Tangeretin vs Ibuprofen, as PPARγ agonists for Autism. What about PPARγ for Epilepsy?

Summary of the therapeutic actions of PPARγ in diabetic nephropathy

From:  Peroxisome proliferator-activated receptors and renal diseases

I did write an earlier post about NSAIDs (Nonsteroidal anti-inflammatory drugs) like Ibuprofen, which I expected to have no effect on autism.

  

Cytokines from the Eruption of Permanent Teeth causing Flare-ups in Autism

However, to my surprise, I found that certain types of autism “flare-up” do respond very well to Ibuprofen.  Based on the comments I received, it seems that many other people have the same experience.

NSAIDs work by inhibiting something called COX-2, but they also inhibit COX-1.  The side effects of NSAIDs come from their unwanted effect on COX-1.

NSAIDs are both pain relievers and, in high doses, anti-inflammatory.  Long term use of NSAIDs is not recommended, due to their (COX-1 related) side effects.

Observational Study

All I can say is that in Monty, aged 11 with ASD, and with his last four milk teeth wobbly but refusing to come out, the increase in the cytokine IL-6 that the body uses to signal the roots of the milk teeth to dissolve seems to account for some of his flare-ups.  I do not think it is anything to do with pain.

This is fully treatable with occasional use of Ibuprofen and then “extreme behaviours” are entirely avoided.

Sytrinol (Tangeretin) vs Ibuprofen

Since Ibuprofen, when given long term, has known problems, I looked for something else.

On my list of things to investigate has been “selective PPAR gamma agonists”, which is quite a mouthful.  The full name is even longer.  The nuclear transcription factor peroxisome proliferator activated receptor gamma (PPARy) regulates genes in anti-inflammatory, anti-oxidant and mitochondrial pathways.  All three of these pathways are affected in autism.

We already know that non-selective PPARy agonists, like pioglitazone, developed to treat type 2 diabetes, can be used to treat autism.  The problem is that being “non-selective” they can have nasty side effects, leading to Pioglitazone being withdrawn in some markets.

  

Effect of pioglitazone treatment on behavioral symptoms in autistic children

  

While looking for a “better” PPARγ agonist, I came across the flavonoid Tangeretin, which is commercially available in a formulation called Sytrinol.

An effective PPARγ agonist would have many measurable effects.  The literature is full of natural substances that may, to some degree, be PPARγ agonists, but you might have to consume them by the bucket load to have any effect.

The attraction of Sytrinol is that it does have a measurable effect in realistic doses.  Sytrinol is sold as a product to lower cholesterol.  Tangeretin is a PPARγ agonist and you would expect a PPARγ agonist to improve insulin sensitivity and also reduce cholesterol. There are clinical trials showing this effect of Sytrinol.

Sytrinol (Tangeretin) Experiment

The most measurable effect of using Sytrinol for six weeks is that we no longer need any Ibuprofen.  It is measurable, since I am no longer needing to buy Ibuprofen any more.

About three days a week Monty’s assistant would need to give him Ibuprofen at school.  This all stopped, even though occasional complaints about wobbly teeth continue.

Nobody markets  Sytrinol (Tangeretin) as a painkiller.

Note:- Sytrinol capsules contain a blend of 270mg PMF (polymethoxylated flavones, consisting largely of tangeretin and nobiletin) + 30mg tocotrienols. Nobiletin is closely related to tangeretin, while tocotrienols are members of the vitamin E family.  All three should be good for you.

Tangeretin and Ibuprofen are both PPARγ agonists

The explanation for all this may indeed be that Tangeretin and Ibuprofen are both PPARγ agonists.  Inhibiting COX-2 may have been irrelevant.

Peroxisome Proliferator-activated Receptors α and γ Are Activated by Indomethacin andOther Non-steroidal Anti-inflammatory Drugs

  

It may be that by regulating the anti-inflammatory genes, via  PPARγ, the Sytrinol has countered the “flare-up” caused by the spike in IL-6.

Anyway, in the earlier post we did see that research shows that dissolving milk teeth is signalled via increased IL-6 and we do know that increased IL-6, caused by allergies, can trigger worsening autism. 

So it does make sense, at least to me.

Regular uses of Sytrinol/Tangeretin looks a much safer bet than any NSAID.

If anyone tries it, particularly those who regularly use NSAIDs, let us all know.

PPARγ and Epilepsy

If you Google PPARγ and autism you will soon end up back at this blog.

For any sceptics, better to Google PPARγ and Epilepsy.  Epilepsy looks to be the natural progression of un-treated classic autism.  If this progression can be prevented, that should be big news.

Prevention is always better than a cure.  All kinds of conditions appear to be preventable, or at least you can minimize their incidence.  

Here are just the ones I have stumbled upon while researching autism:- Asthma  (Ketotifen), type 2 diabetes (Verapamil), prostate cancer (Lycopene) and many types of cancer (Sulforaphane).

There are of course types of epilepsy unconnected to autism, but epilepsy, seizures and electrical activity are highly comorbid with classic autism

PPARgamma, Epilepsy and Therapeutics

Abstract

Approximately 30% of people with epilepsy do not achieve adequate seizure control with current anti-seizure drugs (ASDs). This medically refractory population has severe seizure phenotypes and is at greatest risk of sudden unexpected death in epilepsy (SUDEP). Therefore, there is an urgent need for detailed studies identifying new therapeutic targets with potential disease-modifying outcomes. Studies indicate that the refractory epileptic brain is chronically inflamed with persistent mitochondrial dysfunction. Recent evidence supports the hypothesis that both factors can increase the excitability of epileptic networks and exacerbate seizure frequency and severity in a pathological cycle. Thus, effective disease-modifying interventions will most likely interrupt this loop. The nuclear transcription factor peroxisome proliferator activated receptor gamma (PPARy) regulates genes in anti-inflammatory, anti-oxidant and mitochondrial pathways. Preliminary experiments in chronically epileptic mice indicate impressive anti-seizure efficacy. We hypothesize that (i) activation of brain PPARy in epileptic animals will have disease modifying effects that provide long-term benefits, and (ii) determining PPARy mechanisms will reveal additional therapeutic targets. Using a mouse model of developmental epilepsy, we propose to (1) elucidate the cellular, synaptic and network mechanisms by which PPARy activation restores normal excitability;(2) demonstrate the significant contribution of mitochondrial health in pathologic synaptic activity in epileptic brain;(3) demonstrate inflammatory regulation of PPARy in epileptic brain;and (4) determine whether PPARy activation extends the lifespan of severely epileptic animals. The proposed studies, spanning in vivo and in vitro systems using a combination of techniques in molecular biology, electrophysiology, microscopy, bioenergetics and pharmacology, will provide insight into the interplay of seizures, mitochondria, inflammation and homeostatic mechanisms. The results will have tremendous, immediate translational potential because PPARy agonists are currently used for clinical treatment of Type II Diabetes. PPARy is under investigation as treatment for a wide variety of other neurological diseases with cell death and inflammation as common denominators;therefore, the results of this proposal will have a broad impact.

Public Health Relevance

Approximately 30% of people with epilepsy do not achieve adequate seizure control with current anti-seizure drugs (ASDs). This medically refractory population has severe seizure phenotypes and is at greatest risk of sudden unexpected death in epilepsy (SUDEP). Therefore, there is an urgent need for detailed studies identifying new therapeutic targets with potential disease- modifying outcomes.

Anticonvulsant potential of the peroxisome proliferator-activated receptor γ agonist pioglitazone in pentylenetetrazole-induced acute seizures and kindling in mice.

Activation of cerebral peroxisome proliferator-activated receptors gamma exerts neuroprotection by inhibiting oxidative stress following pilocarpine-induced status epilepticus.

Abstract

Status epilepticus (SE) can cause severe neuronal loss and oxidative damage. As peroxisome proliferator-activated receptor gamma (PPARgamma) agonists possess antioxidative activity, we hypothesize that rosiglitazone, a PPARgamma agonist, might protect the central nervous system (CNS) from oxidative damage in epileptic rats. Using a lithium-pilocarpine-induced SE model, we found that rosiglitazone significantly reduced hippocampal neuronal loss 1 week after SE, potently suppressed the production of reactive oxygen species (ROS) and lipid peroxidation. We also found that treatment with rosiglitazone enhanced antioxidative activity of superoxide dismutase (SOD) and glutathione hormone (GSH), together with decreased expression of heme oxygenase-1 (HO-1) in the hippocampus. The above effects of rosiglitazone can be blocked by co-treatment with PPARgamma antagonist T0070907. The current data suggest that rosiglitazone exerts a neuroprotective effect on oxidative stress-mediated neuronal damage followed by SE. Our data also support the idea that PPARgamma agonist might be a potential neuroprotective agent for epilepsy.

Possible involvement of PPAR-gamma receptor and nitric oxide pathway in theanticonvulsant effect of acute pioglitazone on pentylenetetrazole-induced seizuresin mice

CONCLUSION:

The present study demonstrates the anticonvulsant effect of acute pioglitazone on PTZ-induced seizures in mice. This effect was reversed by PPAR-γ antagonist, and both a specific- and a non-specific nitric oxide synthase inhibitors, and augmented by nitric oxide precursor, L-arginine. These results support that the anticonvulsant effect of pioglitazone is mediated through PPAR-γ receptor-mediated pathway and also, at least partly, through the nitric oxide pathway.

Note that elsewhere in this blog I have already highlighted that PPAR alpha agonists also seem to have an effect against epilepsy.  For example in this research:-

PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings.

          

I was originally interested in PPAR-alpha, because of its role in regulating mast cells.  It seems that PPARγ also affects mast cells.

Activation of PPARγ  restores mast cell numbers and reactivity in all oxan-diabetic rats by reducing the systemic glucocorticoid levels

  

PPARγ modulators – drugs vs neutraceuticals vs functional food

It does seem that many people with inflammatory diseases, epilepsy, autism and even people who are obese, might greatly benefit from selective PPARγ agonists.

The choice would be between drugs, “nutraceuticals” and functional (good) food.

The drugs have not yet arrived that are safe and selective.  The current Thiazolidinedione (TZD) class of drugs TZDs tend to increase fat mass as well as improving insulin sensitivity and glucose tolerance in both lab animals and humans.

PPARγ as a metabolic regulator: insights from genomics and Pharmacology

Since its identification in the early 1990s, peroxisome-proliferator-activated receptor γ (PPARγ), a nuclear hormone receptor, has attracted tremendous scientific and clinical interest. The role of PPARγ in macronutrient metabolism has received particular attention, for three main reasons: first, it is the target of the thiazolidinediones (TZDs), a novel class of insulin sensitisers widely used to treat type 2 diabetes; second, it plays a central role in adipogenesis; and third, it appears to be primarily involved in regulating lipid metabolism with predominantly secondary effects on carbohydrate metabolism, a notion in keeping with the currently in vogue ‘lipocentric’ view of diabetes. This review summarises in vitro studies suggesting that PPARγ is a master regulator of adipogenesis, and then considers in vivo findings from use of PPARγ agonists, knockout studies in mice and analysis of human PPARγ mutations/polymorphisms.

As usual there are numerous “natural substances” that may also modulate PPAR-γ

Modulation of PPAR-γ by Nutraceutics as Complementary Treatment for Obesity-Related Disorders and Inflammatory Diseases

A direct correlation between adequate nutrition and health is a universally accepted truth. The Western lifestyle, with a high intake of simple sugars, saturated fat, and physical inactivity, promotes pathologic conditions. The main adverse consequences range from cardiovascular disease, type 2 diabetes, and metabolic syndrome to several cancers. Dietary components influence tissue homeostasis in multiple ways and many different functional foods have been associated with various health benefits when consumed. Natural products are an important and promising source for drug discovery. Many anti-inflammatory natural products activate peroxisome proliferator-activated receptors (PPAR); therefore, compounds that activate or modulate PPAR-gamma (PPAR-γ) may help to fight all of these pathological conditions. Consequently, the discovery and optimization of novel PPAR-γ agonists and modulators that would display reduced side effects is of great interest. In this paper, we present some of the main naturally derived products studied that exert an influence on metabolism through the activation or modulation of PPAR-γ, and we also present PPAR-γ-related diseases that can be complementarily treated with nutraceutics from functional foods.

Conclusion

If you are one of those people successfully using NSAIDs, like Ibuprofen, to reduce autistic behaviors, you might well be in the group that would benefit from Sytrinol/Tangeretin.

If NSAIDs never help resolve your autism flare-ups, Sytrinol/Tangeretin may not help either.

Tangeretin does appear to have other effects, beyond not needing to use Ibuprofen.  It was found to be a potent antagonist at P2Y2 receptors.

Suramin is another potent P2Y2 antagonist and Suramin is showing a lot of promise in Robert Naviaux’s autism studies at the University of California at San Diego.  Suramin is not viewed as safe for regular use in humans.

Statins for Cancer and Autism? Another case for PTEN?

When I first started this blog and my investigation into the biology of autism, I did shy away from the more complex areas like genetics.  I assumed that this would be best left to the “experts” and be beyond the powers of those without fancy laboratory tools.

My literature review took me early on to oxidative stress and then neuroinflammation.  I deduced that in the case of neuroinflammation, it might be possible to control inflammatory cytokines using statins.  I also noted the use of statins in TBI (Traumatic Brain Injury). I thought it would be harmless to do a quick trial, not really expecting anything to happen; but it did, and from the very first dose.

The literature is full of references to lipid dysfunction in autism and one large sub-group in autism is known to have high cholesterol.  Cholesterol and inflammation are now known to go hand in hand.  When inflammation is present, the body can react by laying down a protective layer of cholesterol.  The problem is that too much cholesterol is not good for you either.  The real culprit is not the cholesterol, it is the inflammation.

If you are in the high cholesterol autism group, a cholesterol lowering drug that is also anti-inflammatory may be “just what the doctor ordered”.

Be warned that another subgroup in autism has very low cholesterol.  In a study at the Kennedy Krieger Institute, 19% of children had extremely low cholesterol, meaning lower than 99% of typical children.

Autism: New Study Discovers Statistically Significant Link Between Abnormally Low Cholesterol Levels And Autism Spectrum Disorders

There is a rare condition, leading to autism called Smith-Lemli Opitz syndrome (SLOS).  SLOS is caused by a mutation in an enzyme involved in cholesterol synthesis; the resulting biochemical characteristics may be predictable. Most patients have lowered plasma cholesterol levels.

Since cholesterol testing is cheap and widely available, you can easily determine which group you are in.

This post is for the high cholesterol cohort.

Note well how meaningless a figure for the "average cholesterol level" in autism would be. In the autism literature they frequently take the mean average for all data, thus missing the point. 

Why Statins for Autism?

My initial logic was that since inflammatory markers are often elevated in autism and that oxidative stress and inflammation are self-reinforcing, it would be logical to find an effective anti-inflammatory agent.  Steroids might fit the bill, but they cause plenty of side effects in long term use; their short term use in autism can be remarkably effective.  So I looked further, and having screened the literature, ended up convincing myself of the potential of statins.  Read all about cytokine storms in the old posts, if you are interested.

I choose  Atorvastatin (also known as Lipitor or Sortis), since it freely crosses the blood brain barrier (BBB) and is safely used my tens of millions of people around the world.

It worked.

Explaining Statin Therapy to others.

The most important thing is to have a therapy that works;  but then you have to explain it to others.

I was recently explaining it again to a doctor relative, who was asking how I could be sure it works.  I explained that every time I stop using it, within a day behaviour changes in the same predictable way.  It is as if people with autism have an inhibitory barrier; there are things they can do, want to do, but something is blocking them from doing them.

Examples are numerous.  Speech being one.  Plenty of kids with autism are non-verbal, everything is physically functional, yet they do not talk, even when they want to communicate.

At the age Monty, now aged 11 with ASD, tried the statin he was relatively verbal.  The immediate change in him was that he suddenly started to play the piano, by himself.  Odd it may sound.

In his earlier years he would often get “stuck”.  He would be upstairs and unable to come downstairs, somebody had to go up and get him.

When I now stop the statin, he will again get “stuck”.  He will stand in the kitchen and want to leave and just say “go that way”, but not move.  You have to take his hand, so that he can “go that way”.

A Better Explanation?

Now I have another explanation of why statins may be effective in one large sub-group of autism.

Statins up-regulate a known key dysfunctional autism gene, and protein, called PTEN.  I mentioned PTEN in a previous post, since one chemical released by eating broccoli also up-regulates PTEN.

Science has already shown that things that down-regulate PTEN (like seizures) make autism worse.

The full science behind PTEN will come in a later post.

Statins and Cancer

Regular readers will recall that PTEN is also a tumor suppressor gene and is therefore a target for cancer research.

Thinking the way I do, I know that statins increase PTEN and that this should slow cancer growth.  Hundreds of millions of people take statins and many millions get cancer, so what about people on statins getting cancer?

A quick check on google and there we have studies showing that people on statins get less cancer and that in common cancers like that of the prostate, the outcome is better when statins are taken.

Now this is not a cancer blog, but you do not have to dig very deep to uncover a wealth of supporting evidence.

Statins and Prostate Cancer: Novel, Encouraging Study

Postoperative statin use and risk of biochemical recurrence following radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database

Conclusion

In this retrospective cohort of men undergoing RP, post-RP statin use was significantly associated with reduced risk of BCR. Whether the association between post-RP statin use and BCR differs by race requires further study. Given these findings, coupled with other studies suggesting that statins may reduce risk of advanced prostate cancer, randomized controlled trials are warranted to formally test the hypothesis that statins slow prostate cancer progression.

Statins and prostate cancer (Harvard Medical School)

Statins could reduce the risk of breast cancer

Statins could reducethe risk of pancreatic cancer

Statin use and risk of liver cancer: an update meta-analysis

 Conclusions This meta-analysis suggests that statin is associated with a significant risk reduction of liver cancer when taken daily for cardiovascular event prevention. However, this preventive effect might be overestimated due to the exposure period, the indication and contraindication of statins and other confounders. Statins might be considered as an adjuvant in the treatment of liver cancer.

Statins and PTEN

I am no cancer expert, but I can read the literature and the evidence is pretty compelling to me.  It is not enough, however, for doctors to prescribe statins to avoid cancer.  They are so busy prescribing statins to over 50s for other reasons, it does not really matter.

We came across PPAR previously.  PPAR gamma is a pathway to treat type 2 diabetes and the old type 2 diabetes drug Pioglitazone has shown promise in an autism study.

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

 Effect of pioglitazone treatment on behavioral symptoms in autistic children

At that time I was more interested in PPAR-alpha, due to its role in mast cell stabilization.

It is via PPAR-gamma, that statins up regulate PTEN.

You do not want to overdo it, because at very high doses too much PPAR gamma protein will be produced and you risk causing type 2 diabetes.

Low doses of statins are trouble free for most people, but high doses are associated with increased risk of diabetes and all kinds of aches and pains.

The statin effect in autism does not increase with higher doses, only a small dose is required.

Regulation of the PTEN promoter by statins and SREBP.

Abstract

Germline mutations in the tumor-suppressor gene PTEN predispose to heritable breast cancer. The transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma) has also been implicated as a tumor suppressor pertinent to a range of neoplasias, including breast cancer. We previously demonstrated that lovastatin may signal through PPARgamma and directly upregulate PTEN expression at the transcriptional level. In our current study, we show that simvastatin, pravastatin and fluvastatin can induce PTEN expression in a dose-dependent manner. This resulted from an increase in PTEN mRNA indicating transcriptional upregulation. In addition, we observed, for the first time, that upregulation of sterol response element-binding protein (SREBP), known to induce PPARgamma expression, can increase PTEN expression. Using reporter assays, we observed that both the statins and SREBP could specifically induce PPARgamma-mediated transcription. However, the statins do not appear to signal through SREBP. Furthermore, our results indicate that SREBP utilizes PPARgamma's transcriptional activity to induce PTEN transcription, whereas the statins signal through PPARgamma's protein activity to upregulate PTEN expression. Overall, our observations suggest that statins signal through another transcription factor, in a PPARgamma-dependent manner, which in turn induces PTEN transcription. We, therefore, studied the full-length PTEN promoter through serial deletion reporter assays and electromobility shift assays and identified a region between -854 and -791 that binds an as-yet-unidentified transcription factor, through which the statins induce PTEN expression. Since PTEN is constitutively active, our data indicate it may be worthwhile to examine statin and SREBP stimulation as mechanisms to increase PTEN expression for therapeutic and preventative strategies in cancer, diabetes mellitus and cardiovascular disease

PTEN dysfunction in Cancer and Autism

I will cover this point in more detail in the post on PTEN, but note that the PTEN gene dysfunctions found in 10% of people with autism are generally different to the ones found in cancer.  We also have the difference between whether the PTEN gene is mutated or there is PTEN loss.

There should be two identical copies of the PTEN gene. When one copy is mutated, the protein it produces was found to inhibit the protein produced by the good copy. In other cases, one copy of the PTEN gene is OK, but the other got deleted.   This turned out to be better than having one mutant version.

Different mutations in PTEN are linked to different outcomes.  The known autism mutations are called H118P, H93R and H123Q.  If you have a C124S mutation you would be at risk of something called thyroid follicular carcinoma and not autism.

It is all very complicated and I have to say some conclusions in the research are contradictory.

But it is reported that about 10% of people with autism have an identifiable PTEN mutation.  I am more interested in whether PTEN is an interesting protein in the other 90%.

We saw in the fragile X research that even though this affects only 1% of cases with autism, some experimental therapies for fragile X worked on people with autism, but without fragile X.  At the time I thought that very odd.

My assumption is that PTEN is interesting for more than the 10%.

Conclusion

So there are now 2 plausible reasons why statin therapy may be effective in people with classic autism and elevated cholesterol:-

·        Reduction in inflammatory cytokines 

·        Up-regulation of PTEN

Maybe it is both.

It may be that in people with autism and low cholesterol, and so not suited to statins, they may also have low levels of PTEN.

We saw in a recent post that when you eat fresh broccoli in addition to Sulforaphane, you also produce Indole-3-carbinol (I3C).   I3C also up-regulates  PTEN.

Using Peter logic, if statins have an immediate effect then quite likely so would I3C.

Whatever Next?

Well, for those few of you who have discovered the “magical” beneficial effects of mast cell stabilizers, like Verapamil and Cromolyn Sodium, on both autistic behaviours and severe allergies, here is a preview of what is coming next:-

PPAR-gamma modulates allergic inflammation through up-regulation of PTEN

Recent studies have indicated that PPAR-gamma plays an important role in anti-inflammatory responses and that PPAR-gamma signaling is associated with regulation of PTEN expression. It is known that up-regulation of PTEN expression reduces asthmatic pathogenesis.

These findings suggest that PPAR-gamma uses PTEN to modulate asthmatic responses The signaling mechanism by which stimulation of PPAR-gamma with the agonists regulates PTEN expression as well as Akt phosphorylation remains to be lucidated. However, our results agree with the observation that the anti-inflammatory action of PPAR-gamma agonists is mediated via up-regulation of PTEN.

In other words, increasing PTEN minimizes allergies.  Perhaps, via feedback loops, increasing allergies reduces PTEN?

Seizures also reduce PTEN.

Reduced PTEN leads to increased autistic behaviours.

Not surprisingly we will come back, yet again, to mast cells.

For us, it really does seem that PTEN is a key piece in the puzzle;  but a puzzle with a solution.

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.