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Wednesday, 6 May 2015

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




Summary of the therapeutic actions of PPARγ in diabetic nephropathy


I did write an earlier post about NSAIDs (Nonsteroidal anti-inflammatory drugs) like Ibuprofen, which I expected to have no effect on 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  The problem is that being “non-selective” they can have nasty side effects, leading to Pioglitazone being withdrawn in some markets.
  

  
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.


  
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




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.




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.




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:-


          

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


  


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.




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




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.








21 comments:

  1. Dear Peter,

    This PPAR-gamma post is terrific. I was at IMFAR last week and as you might have guessed most of the scientists have a lot less insight than you do.

    On PPAR-gamma agonists and autism there are a couple more connections that have popped up:

    1) Cntnap2 gene defect which is one genetic cause of autism can be ameliorated with biochanin A in Zebrafish: https://imfar.confex.com/imfar/2015/webprogram/Paper20670.html Biochanin A is a PPAR-gamma agonist.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4212005/

    2) Luteolin formulations have shown efficacy in autism in some open label trials: http://europepmc.org/abstract/med/22697063, http://www.clinicaltherapeutics.com/article/S0149-2918(13)00178-1/abstract Luteolin is a partial PPAR-gamma agonist. http://www.ncbi.nlm.nih.gov/pubmed/22391103.

    3) IGF-1 seems to show some efficacy in Phellan McDermid syndrome: http://www.molecularautism.com/content/5/1/54. An herb that upregulates IGF-1 also upregulates PPAR-gamma. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117754/ Does IGF-1 also upregulate PPAR-gamma?

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    1. Thanks Seth.

      On IGF-1, a reader just raised the use of colostrum, for different reasons.

      According to Wikipedia ...

      "Supplementation with colostrum, which is rich in IGF-1, can be a useful part of a weight reduction program.Although IGF-1 is not absorbed intact by the body, it does stimulate the production of IGF-1 when taken as a supplement."

      This is interesting because the growth factor IGF-1 is actually being researched used as an autism therapy, but you have to inject it every day.

      Baclofen also stimulates the growth hormone-IGF-I axis.

      It does seem that all these interesting pathways are interconnected. It looks like the growth hormone dsyfunction can be traced back to GABAb.

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    2. Seth

      A problem is always bio-availability. Theoharides uses Luteolin (plus Rutin and Quercetin) in his Neuroprotek formulation. I think it is too weak. It is also very expensive.

      Sytrinol is much cheaper and seems to be potent.

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    3. Which brand of Sytrinol are you using?
      Also, I've been injecting my son with GHRH that claims to raise the IGF-1 levels daily, for almost two months. I just stopped it because you warned me about too much of GH.
      I am confused, your article says IGF-1 is good, how come it is bad for my son?
      I did not see much improvement on those injections. But my son had a "marble-colored" skin since birth and those spots seemed to get lighter. I think those spots have something to do with growth hormones.

      Thank you,

      Polly

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    4. Polly, there is only one producer of sytrinol. Companies buy it and sell it under their name, so just buy the cheapest one.

      People with hypoactive growth hormone signaling could well benefit from an increase provided by IGF-1. But people with already high levels of growth hormone, like those born very large, might very likely not respond to more IGF-1 or respond badly. You can very cheaply measure IGF-1 via a blood test. Many adults who used GHRH products developed health problems later in life. I do not think people should experiment with GHRH at home. I know one person who did use it years ago and now needs new knee and hip joints because of strange bone growths.

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  2. This comment has been removed by a blog administrator.

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  3. Sytrinol has been the best addition for us so far. It has compounded the social and cognitive effects of bumetanide plus added others. All SIB and raging has pretty much subsided over the last twelve days. My daughter is consistently happy, as I have not seen her in a long time. Is much more demonstratively affectionate, especially with her father. More social. She is willing to try novel activities. At a casual eating place with good, loud music, she danced a bit with my husband, even getting up on top of a bench by herself to dance! A little while later, she danced by herself near a crowd of people. I was blown away. She is also imitating readily now. Her motor skills need a lot of practicing, but I was surprised by the way she imitates, watching the other person closely and then looking at herself while trying to replicate the movement, then looking at the other person again, back and forth. Very natural. She is helping more with small chores, like bringing us things, putting away the recycling etc.

    The effects are cumulative. The first couple of weeks, it stopped raging and sib, I did not see anything else. Gradually, more improvements began showing up. I am using the Swanson's brand, twice a day.

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  4. Hi Peter,

    I've communicated with naviaux, and the suramin trial was a success. He now considers suramin safe for human use at low doses he's using. A paper can be expected in the autumn. A new human trial is being planned too.

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    1. That is great, Naviaux is a clever guy.

      For the benefit of others, Naviaux was trialing a single dose of suramin (20 mg/kg suramin in 50 ml of saline) by intravenous infusion.

      https://clinicaltrials.gov/ct2/show/NCT02508259?term=suramin&rank=6

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    2. Hi,

      Can you share how you managed to get in touch with Naviaux. I tried his number twice, and did not hear anything back. This was early last year. I also tried Dr. Haas several times through the hospital and it is a dead end with a voicemail that asks the referring physician to call. No information forthcoming on which number the physician needs to call. Similarly, no response from the office number of Dr. Barstow, another doctor in the same team.

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  5. the sytrinol worked wonders for a few days and then the efficacy wore off... does anyone have any ideas on how to keep the effect from wearing off?

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    1. When sytrinol seems to stop working we make a 1 week pause. During this time I give half dose of ibuprofen instead.

      Jane.

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    2. Hi Audrey,

      For three weeks we had spectacular behavior, that wore off, but in an interesting way. We don't have much of the physiologically provoked rage and SIB such as from allergies etc, rather they are behavioral, and seem to be developmental. Example, refusing to share food, toys etc but wanting everyone else's, and then throwing a tantrum when she doesn't get her way. She is much more aware of herself, her environment, has an increasing need to control both. I also see a much clearer manifestation of ego.

      The other positives such as a big improvement in apraxia, more social comfort, less defensiveness in social contacts etc have stayed. These also seem to be building up in layers over time. I also think that these improvements would only be visible if given the right opportunities, such as actually making her practice writing, though all her previous teachers and therapists have wanted to focus only on typing skills, they thought writing would be too difficult.

      From my experience, I would recommend continuing with it for a bit longer, and also watching more closely. We do two doses per day, and if we miss even one dose, I see the slowness and fog of apraxia creep back in.

      At this point, verapamil, bumetanide and sytrinol are all working synergistically. It may be that the sytrinol is having the effect it has because of the other two.

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  6. Should I expect Sytrinol to work right away -- like taking an ibuprofen? I'm looking for help with "rage like" episodes with head hitting sibs and sometimes aggression. We are entering the worst time of year for my guy (late July/August) I tried it and it doesn't appear to help that much initially, but I don't know if I should try it for a longer period of time.

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    1. That kind of behavior in my son in the summer is resolved by Verapamil. The Biogaia probiotic seems also to help by reducing the allergy itself, so less need for Verapamil. In my son neither ibuprofen nor sytrinol resolve summertime raging.

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    2. Thank you, I've been thinking about that med for a long time. Don't think my son's doctor will prescribe because it is off-label. But it doesn't hurt to ask.

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    3. Peter unfortunately verapamil does not seem to work for my child despite giving lower dosages seems to put her into a more defiant aggressive mood.We are gutted.

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    4. Hi Anonymous, sorry to hear that. Your post reminded me of Dr Goldberg's NIDS protocols, which amongst other things often includes SSRI anidepressants at Very low doses. They are not given for the usual/standard reasons under that protocol, I won't go into details as not relevant to this, but just to say that over the years I have read many reports from parents saying that their child was doing very badly on the lower dosages, with increased aggression and defiance. What Dr G would then do would be to INCREASE dosage of the given drug, and there would be a total turnaround with the child responding extremely well. This new dosage would still be very low, still far less than half standard dosages (when given for depression etc).

      Not to say that verapamil has similar effects and mechanisms of action as low dose SSRIs, but then again no one knows for sure. Especially when it comes to autism, anything is possible. In your place I'd give verapamil another go for a couple of days, at double the dose you tried earlier (as long as doubling the dose would not take you over the safe limits for her weight!).

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  7. Thanks to whoever took the time out to reply .Fear and bravery ..if I can still myself We will try it again at the recommended dose and see

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  8. Peter, what's your take on bezafibrate as a PPAR agonist for asd?

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    1. Bezafibrate activates all three PPAR subtypes (alpha, gamma and delta. It is interesting. It is being trialed in bipolar.

      "Andrew A. Nierenberg, M.D., Harvard University, will conduct a trial of a treatment for bipolar disorder based on a newer concept of bipolar pathophysiology. This concept proposes that bipolar disorder results from dysregulation of mitochondria, the structures in cells responsible for cellular energy production. Bezafibrate, a widely used anticholesterol medication, targets mitochondrial master switches called peroxisome proliferator-activated receptors (PPARs). The trial will assess the safety and tolerability of bezafibrate added to lithium for bipolar depression, especially with regard to worsening manic symptoms and suicidal ideation."

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