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.

PPAR alpha, beta and gamma in Autism, Heart Disease and Diabetes

 

In recent posts we have looked at PPARα (Peroxisome proliferator-activated receptor alpha) and PEA (Palmitoylethanolamide), which activates it.  Both appeared to me to have some very interesting properties.  PPARα has siblings - PPARβ, and PPARγ.  It may not come as a surprise that one of these is currently at the centre on clinical trials for autism.  But is it the right one?

Thiazolidinediones (TZDs) are agonists of PPAR gamma (PPARγ), a nuclear hormone receptor which modulates insulin sensitivity, and have been shown to induce apoptosis in activated T-lymphocytes and exert anti-inflammatory effects in glial cells. The TZD pioglitazone (Actos) is an FDA-approved PPARγ agonist used to treat type 2 diabetes, with a good safety profile. Pioglitazone is currently in Phase 2 trials for autism.

Dose Finding Study of Pioglitazone in Children With Autism Spectrum Disorders (ASD)

The full version of the earlier study was:-

Effect of pioglitazone treatment on behavioral symptoms in autistic children

Conclusion

In view of its established safety profile, the current results provide the rationale or further testing of pioglitazone in autism and other forms of ASD. 

It is interesting that  PPARγ agonists are currently used in type 2 (non-insulin dependent) diabetes because in my earlier post is was shown that activating PPARα could treat a nasty side effect of both type 1 and type 2 diabetes, Peripheral Neuropathy;  this is damage to the peripheral nervous system.  An example is sharp pain in the sole of your feet, even when lying down.

 

Fibrates

Fibrates are a class of drug identified in the 1930s and are used in accessory therapy in many forms of hypercholesterolemia, usually in combination with statins. Clinical trials do support their use as monotherapy agents. Fibrates reduce the number of non-fatal heart attacks, but do not improve all-cause mortality and are therefore indicated only in those not tolerant to statins.

Although less effective in lowering LDL and triglyceride levels by increasing HDL levels and decreasing triglyceride levels, they seem to improve insulin resistance when the dyslipidemia is associated with other features of the metabolic syndrome (hypertension and diabetes type 2). They are therefore used in many hyperlipidemias. Fibrates are not suitable for patients with low HDL levels.

In the 1990s, the mechanism of action was discovered;  fibrates activate PPARα.

Fibrates are the main PPARα activating drugs in use, but there do seem to be various problematic side effects.  In an earlier post we did discover a naturally occurring PPARα activator that seems to have no side effects or contraindications, PEA (Palmitoylethanolamide).

Heart Disease

Heart disease is the leading cause of death in developed countries and so is very well researched.  What is remarkable is how closely related autism is to heart disease.

Almost all of the ingredients in my autism Polypill are actually drugs normally given to people with heart disease and of course people with autism are known to be prone to heart disease.

Atherosclerosis is a chronic inflammatory disease as well as a disorder of lipid metabolism.  So is autism.

Let’s look what we can learn from research into PPARs in heart disease.

 

PPARs in atherosclerosis: the clot thickens

"Atherosclerosis is a chronic inflammatory disease as well as a disorder of lipid metabolism. The accumulation of cholesterol-rich lipoproteins in the artery wall results in the recruitment of circulating monocytes, their adhesion to the endothelium, and their differentiation into tissue macrophages. Lipid-loaded macrophages play an important role in the production of chemokines, cytokines, and reactive oxygen species in the early stages of lesion formation. Therefore mechanisms that limit macrophage cholesterol accumulation and/or prevent the production of inflammatory mediators all have the potential to inhibit lesion development.

The PPAR family is comprised of 3 different proteins: PPARα, PPARβ, and PPARγ. Natural ligands for these receptors include fatty acids and oxidized fatty acids. The relevance of PPAR pathways to metabolic disease is underscored by the use of the fibrates (PPARα agonists) and thiazolidinediones (PPARγ agonists) to treat hyperlipidemia and type 2 diabetes, respectively."

 

 

"PPAR signaling pathways influence macrophage gene expression and foam-cell formation. Ligand activation of PPARα and PPARγ, but not PPARβ/δ, inhibits the development of atherosclerosis in LDLR_/_ mice. Both systemic and local mechanisms might contribute to these beneficial effects. Previous studies have suggested that PPARα and PPARγ increase LXRα expression in macrophages and promote expression of ABCA1, which mediates cholesterol efflux to apoAI. Results from the study in this issue by Li et al.  suggest that PPARγ may also inhibit cholesterol accumulation in macrophages through direct regulation of ABCG1, which has been implicated in cholesterol efflux to HDL. Activation of each of the PPARs with selective agonists also inhibits the expression of inflammatory markers in the artery wall. These findings reinforce potential use of PPAR agonists as antiatherosclerotic therapies."

"The study by Li et al.  provides new insights into pathways regulating macrophage lipid accumulation and rounds out the family picture of PPARs in atherosclerosis. Both The study by Li et al. provides new insights into pathways regulating macrophage lipid accumulation and rounds out the family picture of PPARs in atherosclerosis. Both PPARα and PPARγ ligands were shown to protect against atherosclerosis in LDLR–/– mice and inhibit macrophage foam-cell formation. ligands were shown to protect against atherosclerosis in LDLR–/– mice and inhibit macrophage foam-cell formation. In contrast, the authors did not observe any effect from PPARβ activation. Given the discrepancies between PPARβ agonist effects in mice and primates, however, the possibility that PPARβ ligands may have beneficial effects on cardiovascular disease in humans is not excluded by the present study."

So it would appear that activating PPARα and PPARγ has benefit in heart disease, but likely not PPARβ.

It seems that the traditional PPARα activator drugs, the fibrates, are problematic.  PPARγ activators are widely used in diabetes therapy and there are safe choices.

In autism, a PPARγ activator has already been shown itself to be effective in initial phase 1 trials.  

Conclusions

Heart disease is well researched by clever, very well-funded, people so I am sure they will have figured out to trial PEA instead of Fibrates as a PPARα activator and of course to look at the benefits of Pioglitazone as a PPARγ activator.

Autism is not so well researched.  The PPARγ activator trial is proceeding slowly forward in Toronto.  The PPARα activator trial will commence shortly, but not with Fibrates.

 

PPARα (Peroxisome proliferator-activated receptor alpha) - and why PEA might be an alternative to the Ketogenic Diet in Epilepsy and Potentially useful in Autism

There is no doubt that most parents’ ideal autism therapy would be a special diet.  The most popular diet is the gluten and casein free diet; in a sub-type of autism this diet clearly is very effective. Another very interesting diet is the Ketogenic diet and its easier to implement cousin, the Modified Atkins diet.  There is also the GAPS diet.

Many scientists are very skeptical of the therapeutic value of special diets.

I am always looking for connections in the science.  If I can find from multiple starting points the same conclusion, this triggers my interest, regardless if anyone else has highlighted the area as an issue for autism.

Today my reinforcing arguments is indeed a diet; the Ketogenic diet.

Remember that epilepsy is highly comorbid with autism, and trials have shown the ketogenic diet to reduce the incidence of seizures by half.

This post was supposed to be a short one, but it just kept growing.  You can skip the complicated parts and go to the conclusions.

 

Ketogenic Diet

The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that in medicine is used primarily to treat difficult-to-control epilepsy in children. The diet forces the body to burn fats rather than carbohydrates. Normally, the carbohydrates contained in food are converted into glucose, which is then transported around the body and is particularly important in fuelling brain function. However, if there is very little carbohydrate in the diet, the liver converts fat into fatty acids and ketone bodies. The ketone bodies pass into the brain and replace glucose as an energy source. An elevated level of ketone bodies in the blood, a state known as ketosis, leads to a reduction in the frequency of epileptic seizures.

The original therapeutic diet for paediatric epilepsy provides just enough protein for body growth and repair, and sufficient to maintain the correct weight for age and height. This classic ketogenic diet contains a 4:1 ratio by weight of fat to combined protein and carbohydrate. This is achieved by excluding high-carbohydrate foods such as starchy fruits and vegetables, bread, pasta, grains and sugar, while increasing the consumption of foods high in fat such as cream and butter. 

Modified Atkins

First reported in 2003, the idea of using a form of the Atkins diet to treat epilepsy came about after parents and patients discovered that the induction phase of the Atkins diet controlled seizures. The ketogenic diet team at Johns Hopkins Hospital modified the Atkins diet by removing the aim of achieving weight loss, extending the induction phase indefinitely, and specifically encouraging fat consumption. Compared with the ketogenic diet, the modified Atkins diet (MAD) places no limit on calories or protein, and the lower overall ketogenic ratio (approximately 1:1) does not need to be consistently maintained by all meals of the day. The MAD does not begin with a fast or with a stay in hospital and requires less dietitian support than the ketogenic diet. Carbohydrates are initially limited to 10 g per day in children or 20 g per day in adults, and are increased to 20–30 g per day after a month or so, depending on the effect on seizure control or tolerance of the restrictions. Like the ketogenic diet, the MAD requires vitamin and mineral supplements and children are carefully and periodically monitored at outpatient clinics.

The modified Atkins diet reduces seizure frequency by more than 50% in 43% of patients who try it and by more than 90% in 27% of patients. Few adverse effects have been reported, though cholesterol is increased and the diet has not been studied long term.
 

Why does ketosis reduce seizures?

For a change, Wikipedia cannot tell you why ketosis is good for epilepsy.

If you look deeper in the research you can find a very good likely reason why it may be so effective; we have yet another tongue twister, Peroxisome proliferator-activated receptor alpha, known as PPARα.

It is PPARα which is the connection to my early post all about growth factors in autism. It is my belief that Growth Hormone (GH) and its related growth factors are of key importance in understanding and treating autism.   In that very lengthy post I introduced PEA (Palmitoylethanolamide) as an interesting substance that, amongst other things, modulates the release of nerve growth factor (NGF) from mast cells.  PEA has been extensively researched and has interesting effects including treating pain, inflammation and indeed epilepsy.

I started to look into how PEA works and to see what that mechanism might be.  After a dead end looking at Endocannabinoids, I found what I was looking for – PPARα.

PEA - Pain Relief and Neuroprotection Share a PPARα -Mediated Mechanism

So it appears there is an interesting connection linking the apparently successful Ketogenic diet, and the supplement PEA.  The Ketogenic diet does have some side effects and drawbacks; apparently PEA has no side-effects or contra-indications.

Another interesting point is that a diet very rich in olive oil has been shown to have the benefits of the Ketogenic diet and olive oil directly raises oleylethanolamide (closely related to palmitoylethanolamide) and also a PPARα activator. 

Peroxisome proliferator-activated receptor alpha

PPAR-alpha is a transcription factor and a major regulator of lipid metabolism in the liver. PPAR-alpha is activated under conditions of energy deprivation and is necessary for the process of ketogenesis, a key adaptive response to prolonged fasting.  Activation of PPAR-alpha promotes uptake, utilization, and catabolism of fatty acids by upregulation of genes involved in fatty acid transport, fatty binding and activation, and peroxisomal and mitochondrial fatty acid β-oxidation. PPAR-alpha is primarily activated through ligand binding. Synthetic ligands include the fibrate drugs, which are used to treat hyperlipidemia, and a diverse set of insecticides, herbicides, plasticizers, and organic solvents collectively referred to as peroxisome proliferators. Endogenous ligands include fatty acids and various fatty acid-derived compounds.

You may recall from earlier post that in autism there appears to be strange things going on with the lipid mechanism.  Here is a paper for those interested:- 

The Neurobiology of Lipid Metabolism in Autism Spectrum Disorders

 

PPARα and the ketogenic diet (and cancer) 

The following paper does cover the role of PPARα in the ketogenic diet (KD) but its main thrust is the use as a cancer therapy.  We have already come across other autism drugs that have potential in cancer therapy.  NAC was shown to be beneficial in cases of both prostate cancer and breast cancer.

I know some readers are also interested in some forms of cancer, so I have included the cancer part.  Others may want to skip this part. 

Peroxisome Proliferator Activated Receptor α  Ligands as Anticancer Drugs Targeting Mitochondrial Metabolism

 

Calorie restricted KetoCal diet significantly decreased the intracerebral growth of both tumor types and decreased the intratumoral microvessel density.  Implementation of this diet resulted in elevation of plasma concentrations of ketone bodies, which might trigger the energetic imbalance in the tumors, since tumor tissue showed reduced activity of the enzymes required for ketone body oxidation: hydroxybutyrate dehydrogenase and succinyl-CoA: 3- ketoacid-CoA transferase comparing to conlateral normal brain tissue. Moreover, in some cases of advanced malignant tumors (anaplastic astrocytoma and cerebellar astrocytoma), patients respond well to CRKD dietary regimen. The question about the safety of CRKD in patients who are likely to develop cachexia due to tumor burden may arise, nevertheless malnutrition or undernourishment have not been reported. 

Remarkably, ketogenic diet is also beneficial for patients with neurological disorders, especially in epilepsia. The first observations revealed that starvation – mimicking diet, and CRKD in particular, have anti-seizure properties. Further investigation stated that both high fat content and reduced total caloric intake are important because they induce hormonal responses favoring ketogenesis: low insulin and high glucagon, as well as increased cortisol blood levels promote acetyl-CoA conversion to ketone bodies and release to circulation. Increase in blood fatty acid concentration, which physiologically activates PPAR α, was observed in CRKD as a result of fat reserves mobilizationand high fat intake  Fig. (3). Ketone bodies are avidly consumed by brain tissue during glucose deprivation. In limited glucose availability, astrocytes protect neurons from the energetic stress by performing fatty acid oxidation and ketogenesis and supply the surrounding neurons with ketone bodies. Ketone bodies are prioritized energetic substrates and they are metabolized before glucose and free fatty acids. Their cellular uptake is mediated by monocarboxylate transporter MCT1, which transcription is positively regulated by PPAR. Importantly, both endogenous (free fatty acids) and synthetic PPARα  ligands are free to flow through the blood-brain barrier and they may reach high levels in the brain tissue. In addition to the role in brain tumors, ketogenesis may also become a prognostic factor in colon carcinoma. 3-Hydroxy-3-methylglutaryl-CoA synthase is severely downregulated by c-Myc in colon cancer cell lines with high activity of Wnt/ 􀀂-catenin/ T cell factor 4 (TCF-4)/ c-Myc pathway. Ketogenic capability and HMGCS expression levels are positively correlated with enterocyte differentiation and decreased in colon or rectal carcinomas, especially those poorly differentiated. 

In theory, PPAR α activation could counteract c-Myc induced alterations of mitochondrial metabolism by restoring the HMGCS and ketogenesis levels and by inhibiting glutaminolysis through transcriptional repression of the two enzymes crucial for this pathway: glutaminase and glutamate dehydrogenase. Moreover, PPAR α and pan-PPAR agonists like bezafibrate stimulate oxidative  hosphorylation and respiratory capacity by inducing PGC-1􀀁 mediated mitochondrial biogenesis. Although this activity goes in line with c-Myc action, which was reported to stimulate mitochondrial proliferation, this could cause either normalization of cancer cell energetic balance or induce a 'metabolic catastrophe' in the cells with genetically impaired mitochondrial function. 

Recent studies on mice bearing different tumors revealed that dietary restrictions do not affect those with constitutive activation of PI3K/Akt pathway. Other cancer characterized by transformed HRAS/ KRAS, BRAF or with loss of TP53, show a significant decrease of the growth rate and increased apoptosis when the host animals were subjected to dietary restriction. Resistance to dietary restriction depended on the Akt phosphorylation status and its activation, which lead to FOXO1 phoshorylation and cytoplasmic sequestration. When arrested in the cytoplasm, FOXO1 is unable to exert its proapoptotic functions. There are several proteins that negatively affect Akt activity, namely protein phosphatases PTEN, SHIP and PPA2 that directly dephoshorylate Akt; and TRB3 (mammalian homolog of Drosophila protein tribbles), a protein that binds to Akt and blocks its phosphorylation. TRB3 expression in liver rises during fasting and is driven by PGC-1􀀁 in PPAR α dependent manner, as there are functional PPRE elements in the TRB3 promoter. Metabolic function of TRB3 is to block insulin dependent Akt activation in fasting, in parallel to PGC-1􀀁 / PPARα induced gluconeogenesis and fatty acid oxidation. This seems to be a part of a SIRT1/ LKB1/ AMPK/ PGC-1􀀁 pathway which constitutes an adaptive response to CR, because in mice with muscle – specific LKB1 knockout in which the PGC-1􀀁, PPAR α and TRB3 were severely decreased. Interestingly, TRB3 upregulation in lymphocytes is induced by fibrates in PPAR α independent fashion with utilization of C/EBP and C/EBP homologous proteins.

Therefore it is reasonable to speculate that pharmacological PPAR 􀀁 activation together with CRKD might improve the anticancer outcome in case of dietary restriction resistant tumors with overactive PI3K or nonfunctional PTEN. The

situation would probably be different in tumors with constitutively active plasma membrane associated Akt mutants (with activating Akt mutations or in model systems with the introduction of myristoylated Akt), as in these cases TRB3 possibly would not affect the already phosphorylated Akt.

Although these hypotheses need to be verified, the negative influence of TRB3 on Akt phosphorylation seems to be a general phenomenon.

 

7. CONCLUSION

PPAR α activators have a great potential of supplementing conventional anticancer therapies by modulating cancer cell energy metabolism and signaling pathways. This notion is based on multiple observations, which include PPAR α-mediated inhibition of two prominent oncogenes: c-Myc and Akt Fig. (3). In this inhibitory action, PPAR α suppresses glutaminolysis and glutamine catabolism in mitochondria, as well as activates ketogenesis by promotion of fatty acid oxidation and transactivation of HMGCS. In cancer cells these processes are c-Myc regulated. Next, PPAR 􀀁 actions slow down glycolysis by inhibiting Akt and blocks Akt induced fatty acid synthesis by repressing PDH activity in mitochondria

via PDK4 upregulation. Finally PPAR α functionally cooperates with AMPK, SIRT1 and PGC-1􀀁 in regulating the cellular response to calorie restriction. In perspective, it would be important to elucidate the details of possible interplay between these regulatory proteins, and to verify the role of PPAR α activation in the of CRKD applied to in vivo cancer models. Of note, the potential use of clinically tested synthetic ligands for PPAR α  against cancer, although seems to be a straightforward and fairly safe procedure, it still requires our careful consideration. There are still debates over fibrate drugs safety and three main caveats have been are presented : (1) fibrate ability to bind hemoglobin which reduces its affinity to oxygen; (2) fibrates may disrupt mitochondrial electron transfer chain particularly by inhibiting complex I; and (3) fibrates induce mitochondrial ROS production. These potentially harmful activities are presently understood to be receptor-independent, which implies the need for new generation of PPAR α ligands which would possess improved physiological and pharmacological characteristics.
 

 Peroxisomeproliferator-activated receptor alpha and the ketogenic diet

“The roles of PPARs in brain and, more specifically, the functional consequences of PPARα activation, have been discussed previously. PPARα plays a key role in regulating ketogenesis (an obvious hallmark of the KD) and a more extended role in regulating hepatic amino acid metabolism with the potential consequences on neurotransmitter concentrations if PPARα is activated within brain .”

“There is now increased understanding of the KD and the implications for the actions of small molecule anticonvulsants that interact with PPARα. Especially, with the emerging evidence that PPARα is expressed at low but functionally significant levels in many nerve cells throughout the body, the possibility exists for common modes of action of different anticonvulsants in spite of their differential seizure-type efficacy. For example, although valproate, palmitoylethanolamide, and the KD have a limited overlap in seizure-type efficacy, they may still share a common mechanism of action, taking into account their pharmacodynamic/pharmacokinetic differences acting on a common but widely distributed molecule such as PPARα”

PPARα and the high olive oil diet 

“However, a recent report shows that a 30% fat diet enriched in olive oil directly raises oleylethanolamide (closely related to palmitoylethanolamide and also a PPARα activator) within rat brain. Thus, modifications to the fatty acid profile of the much higher (80%) classic ketogenic diet may also be predicted to directly modify PPARα-activating molecules in brain, potentially providing a broader spectrum of anticonvulsant effect.”

The above actually refers to rats, but here is the abstract of that paper:-

Influence of dietary fatty acids on endocannabinoid andN-acylethanolamine levels in rat brain, liver and small intestine.

 

Abstract

Endocannabinoids and N-acylethanolamines are lipid mediators regulating a wide range of biological functions including food intake. We investigated short-term effects of feeding rats five different dietary fats (palm oil (PO), olive oil (OA), safflower oil (LA), fish oil (FO) and arachidonic acid (AA)) on tissue levels of 2-arachidonoylglycerol, anandamide, oleoylethanolamide, palmitoylethanolamide, stearoylethanolamide, linoleoylethanolamide, eicosapentaenoylethanolamide, docosahexaenoylethanolamide and tissue fatty acid composition. The LA-diet increased linoleoylethanolamide and linoleic acid in brain, jejunum and liver. The OA-diet increased brain levels of anandamide and oleoylethanolamide (not 2-arachidonoylglycerol) without changing tissue fatty acid composition. The same diet increased oleoylethanolamide in liver. All five dietary fats decreased oleoylethanolamide in jejunum without changing levels of anandamide, suggesting that dietary fat may have an orexigenic effect. The AA-diet increased anandamide and 2-arachidonoylglycerol in jejunum without effect on liver. The FO-diet decreased liver levels of all N-acylethanolamines (except eicosapentaenoylethanolamide and docosahexaenoylethanolamide) with similar changes in precursor lipids. The AA-diet and FO-diet had no effect on N-acylethanolamines, endocannabinoids or precursor lipids in brain. All N-acylethanolamines activated PPAR-alpha. In conclusion, short-term feeding of diets resembling human diets (Mediterranean diet high in monounsaturated fat, diet high in saturated fat, or diet high in polyunsaturated fat) can affect tissue levels of endocannabinoids and N-acylethanolamines.

 

So it does appear that you should choose your fat wisely.  Olive oil (OA) seems the wise choice.

 

PPARα and PEA (Palmitoylethanolamide)

Here are two papers that show that PPARα mediates the anti-inflammatory effects of PEA:-

The Nuclear Receptor Peroxisome Proliferator-Activated Receptor alpha Mediates the Anti-Inflammatory Actions of Palmitoylethanolamide

 

PEA attenuates inflammation in wild-type mice but has no effect in mice deficient in PPARα. The natural PPARα agonist oleoylethanolamide (OEA) and the synthetic PPARα agonists GW7647 and Wy-14643 mimic these effects in a PPARα dependent manner.

These findings indicate that PPARα  mediates the anti-inflammatory effects of PEA and suggest that this fatty-acid ethanolamide may serve, like its analog OEA, as an endogenous ligand of PPARα.

 

Palmitoylethanolamide Is a Disease-Modifying Agent in Peripheral Neuropathy: Pain Relief and Neuroprotection Share a PPAR-Alpha-Mediated Mechanism

 

Repeated treatments with PEA reduced the presence of oedema and macrophage infiltrate, and a significant higher myelin sheath, axonal diameter, and a number of fibers were observable. In PPAR-α null mice PEA treatment failed to induce pain relief as well as to rescue the peripheral nerve from inflammation and structural derangement. These results strongly suggest that PEA, via a PPAR-α-mediated mechanism, can directly intervene in the nervous tissue alterations responsible for pain, starting to prevent macrophage infiltration. 

The present results demonstrate the neuroprotective properties of PEA in a preclinical model of neuropathic pain. Antihyperalgesic and neuroprotective properties are related to the anti-inflammatory effect of PEA and its ability to prevent macrophage infiltration in the nerve. PPAR-α stimulation is the common pharmacodynamic code.

 

Ketogenic Diet & Autism 

Application of a ketogenic diet in children with autistic behavior: pilot study.

A pilot prospective follow-up study of the role of the ketogenic diet was carried out on 30 children, aged between 4 and 10 years, with autistic behavior. The diet was applied for 6 months, with continuous administration for 4 weeks, interrupted by 2-week diet-free intervals. Seven patients could not tolerate the diet, whereas five other patients adhered to the diet for 1 to 2 months and then discontinued it. Of the remaining group who adhered to the diet, 18 of 30 children (60%), improvement was recorded in several parameters and in accordance with the Childhood Autism Rating Scale. Significant improvement (> 12 units of the Childhood Autism Rating Scale) was recorded in two patients (pre-Scale: 35.00 +/- 1.41[mean +/- SD]), average improvement (> 8-12 units) in eight patients (pre-Scale: 41.88 +/- 3.14[mean +/- SD]), and minor improvement (2-8 units) in eight patients (pre-Scale: 45.25 +/- 2.76 [mean +/- SD]). Although these data are very preliminary, there is some evidence that the ketogenic diet may be used in autistic behavior as an additional or alternative therapy. 

Ketogenic gluten and casein free diet

 Martha Herbert again:-

We report the history of a child with autism and epilepsy who, after limited response to other interventions following her regression into autism, was placed on a gluten-free, casein-free diet, after which she showed marked improvement in autistic and medical symptoms. Subsequently, following pubertal onset of seizures and after failing to achieve full seizure control pharmacologically she was advanced to a ketogenic diet that was customized to continue the gluten-free, casein-free regimen. On this diet, while still continuing on anticonvulsants, she showed significant improvement in seizure activity. This gluten-free casein-free ketogenic diet used medium-chain triglycerides rather than butter and cream as its primary source of fat. Medium-chain triglycerides are known to be highly ketogenic, and this allowed the use of a lower ratio (1.5:1) leaving more calories available for consumption of vegetables with their associated health benefits. Secondary benefits included resolution of morbid obesity and improvement of cognitive and behavioral features. Over the course of several years following her initial diagnosis, the child’s Childhood Autism Rating Scale score decreased from 49 to 17, representing a change from severe autism to nonautistic, and her intelligence quotient increased 70 points. The initial electroencephalogram after seizure onset showed lengthy 3 Hz spike-wave activity; 14 months after the initiation of the diet the child was essentially seizure free and the electroencephalogram showed only occasional 1-1.5 second spike-wave activity without clinical accompaniments. 

PEA clinical trials and dosage in pain therapy

The following paper gives a great deal of information about the clinical use of PEA:-

New Targets in Pain, Non-Neuronal Cells, and the Role of Palmitoylethanolamide

Conclusion

While many kids with autism are given fish oil supplements, it is olive oil that I make a point of using extensively.  Today’s post indicates that olive oil is a potent PPARα activator and so another reason to use olive oil liberally.

PEA (Palmitoylethanolamide) itself almost looks too good to be true.  It does not interact with other drugs and it seems to have no side effects.  It has been trialed on many occasions, mainly as a pain therapy, rather than in its anti-inflammatory capacity.

PEA also seems to have potential as an adjunct anti-cancer therapy, rather like NAC also does.

It would be reasonable to expect a benefit from PEA in autism, at least in certain subtypes – high histamine and seizures - and particularly where a sibling has epilepsy, but no ASD.