtec/Xyzal are relatively cheap, in theory they are long lasting drugs.  In Monty, aged 10 with ASD, they all work for summertime time raging, but not for long.  Adults should take one per 24 hours.  Monty would need one every 3 hours.

The, supposedly better, mast cell stabilizers like Ketotifen and Rupatadine take a few days before they have any effect at all.  Azelastin is available as a nasal spray and is supposed to be effective quickly as an allergy treatment.

My preferred mast cell stabilizing, IL-6 inhibiting, strategy is to combine PEA (palmitoylethanolamide) which is already naturally in your body, with the flavonoid quercetin, which is found in the skin of red apples and red grapes.  In theory, according to the research, this is both a potent combination and should be free of harmful side effects.

Very frequent doses of Claritin/Zrtec/Xyzal are not going to be good.

Links

Blog with 1000s of parent comments, some are very insightful

  

Theoharides on mast cells

On this blog:-

http://epiphanyasd.blogspot.com/2014/02/is-subtype-of-autism-allergy-of-brain.html

http://epiphanyasd.blogspot.com/2014/03/palmitoylethanolamide-pea-vs-flavonoids.html

http://epiphanyasd.blogspot.com/2013/07/histamine-allergies-and-reducing.html

http://epiphanyasd.blogspot.com/2013/11/seasonal-autistic-mastocytosis.html

Let’s be Serious about the Data - Flavonoids, Cytokines & Autism

You may be wondering why, with so many research papers written about autism, so little progress has been made.  It is a very complex task, but nobody is coordinating it.

How do you find a Boeing 777 missing somewhere in Asia?  Another daunting challenge, but with the right people and resources it can be done.  With the wrong people, it will prove to be impossible.

Ashwood et al have documented the level of various inflammatory markers in autism.  Very helpfully, they created three groups: typical children, children with non-regressive autism, and children with regressive autism.

Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome

Table 2, on the third page, tells us what we need to know.  Certain cytokine levels are markedly elevated in regressive autism, including IL-6 and TNF-alpha.  Furthermore, the difference between the two types of autism is dramatic; rather implying the existence of two distinct conditions.

 

So now, I move on to what could have been an amazingly helpful study, had they spent 1% more time on it and collected some blood samples and split the kids into regressive and non-regressive groups.

Last year in Athens, a study was done using Theoharides’ mix of luteolin and quercetin flavonoids to look at the effect of mast cell stabilization on behaviour in autism.  From recent posts, you will recall that these flavonoids reduce the level of inflammatory cytokines, histamine and nerve growth factor, by stabilizing so called mast cells.  In effect, the study was looking at the impact of inhibiting certain cytokines on behaviour in autism.

An Open-Label Pilot Study of a Formulation Containing the Anti-Inflammatory Flavonoid Luteolin and Its Effects on Behavior in Children With Autism Spectrum Disorders

This sounds great and just what I wanted to find.  Get 40 kids with ASD measure their level of these cytokines/histamine and assess their behaviour.  Give them the cytokine inhibitor/mast cell stabilizer for six months, measure the levels in their blood and assess the behaviour again.

Sadly, they did not bother to take the before and after blood samples and send them downstairs to the hospital’s laboratory.

So we have a paper that took years of planning that tells us that the flavonoids do seem to help; but we do not know exactly why and we cannot correlate improvement in behaviour with change in cytokine levels.

What a pity.  

  

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.