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they can have nasty side effects, leading to Pioglitazone being withdrawn in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.
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.
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.
Dear Peter,
ReplyDeleteThis 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?
Thanks Seth.
DeleteOn 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.
Seth
DeleteA 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.
Which brand of Sytrinol are you using?
DeleteAlso, 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
Polly, there is only one producer of sytrinol. Companies buy it and sell it under their name, so just buy the cheapest one.
DeletePeople 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.
This comment has been removed by a blog administrator.
ReplyDeleteSytrinol 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.
ReplyDeleteThe 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.
Hi Peter,
ReplyDeleteI'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.
That is great, Naviaux is a clever guy.
DeleteFor 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
Hi,
DeleteCan 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.
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?
ReplyDeleteWhen sytrinol seems to stop working we make a 1 week pause. During this time I give half dose of ibuprofen instead.
DeleteJane.
Hi Audrey,
DeleteFor 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.
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.
ReplyDeleteThat 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.
DeleteThank 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.
DeletePeter 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.
DeleteHi 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).
DeleteNot 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!).
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
ReplyDeletePeter, what's your take on bezafibrate as a PPAR agonist for asd?
ReplyDeleteBezafibrate activates all three PPAR subtypes (alpha, gamma and delta. It is interesting. It is being trialed in bipolar.
Delete"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."
Before I forget about it, I should report our n=2 trial with Sytrinol/Tangeretin. 2 capsules a day.
ReplyDeleteDuration was only 10 days, but from the comments here that should be enough.
During these 10 days we noticed.. ..nothing.
But, when we stopped, we had some kind of flare with aggression in one participant and histamine spots on the other one. These effects went away within 2-3 days.
I am not sure how to interprete these results, but maybe there was some feedback loop activated? Strange though that we did not experience any good effects first.
/Ling