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  The problem is that being “non-selective” they can have nasty side effects, leading to Pioglitazone being withdrawn in some markets.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.