Antabine (Anatabloc) and Autism - a Supplement or a Drug?

This is another post prompted by a comment received on this blog.

My 15 year-old daughter has classic regressive type ASD. I started her on an anti-inflammatory, Anatabloc, over a year ago and it allowed me to take her off atypical anti-psychotics ( she was on them for aggression) Do you know anyone else using this dietary supplement?  

I found this very interesting and so I did some quick research.

Anatabloc was until very recently sold in the US as a supplement, it was withdrawn from sale by the producer following a corruption trial and a dispute with the FDA over approvals.  Nobody is saying the supplement does not work, rather it is a drug.

Anatabloc, supplement at center of McDonnell trial, to be taken off the market

Anatabloc

Anatabloc was sold as an anti-inflammatory supplement based on a substance called Anatabine, found in tobacco and in lower concentrations in green tomatoes, green potatoes, ripe red peppers, tomatillos, and sundried tomatoes.

Anatabine has been studied in animal models and in cells to see if it might be useful for treating nicotine addiction and inflammation, and has been studied in models of diseases characterized by inflammation, such as Alzheimer's Disease, thyroiditis, and multiple sclerosis.

On a biochemical level, it appears to be active against certain nicotinic acetylcholine receptors.

Regular readers will recall extensive earlier posts on the cholinergic system and nicotinic acetylcholine receptors.

IBS, IBD and Autism, leading to Cholinergic Signaling and the Vagus Nerve

Nicotine Patches -Autism, Alzheimer's and MCI

Biomarkers in Autism: The Cholinergic system – In need of caffeine & nicotine or maybe just choline

The conclusion of all those posts was that, most definitely, in some people’s autism, an effective strategy is to adjust the cholinergic system.  Possible methods include:-

·        Vagus nerve stimulation – still in development

·        Nicotine patches – cheap and effective in some people

·        Two Alzheimer's drugs Donepezil and Galantamine, that are acetylcholinesterase inhibitors

So at first it seemed that Anatabloc may be “just another” cholinergic drug.  However on analyzing the patent submitted by the producer, it seems there may be an alternative mode of action.

Patent for Antabine use in Autism

METHODS OF ADMINISTERING ANATABINE TO TREAT AUTISM SPECTRUM DISORDERS AND SEIZURE DISORDERS

32| Anatabine is an alkaloid present in tobacco and, in lower concentrations, in a variety of foods, including green tomatoes, green potatoes, ripe red peppers, tomatillos, and sundried tomatoes. Without being bound by this explanation, data presented in Examples I and 2 below indicate that anatabine reduces transcription mediated by nuclear factor B (NFKB). NFKB is a transcription factor which operates in cells involved in inflammatory and immune reactions.

The nuclear factor NF-κB pathway

NF-κB is seen as being clinically significant in cancer and inflammation.

The NF-κB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-κB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules.  

NF-κB has long been considered the “holy grail” as a target for new anti-inflammatory drugs.

Because NF-κB controls many genes involved in inflammation, it is not surprising that NF-κB is found to be chronically active in many inflammatory diseases, such as inflammatory bowel disease, arthritis, sepsis, gastritis, asthma, atherosclerosis and others. It is important to note though, that elevation of some NF-κB inhibitors, such as osteoprotegerin (OPG), are associated with elevated mortality, especially from cardiovascular diseases.  Elevated NF-κB has also been associated with schizophrenia.

I take the, perhaps unconventional, view that schizophrenia is adult-onset autism.  It has already shown that in terms of genetics, there is a great overlap between these two conditions.

The interaction of nuclear factor-kappa B and cytokines is associated with schizophrenia.

CONCLUSIONS:

Schizophrenic patients showed activation of the cytokine system and immune disturbance. NF-kappaB activation may play a pivotal role in schizophrenia through interaction with cytokines

The Nuclear Factor NF-κB Pathway in Inflammation

Abstract

The nuclear factor NF-κB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-κB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. In this article, we describe how genetic evidence in mice has revealed complex roles for the NF-κB in inflammation that suggest both pro- and anti-inflammatory roles for this pathway. NF-κB has long been considered the “holy grail” as a target for new anti-inflammatory drugs; however, these recent studies suggest this pathway may prove a difficult target in the treatment of chronic disease. In this article, we discuss the role of NF-κB in inflammation in light of these recent studies.

Clinical trials using Anatabloc

The producer behind Anatabloc is well advanced with clinical trials, as you can see below.

http://clinicaltrials.gov/ct2/results?term=anatabloc&Search=Search

I suspect that Anatabloc will disappear as a supplement and reappear a few years later on as an FDA approved drug for various conditions.

Conclusion

It is a pity that Anatabloc has been taken off the market.

It looks plausible that it could be effective in other people’s autism, not just the reader of this blog.

For the time-being, other than taking up smoking, a good source would be those tasty sun-dried tomatoes.

P.S.


Having re-read this post and taken a closer look at the patent and the company, I wonder if the original comment is genuine.  The patent is not very convincing and in Table 1 on page 44 it is quoting Wakefield et al, as one of only two sources that link inflammation to autism.  I could have written a much better patent application myself.

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.

Monty’s First Joke

Today at 6.30 in the morning something very unexpected happened;  Monty, aged 10 with ASD, made his first joke.  For a boy of few words this is quite a big step.

“I hit my head and now I can see birdies”

Elder brother Ted, when he finally arose, was impressed. It was very much his kind of humour, making a joke about your own weaknesses.

Regular readers will know that we are currently investigating the role of the vagus nerve in autism; all I can say is that nobody mentioned that the vagus nerve also mediates your sense of humour.  It may just be a happy coincidence, but this happened within 24 hours of our latest little experiment.  


 

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)