“Autism treatments proposed by clinical studies and human genetics are complementary” & the NSAID Ponstan as a Novel Autism Therapy

Today’s post was not my idea at all, it was the author of one of the papers who has drawn my attention to the subject.

Genetic studies are complicated and are not the sort of thing I would have chosen to read, let alone write about, before starting this blog. 

The optimal time to initiate pharmacological 

intervention in Autism?

However, much of the complex subject matter has now already been covered, step by step, in earlier posts. Regular readers should not feel put off.

It is perhaps easier to think about ion channel dysfunctions, or channelopathies.  Some of the key genetic dysfunctions produce these channelopathies.  There are many posts in this blog about channelopathies, partly because many therapies already exist to treat them.

Then we have the complex signaling pathways which are often the subject of cancer research, but we have seen that certain ones like RAS and PTEN are key to conditions like some autism and some MR/ID.

So it is not a big leap therefore to consider the findings of a statistical reassessment of the existing genome-wide association studies (GWAS).  As is often the case in medical science, it is the acronyms/abbreviations, like GWAS, that make it look more complex than it really is.

If you only ever read one paper about the genetics of autism, I suggest you make it this one.

Fortunately, the conclusion from the genetic study really fits nicely with the clinical studies reviewed on this blog and even my own first-hand experience of investigating and treating my n=1 case of autism.

Knut, the Biometrician

It was Knut who left a brief comment on this blog and, after a little digging, I was very surprised how much a statistician/biometrician could figure out about autism, from re-analyzing the existing genome-wide association studies (GWAS).

I think the Simons Foundation could save themselves a decade or two by giving him a call.

The Research

For those wanting the science-lite version, there is a short article reviewing the research in lay terms:-

Biostatistics provides clues to understanding autism: an interview with Dr Knut M. Wittkowski

“Hence, modulation of ion channels in children at the age of about 12 months, when the first symptoms of autism can be detected, may prevent progression to the more severe end of the spectrum.” .

The actual research paper is here:-

You may find it heavy going and I have highlighted some key parts.

A novel computational biostatistics approach implies impaired dephosphorylationof growth factor receptors as associated with severity of autism

  

“Despite evidence for a likely involvement of de novo and environmental or epigenetic risk factors, including maternal antibodies or stress during pregnancy  and paternal age, we contend that coding variations contribute substantially to the heritability of ASD and can be successfully detected and assembled into connected pathways with GWAS—if the experimental design, the primary outcome, the statistical methods used, and the decision rules applied were better targeted toward the particulars of non-randomized studies of common diseases.”

The data comes from the Autism Genome Project (AGP), and there are two sets of data AGPI and AGPPII.

The third data set is for Childhood Absence Epilepsy (CAE)

What I would call Classic Autism, others call severe autism or autistic disorder; Knut calls it Strict Definition Autism (SDA).  HFA is high functioning autism, much of which is Asperger’s Syndrome.

“Study design We aimed at risk factors specific to strict definition autism (SDA) by comparing case subpopulations meeting the definition of SDA and milder cases with ASD (excluding SDA), for which we here use the term ‘highfunctioning autism’ (HFA). To reduce variance, we included only subjects of European ancestry genotyped on the more frequently used platform in either stage. In AGP II, we also excluded female cases because of confounding between chip platform and disease severity. The total number of subjects included (m: male/f: female) was 547/98 (SDA) and 358/68 (HFA) in AGP I and 375 (SDA) and 201 (HFA) in AGP II.

Overall, the results (see Supplementary Figure 1 for a Manhattan plot) are highly consistent with previously proposed aspects of the etiology of ASD. The clusters of genes implicated in both of the independent stages (Figure 2a/b) consistently overlap with our published CAE results (Figure 2c), confirming the involvement of ion channels (top right) and signaling downstream of RAS (bottom left), with two noticeable additional gene clusters in ASD. Both stages implicate several genes involved in deactivation of growth factor (GF) receptors (Figure 2a/b, top left) as ASD-specific risk factors and chloride (Cl − ) signaling, either through Ca2+ activated Cl− channels

Click to enlarge the figure 

A new term is PTPR (protein tyrosine phosphatases receptor), just to confuse us it is also called RPTP.

Receptor Protein Tyrosine Phosphatases in Nervous System Development

 

For example, the receptor protein tyrosine phosphatases gamma (PTPRG) and zeta (PTPRZ) are expressed primarily in the nervous system and mediate cell adhesion and signaling events during development.

In an earlier post I highlighted the numerous dysfunctions in growth factors (GF) in autism.  Knut is highlighting here the effect of PTPR on growth factors.  Later it is suggested that this cascade of GF dysfunctions could be halted, pharmacologically if it was identified very early.  But, as Courchesne from UC San Diego noted, by the time people have been identified as having autism, around three years old, the accelerated brain growth has already run its course.

You would need to intervene around one year old.

Broad evidence for involvement of PTPRs One of the most striking observations is the involvement of at least five PTPRs in ASD (Figure 2, 10 o’clock position). PTPRs (Table 1e) regulate GF signaling through reversible protein tyrosine dephosphorylation.72 PTPRT (90th/20th, 8.57) was implicated in ASD by a deletion73 (Table S2 AU018704) and a somatic mutation

It was my post pondering the reasons for the positive effect of potassium supplementation that drew Knut’s attention to this blog.  Now we move on to Knut’s ideas on potassium and chloride channels.

K+ and Cl− ion channels as drug targets

Aside from PTPRs (Figure 2, 10 o’clock) as a risk factor for protracted GF signaling, our results suggest a second functional cluster of genes, involved in Cl− transport and signaling, as specific to ASD (Table 1f). In AGP I, the CaCCs ANO4 and ANO7 scored 1st and 70th, respectively. In AGP II, the lysosome membrane H+ /Cl- exchange transporter CLCN7 scored 21st, followed by CAMK2A, which regulates ion channels, including anoctamins82 (55th), and LRRC7 (densin-180), which regulates CAMK2A83 (Figure 2a/b, 2 o’clock). The role of the anoctamins in pathophysiology is not well understood, except that CaCC activity in some neurons is predicted to be excitatory84 and to have a role in neuropathic pain or nerve regeneration. More recently, CaCCs have also been suggested as involved in ‘neurite (re)growth’. Finally, we compared the HFA and SDA cases as separate groups against all parental controls in the larger AGP I population. Overall, the level of significance is lower and the enrichment is less pronounced, especially for the SDA cases (Supplementary Figure 9), as expected when cases and some controls are related. For the HFA cases (Figure 4, and Supplementary Figure 8), however, a second anoctamin, ANO2, located on the other arm of chromosome 12, competes with ANO4 (Figure 1, left), for the most significant gene among the result. Hence, drugs targeting anoctamins might have broader benefits for the treatment of ASD than in preventing progression to more severe forms of autism. ANO2 and ANO6 are associated with panic disorder and major depressive disorder, respectively. ANO3, ANO4, ANO8 and ANO10, but not ANO1, are also expressed in neuronal tissue.86 As ‘druggable channels’, anoctamins ‘may be ideal pharmacological targets to control physiological function or to correct defects in diseases’.  Few drugs, however, target individual anoctamins or even exclusively CaCCs. Cl− channel blockers such as fenamates, for instance, may decrease neuronal excitability primarily by activating Ca2+-dependent outward rectifying K+ channels.

Here is a follow-up paper with consideration of the possible next steps.

Early Pharmacological Intervention in Autism: Wide-Locus GWAS Leading to Novel Treatment Options

Gene gene environment behavior development interaction at the core of autism:

Here, we combine a recent wide-locus approach with novel decision strategies fine-tuned to GWAS. With these methodological advances, mechanistically related clusters of genes and novel treatment options, including prevention of more severe forms of ASD, can now be suggested from studies of a few hundred narrowly defined cases only.

(Nonsyndromic) autism starts with largely unknown prenatal events (♂: age, ♀: virus/stress ...)

• Mutations in growth factor regulators (PTPRs) lead to neuronal overgrowth (brain sizes).

• Mutations in K+/Cl− channels cause Ca2+ mediated over excitation of neurons (“intense world”).

• Stressful environments (urbanization) contribute to epistatic interaction (increasing prevalence).

• This GGE interaction causes “migraine-like” experiences during the “stranger anxiety” period where children learn verbal/social skills, leading to behavioral maladaptation (“tune-out”).

• The lack of verbal/social stimuli causes “patches of disorganization” (Stoner 2014, NEJM) as a form of developmental maladaptation when underutilized brain areas are permanently “pruned”. The PTPRs point to a short window of opportunity (WoO) for pharmacological intervention:

• Treatment has to begin as early as possible, while neurons are still growing (12 months of age. Broad support for the proposed unifying etiology and the 2nd year of life as the WoO:

• Regression (“loss of language”) seen in some children >12 mos of age.

• “Patches of disorganization” in >2 yr old brains.

• Romanian orphans developed “quasi-autism” when placed into foster care at >24 mos of age. 

• Hearing impairment leading to intellectual disability when diagnosed >24 mos of age.

 A rational drug target: treating either of two epistatic risk factors suffices:

• Blocking growth factors (Gleevac, ...) is unacceptable in children merely at risk of ASD.

• Ion channel modulators have been used in small children for arthritis and seizures.

Here is a response to Knut’s first paper from a professor at the UCLA medical school who suggests the combination of the specific NSAID and bumetanide. 

The professor would better understand the mechanism of action of bumetanide in autism if he read Ben Ari’s research more thoroughly, or even this blog.

  

Autism treatments proposed byclinical studies and human genetics are complementary

  

The article by Wittkowski et al.¹ reports results of human genetic studies that suggest that a nonsteroidal anti-inflammatory drug (NSAID) given for a few months from the time of the first symptoms might help some children who are at risk of developing more severe forms of atrial septal defect.

While the authors mention the recent article by Lemonnier et al.,² which reported that a clinical study of the diuretic Bumetanide was partially effective in children with milder forms of autism, they seem to have overlooked that these two treatments may well be complementary, leading to sequential interventions, each targeting specific risks related to well-defined stages in the development of brain and social interactions.

Since abnormal brain development in autistic disorder goes through different stages from infancy to childhood, targeting different developmental stages with different treatment interventions may well be necessary to foster continued normalization of brain growth.

Bumetanide is known to block inward chloride transporters, yet the relation of this mechanism to the etiology of autism is unknown. Wittkowski et al. identified mutations in calcium-activated (outward) chloride channels as associated with autistic disorder, suggesting loss-of-function mutations in anoctamins as one of the risk factors for autism. This provides a testable hypothesis for the mechanism by which Bumetanide alleviates symptoms of autism. For example, mouse models could test whether Bumetanide ameliorates a stress-induced phenotype caused by a knockout/down in ANO2 and/or ANO4.

A second cluster of genes identified receptor protein tyrosine phosphatases, which downregulate growth factors. These findings support the notion that successful treatment should start as early as possible,³ while neuronal development still takes place.

The rationale for combining these two treatments rests on the fact that Bumetanide is contraindicated in infancy because it is known to interfere with neuronal development when used long term. In contrast, the NSAID proposed in the second study has been given for decades to children with juvenile idiopathic arthritis from 6 months of age on, with no adverse effects on brain development. It is known to modulate chloride channels (see above) as well as potassium channels.⁴

In conclusion, I wish to extend their hypothesis based on the synergy of the two treatment approaches: (1) early treatment with NSAID can reduce early maladaptive behaviors that cause abnormal pruning of neurons in the cortical areas; (2) these children could subsequently benefit from Bumetanide, which would compensate for the primary ion channel defect, but could not reverse the secondary effect of abnormal pruning.

This hypothesis allows for a novel two-way interaction between behavior and molecular events. Traditionally, one assumes that molecular events determine behavior. The new hypothesis, based on human genetics, also allows for symptoms (such as the absence of social interactions, delayed speech onset and language development) during certain sensitive periods to change molecular events (pruning of neurons in areas required for normal development).

Therapeutic implications from the genetic analysis

Some of the therapies that Knut is proposing, based on the genetic analysis, have already been reviewed in this blog.  Some have not.  A few therapeutic ideas in this blog actually target genes Knut has identified, but not highlighted a therapy.

I will just review the drugs and genes that the above study highlights.

Benzodiazepines

Low dose clonazepam fits in this category.  We have the work of Professor Catterall to support its use.  At higher doses, benzodiazepines have different effects but use is associated with various troubling side effects.

Bumetanide

Bumetanide is at the core of my suggested therapy for classic autism or what Knut calls SDA (strict definition autism).  We have Ben-Ari to thank for this

Fenamates (ANO 2/4/7 & KCNMA1)

Here Knut is trying to target the ion channels expressed by the genes ANO 2/4/7 & KCNMA1. 

·        ANO 2/4/7 are calcium activated chloride channels. (CACCs)

·        KCNMA1 is a calcium activated potassium channel.  KCNMA1 encodes the ion channel K_Ca1.1, otherwise known as BK (big potassium).  This was the subject of post that I never got round to publishing.

  

Fenamates are an important group of clinically used non-steroidal anti-inflammatory drugs (NSAIDs), but they have other effects beyond being anti-inflammatory.  They act as CaCC inhibitors and also stimulate BKCa channel activity.

  

Fenamates stimulate BKCachannel osteoblast-like MG-63 cells activity in the human.

 “The fenamates can stimulate BKCa channel activity in a manner that seems to be independent of the action of these drugs on the prostaglandin pathway”

Molecular and functional significance of Ca2+-activated Cl− channels in pulmonary arterial smooth muscle

“Of this “first generation” of CaCC inhibitors, NFA (a fenamate called niflumic acid)  is the most potent blocker of these channels and the compound most frequently used to investigate the physiological role of CaCCs”

Choice of Fenamate

There are several fenamate-type NSAIDs, but one is a very well used generic drug, Mefenamic acid known as Ponstan, Ponalar, Ponstyl, Ponstel and other generic names.  It is even available as a syrup for children.

 It is not available in all countries.

Gabapentin

Gabapentin is used primarily to treat seizures and neuropathic pain. It is also commonly prescribed for many off-label uses, such as treatment of anxiety disorders, insomnia, and bipolar disorder.

Some people with autism are prescribed Gabapentin.  Some people suffer side effects and others do not.

If you have a dysfunction of voltage operated calcium channels, Gabapentin should help.

Memantine

This is all about modifying NMDA receptors.  Memantine is but one method.

http://epiphanyasd.blogspot.rs/2015/06/altered-homeostasis-in-autism-cl-k-ca2.html

Minocycline

Minocycline is an antibiotic with several little known extra properties.  In autism, we looked at its ability to reduce microglial activation and so improve autism.  A clinical trial showed that it did not help autism.

Minocycline also affects MMP-9.  MMP-9 is an enzyme found to be associated with numerous pathological processes, including cancer, immunologic and cardiovascular diseases.

High MMP-9 activity levels in fragile X syndrome are lowered by minocycline.

 “ The results of this study suggest that, in humans, activity levels of MMP-9 are lowered by minocycline and that, in some cases, changes in MMP-9 activity are positively associated with improvement based on clinical measures.”

So if you are treating a case of Fragile-X, or partial "Fragile-X-like" autism, better take note.

Rapamycin

Rapamycin and mTOR was the subject of the following post:

mTOR – Indirect inhibition, the Holy Grail for Life Extension and Perhaps Some Autism

Both too much and too little mTOR can occur in autism.

Conclusion

My conclusion is probably different to yours.

For me, it seems that all the pieces really are fitting together and so this blog on the cause and treatment of classic autism will eventually cover the current scientific knowledge, in its entirety.  No complex areas are off limits, because in the end they are not as complex as they seem, when you lift the veil of jargon and acronyms.

From the all-important therapeutic perspective, new insights from today’s post are:-

·        Those with a dysfunction of voltage operated calcium channels might want to give Gabapentin (Neurontin) a try.

·        The fenamate-type NSAID mefenamic acid,  widely known as Ponstan, really should be tested, either at home, or in a clinical trial.

This statistical analysis is based on “all autism”, so any one person would be highly unlikely to have all the mentioned dysfunctions.  These are the most common genetic dysfunctions and many can both hypo and hyper, as in the case of NMDA dysfunctions and indeed mTOR. 

In Knut’s chart, I would add a green line pointing to RAS and PTEN with the word Atorvastatin.  Baclofen would point to the growth factors.  Verapamil would point in multiple places.

The motto of University of Tübingen, where Knut originally comes from, is Attempto !  The Latin for "I dare".

This might be a useful motto for readers of this blog, and also a good tittle for a book on treating autism.

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.