Showing posts with label Sytrinol. Show all posts
Showing posts with label Sytrinol. Show all posts

Monday, 8 May 2017

Pan-agonists of PPARs and PGC-1α in Mitochondrial Disease, Autism and Sport

Today’s post should be of interest to those concerned about mitochondrial disease and mTOR.

mTOR is a very important signaling cascade that often dysfunctional in autism. Many aspects of autism and its comorbidities can be traced back to mTOR.
The going is easier with a PPAR pan-agonist 

mTOR integrates the input from upstream pathways, including insulin, growth, and amino acids.   mTOR also senses cellular nutrient, oxygen, and energy levels. The mTOR pathway is a central regulator of metabolism and physiology, with important roles in the function of tissues including liver, muscle, adipose tissue, and the brain.  It is dysregulated in human diseases, such as diabetes, obesity, certain cancers and indeed autism.

One important process affected by mTOR is the creation of new mitochondria in your cells.  Each cell has many mitochondria, but in some people there are not enough and/or they may not work properly.  
In the above post we saw that Oxidative phosphorylation (or OXPHOS in short) is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing energy.  This takes place inside mitochondria.

The five enzymes required have simplified names: complex I, complex II, complex III, complex IV, and complex V.

The most common problem in autism is a lack of complex 1, this leads to a lack in the production of energy (ATP) in cells.  In your muscles this will appear as a lack of exercise endurance and in your brain as a lack of cognitive function.

On that rather intimidating chart (below), all about mTOR, tucked away at the bottom right is PGC-1α.
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is the master regulator of mitochondrial biogenesis.

PGC-1α may be also involved in controlling blood pressure, regulating cellular cholesterol homoeostasis, and the development of obesity.

PGC-1α is thought to be a master integrator of external signals. It is known to be activated by a many factors, including:-

·         Exercise  (gradual endurance training)

·         PPARδ , PPARγ and it was thought PPARα

·         AMPK (Metformin, or AICAR)

·         Sirt-1 (resveratrol and other polyphenolic ‎compounds)

Interestingly, massage therapy appears to increase the amount of PGC-1α which leads to the production of new mitochondria. Many autism parents believe in various massage therapies. 

Metformin is a very old drug to treat diabetes, it does activate AMPK but unfortunately it also inhibits the Complex 1 mitochondrial enzyme. This might explain why one reader of this blog found it had a negative effect in her son.  In some types of cancer metformin can be used to “starve” the cancer cells of energy and stop them proliferating.

AICAR was thought to have been used by cyclists in the 2009 Tour de France, it is a heart drug from the 1980s. It activates AMPK and increases nitric oxide production from endothelial nitric oxide synthase.

Here is the lower right part enlarged:-


The above chart, while complex does not give the complete picture regarding PPAR.

It appears that the type of PPAR that is needed to activate PGC-1α  is actually PPARδ  (PPAR delta). For a long time researchers thought it was PPAR α (PPAR alpha).

PGC-1 alpha induces mitochondrial biogenesis in muscle and its activity has been related to insulin sensitization. Here, we report that fibrates induce PGC-1 alpha gene expression in muscle both in vivo and in vitro. However, only activation via PPAR delta but not PPAR alpha underlies this effect. PPAR delta induces PGC-1 alpha gene transcription through a PPAR-response element in the PGC-1 alpha promoter. Moreover, PGC-1 alpha coactivates the PPAR delta-responsiveness of its own gene. A further positive autoregulatory loop of control relies on the induction of PPAR6 expression by PGC-1 alpha. These data point to a distinct value of PPARdelta rather than PPAR alpha agonists in the improvement of oxidative metabolism in muscle.

Peroxisome proliferator-activated receptors (PPARs)

There was a post in this blog a long time ago about all the PPARs. There are three types (alpha, delta and gamma) just to confuse us, sometimes delta is called beta.

  • α (alpha) - expressed in liver, kidney, heart, muscle, adipose tissue, and others
  • β/δ (beta/delta) - expressed in many tissues but markedly in brain, adipose tissue, and skin
  • γ (gamma) - although transcribed by the same gene, this PPAR through is expressed in three forms:
    • γ1 - expressed in virtually all tissues, including heart, muscle, colon, kidney, pancreas, and spleen
    • γ2 - expressed mainly in adipose tissue
    • γ3 - expressed in macrophages, large intestine, white adipose tissue.

It does seem that activating alpha, gamma and delta has potential benefit.

The PPAR alpha agonist PEA is available as a supplement and as food for medical purposes In Italy and Spain.  It has been proposed for various inflammatory and pain syndromes. A large trial at a Skoda car factory in 1972 showed that PEA was protective against flu and the common cold.

Fibrate drugs are PPAR alpha agonist drugs used to lower cholesterol. A key point here is that these drugs also activate other types of PPAR as well.
PPAR gamma agonists are widely used to treat diabetes.  They improve insulin sensitivity and decrease some inflammatory responses. They lower cholesterol.
PPAR delta has various antidiabetic effects and agonism of PPAR delta changes the body's fuel preference from glucose to lipids. Recently it was shown that PPAR delta can be activated to promote biogenesis of mitochondria.
It does appear likely that there is some interaction between the PPARs.
Using the mild PPAR gamma agonist, Sytrinol, which gives a long term cholesterol lowering effect, gives a short term cognitive and behavioral improvement in autism.
Pioglitazone is used to lower glucose levels in type 2 diabetes and is a PPAR gamma agonist.  It has been shown to have a positive effect in autism and more trials are in progress. It also binds to a lesser extent to PPAR alpha.
Our reader Maja is investigating whether Sytrinol will maintain its initial good effect when combined with a mild PPAR alpha agonist, like PEA. 

Pan-agonists of PPAR

Bezafibrate appears to be the best known “pan-agonist” of PPAR alpha, gamma and delta.

The PPARpan-agonist bezafibrate ameliorates cardiomyopathy in a mouse model of Barth syndrome 

Bezafibrate as treatment option in patients with mitochondrial complex I (CI) deficiency

These results support bezafibrate as a promising treatment option for specific subgroups of patients with CI deficiency.

Less well known is the natural substance Berberine. 

The multifaceted drug Telmisartan, from a recent post, is also a pan-agonist of PPARs. It is usually quoted as being a PPAR delta agonist. 


The drug AICAR is thought of as an AMPK activator rather than a PPAR agonist, but it does affect all three types of PPAR.

Treatment with AICAR induced gene expression of all three PPARs, but only the Ppara and Pparg regulation were dependent on AMPK.


It looks like some athletes, seeking an advantage, are already using the above strategies to improve their exercise endurance; having more mitochondria is of course a competitive advantage.  A list of all the substances banned in sport might be another good source of therapies not only for autism, but also dementia.
Since mitochondrial dysfunction is a feature of Parkinson’s, Huntington’s and Alzheimer’s there are some investigations ongoing. There is even a trial to perk up the mitochondria in people with Bipolar using Bezafibrate.
It is odd that Sytrinol has only a short term positive effect in most people with autism, although our reader RG’s daughter has a long term benefit. I suspect some people may need a pan-agonist, there may be some interaction/crosstalk/ feedback that we are not aware of.
It would be nice to have some data on the relative potency of Bezafibrate,  Telmisartan and Berberine across alpha, delta and gamma receptors, otherwise we are left with trial and error.
The advantage of Berberine is that it is an OTC supplement.
AICAR is also interesting.

Monday, 6 March 2017

Time to update the Autism Polypill?

It has been a long time since I added anything new to my autism Polypill. This is the combination of therapies that consistently, and materially reduce the symptoms of autism in Monty, now aged 13 with ASD.

As regular readers will be aware, due to the heterogeneous nature of autism, what works wonders for one person with autism may be totally ineffective, or even make matters worse, in another person with a different type of autism.
However, once you have found one therapy that is effective you have an opportunity to identify the underlying biological dysfunction that you have stumbled upon, without the need for any fancy genetic or metabolic testing.  Then you can look for other therapies for that dysfunction and other people who fall into that sub-group of autism and see what else works for them.
I am surprised how many people do respond to some of the therapies I am highlighting in this blog. 

Time to update?

I had been expecting to add the Biogaia Protectis probiotic bacteria to the Polypill.  It does indeed work in Monty and in other readers, but prolonged use does have a problem, at least in some people.  The behavioral effects fade and, in our case, it switches from suppressing allergy to promoting allergy.
The person who originally told us about Biogaia for autism uses the more potent Biogaia Gastrus, which contains the Protectis bacteria and a second one.  She uses a high dosage and uses it three weeks on and one week off.
Like some other readers found, Monty had an immediate negative reaction to the second bacteria in Biogaia Gastrus.  We are users of Biogaia Protectis, but not every day.
A long time ago I proposed the flavonoid Tangeritin/Sytrinol as a safe PPAR gamma agonist that is also a P2Y2 receptor antagonist. Research studies have shown that the flavonoids Tangeritin and kaempferol are antagonists at P2Y2 receptors and may be of interest as potential anti-inflammatory drugs.  Robert Naviaux, from the University of California at San Diego, believes that antipurinergic therapy is a key potential strategy to treat autism and also chronic fatigue syndrome and fibromyalgia.
The broccoli sprout powder already in the Polypill is a rich source of kaempferol.
Tangeritin/Sytrinol has been shown to have sufficient bioavailability to reduce the level of cholesterol in people with high cholesterol.   


The most likely contender to enter the Polypill for everyday use is potassium bromide (KBr), it does seem to tick all the boxes. 

·        It works

·        It continues to work after longer term use

·        Mode of action is understood

·        Safety record is very well understood

·        Effective at a low dosage

·        Not expensive, about 30 cents a day.  Much less if you use bulk KBr.

KBr should be effective in people who respond to bumetanide, since they both reduce intra-cellular chloride levels, but by different mechanisms.
In people who stop responding to bumetanide, I think KBr might be a good choice.  In responders to bumetanide, increasing inflammation due to an unrelated condition, may further reduce the expression of the KCC2 transporter that lets chloride exit neurons. So the inflammation increases the level of intracellular chloride and wipes out the benefit that was being produced by the bumetanide.  The effect of the KBr will be to reduce chloride again, this time by substitution with the relatively inert bromide.
It is also possible that some people with severe autism do not respond to bumetanide because their chloride level is so high that bumetanide is not sufficiently potent.  In those people the additive effect of KBr might just tip the balance.
In some countries bumetanide tablets include potassium chloride (KCl) to compensate for potassium lost in diuresis.  The cleverer thing in autism would be to add KBr, since you benefit from the K+ and the Br-.
Due to the very long half-life, you need to take a low dosage of KBr for 4 to 6 weeks until you reach the peak level of Br- in your body.  Only then can you judge whether you are a responder or not. 
What I am considering the autism dose (8mg/Kg) is far lower than the dose used for intractable pediatric epilepsy (30-50mg/Kg), specifically to avoid the known side effects.  The main side effect at high doses is bromo-acne. Children with intractable epilepsy opt for some facial spots over seizures.
Quite possibly a higher KBr dosage would be even more effective in autism, but then you will for sure be dealing with bromo-acne.

Summertime Add-ons

One conclusion from the gene studies is that often in autism and schizophrenia there are variances in the genes linked to the immune system. So the immune–related therapies that help Monty a great deal during spring and summer may indeed be applicable to a substantial sub-group of autism. For others they are likely to be ineffective.
I am hopeful of yet another step forward this summer using the amino acid L-histidine.  Histidine is very closely related to histamine and you might think that would be the last thing that could help in those prone to allergy-driven autism flare-ups.  However in an earlier post we saw that there is a paradoxical effect when raising the level of histidine, inhibits the release of histamine from mast cells.  We also saw that histidine has an inhibitory effect on mTOR, one of the suggested common core autism pathways that was highlighted yet again in the gene studies.
L-histidine, is an essential amino acid that is not synthesized in humans.  You have to eat it.

Friday, 25 March 2016

“Type 3” Diabetes in Alzheimer’s, but maybe also in some Autism

Intranasal insulin, for cognitive enhancement in Alzheimer’s and …

Today’s post was sparked by another little experiment of mine; no, not intranasal insulin.

Recently I have been using a reduced number of therapies on Monty, aged 12 with ASD.  Some people think there are just too many pills.

I wrote many posts last year about something called PPAR gamma (Peroxisome proliferator-activated receptor gamma, PPAR-γ or PPARG, also known as the glitazone receptor).

As you can read in Wikipedia:-

PPAR-gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis, and cancer. PPAR-gamma agonists have been used in the treatment of hyperlipidaemia andhyperglycemia. PPAR-gamma decreases the inflammatory response of many cardiovascular cells, particularly endothelial cells. PPAR-gamma activates the PON1 gene, increasing synthesis and release of paraoxonase 1 from the liver, reducing atherosclerosis.
Many insulin sensitizing drugs (namely, the thiazolidinediones) used in the treatment of diabetes target PPARG as a means to lower serum glucose without increasing pancreatic insulin secretion.

What we found out in earlier posts that PPAR-gamma can be used to reduce microglial activation, which should turn down the body’s “immunostat”.  A key feature of many people’s autism appears to be an over-activated immune system, reflected by activated microglia.

PPAR-gamma agonists as regulators of microglial activation and brain inflammation.

The present review summarizes the several lines of evidence supporting that PPAR-gamma natural and synthetic agonists may control brain inflammation by inhibiting several functions associated to microglial activation, such as the expression of surface antigens and the synthesis of nitric oxide, prostaglandins, inflammatory cytokines and chemokines. 
Although most of the evidence comes from in vitro observations, an increasing number of studies in animal models further supports the potential therapeutic use of PPAR-gamma agonists in human brain diseases including multiple sclerosis, Parkinson's disease and Alzheimer's disease.


The potent PPAR-gamma agonist drugs like Rosiglitazone, have side effects which I think make them unsuitable for autism.  I use a flavanol called Tangeritin, in the form of a supplement called Sytrinol.

For two months we have not used Sytrinol, but yesterday Monty had one pill after lunch.

The piano lesson was great and then Monty had three hours with his Assistant, doing academic work and then some more piano practice.

Before she went home, Monty’s Assistant spent ten minutes telling me, and Monty’s big brother, just how great the afternoon had been.

“Monty was amazing today”

“When he was doing math, it was like he wasn’t autistic”

(we live in a country where autism means strict definition autism, what in the US is called severe autism)

“Did you hear how he played the piano?”

I told Monty’s brother to make a mental note of this and tell it to Mum/Mom later.

The next day the effect of Sytrinol was not as profound.

This actually is a recurring theme, the effect of various interventions is the greatest at the beginning  and then, as the body’s feedback loops get involved, the effect reduces.  

The same is true with cinnamon, another food-based intervention, that also helps people with diabetes.  The effect in (some) autism is greatest when you start.

It would be great if it was possible to keep the full initial effect of both Sytrinol and Cinnamon, and avoiding the dampening reaction caused by feedback loops.

I think if this is possible, it will be via targeting the therapy directly at the brain, rather than the entire body.  This can be achieved via the intranasal route, as used with oxytocin.

What to put in the spray?  This would be a very personalizable solution, since different people have different dysfunctions and to varying degrees.  Some possibilities might include:-

·        Insulin  (read on to learn why)
·        IGF-1
·        T3 thyroid hormone
·        TRH
·        Type 2 iodothyronine deiodinase (D2) 
·        Oxytocin
Fine tuning Cognition

It is difficult to be certain what therapy is responsible for what effect.

I recently told one researcher/parent that interventions in autism seem to take effect very quickly and so you can pretty rapidly run through a series of mini-trials to see what helps, what makes things worse and what does nothing.  Being a researcher, his view is that you need to try things for much longer.

One problem of trials lasting months is that external factors may then change, that cause behavior to change and distort the result. This is why I try to avoid trials from May to October, the allergy season.

Many people do find that some supplements help a lot for a week or two and then make things worse.  This includes things like some B vitamins and carnitine.  For other people continued use keeps giving a positive effect.

Previous Experience with Sytrinol

Monty’s assistant at school last year thought Sytrinol made him cleverer.

She also thought the PAK inhibiting propolis (BIO 30) had a similar effect.  This propolis is quite expensive and I concluded the effect was small and this might be because it just was not potent enough. 

One reader of this blog is using a much more potent PAK inhibitor, FRAX486, and some people in the US use Ivermectin.

Ivermectin is an anti-parasite drug which also happens to be a PAK inhibitor.  It is not suitable for long term use.

 Why would Sytrinol improve cognition?

I have written a lot about PPAR gamma in the past, so today has a new angle on the subject.

I did a quick check on PPAR gamma and cognition.

I was surprised what I found.



PPARγ Recruitment to Active ERK during Memory Consolidation Is Required for Alzheimer's Disease-Related Cognitive Enhancement

Cognitive impairment is a quintessential feature of Alzheimer's disease (AD) and AD mouse models. The peroxisome proliferator-activated receptor-γ (PPARγ) agonist rosiglitazone improves hippocampus-dependent cognitive deficits in some AD patients and ameliorates deficits in the Tg2576 mouse model for AD amyloidosis. Tg2576 cognitive enhancement occurs through the induction of a gene and protein expression profile reflecting convergence of the PPARγ signaling axis and the extracellular signal-regulated protein kinase (ERK) cascade, a critical mediator of memory consolidation. We therefore tested whether PPARγ and ERK associated in protein complexes that subserve cognitive enhancement through PPARγ agonism. Coimmunoprecipitation of hippocampal extracts revealed that PPARγ and activated, phosphorylated ERK (pERK) associated in Tg2576 in vivo, and that PPARγ agonism facilitated recruitment of PPARγ to pERK during memory consolidation. Furthermore, the amount of PPARγ recruited to pERK correlated with the cognitive reserve in humans with AD and in Tg2576. Our findings implicate a previously unidentified PPARγ–pERK complex that provides a molecular mechanism for the convergence of these pathways during cognitive enhancement, thereby offering new targets for therapeutic development in AD.

Cognitive Enhancementwith Rosiglitazone Links the Hippocampal PPAR gamma and ERK MAPK Signaling Pathways

Pathogenesis of Alzheimer’s and Diabetes

The pathogenesis of a disease is the biological mechanism (or mechanisms) that lead to the diseased state.

I am not suggesting that autism leads to Alzheimer’s.  (We do though know that most people with Down Syndrome will develop early Alzheimer’s in their 40s or 50s)

Many complex diseases like Alzheimer’s, cancer and indeed autism have multiple biological mechanisms behind them.

By studying the molecular pathways involved in one disease it may help understand another disease.  This is why some readers of this blog follow the cancer/oncology research.

For some time I have been intrigued at the overlap between diabetes and autism.  What is good for autism really does seem to be good for diabetes and vice versa.

Alzheimer’s Disease as Type 3 Diabetes

I was surprised to learn that some clinicians now consider Alzheimer’s Disease as Type 3 Diabetes.           

You will recall that Type 1 diabetes is when your pancreas packs up making insulin and then you have to inject yourself with supplementary insulin.

Type 2 diabetes occurs in late middle age, often linked to obesity, and is characterized by high blood sugar, insulin resistance (insulin sensitivity), and relative lack of insulin.

Insulin resistance (IR) is generally regarded as a pathological condition in which cells fail to respond to the normal actions of the hormone insulin. The body produces insulin. When the body produces insulin under conditions of insulin resistance, the cells in the body are resistant to the insulin and are unable to use it as effectively, leading to high blood sugar. Beta cells in the pancreas subsequently increase their production of insulin, further contributing to a high blood insulin level. This often remains undetected and can contribute to a diagnosis of Type 2 diabetes.  Despite the ill-effects of severe insulin resistance, recent investigations have revealed that insulin resistance is primarily a well-evolved mechanism to conserve the brain's glucose consumption by preventing muscles from taking up excessive glucose.[

Eventually Type 2 diabetes may progress to Type 1 diabetes mellitus, where the body's own immune system attacks the beta cells in the pancreas and destroys them. This means the body can no longer produce and secrete insulin into the blood and regulate the blood glucose concentration. We saw how the use of Verapamil can stop beta cells being destroyed.

Some clinicians/researchers propose that diabetes of the brain should be called Type 3 diabetes.

The research does support the view that Alzheimer’s does incorporate this brain-specific type of diabetes.  But I know wonder if this applies to some autism.

Alzheimer’s disease (AD) has characteristic histopathological, molecular, and biochemical abnormalities, including cell loss; abundant neurofibrillary tangles; dystrophic neurites; amyloid precursor protein, amyloid-β (APP-Aβ) deposits; increased activation of prodeath genes and signaling pathways; impaired energy metabolism; mitochondrial dysfunction; chronic oxidative stress; and DNA damage. Gaining a better understanding of AD pathogenesis will require a framework that mechanistically interlinks all these phenomena. Currently, there is a rapid growth in the literature pointing toward insulin deficiency and insulin resistance as mediators of AD-type neurodegeneration, but this surge of new information is riddled with conflicting and unresolved concepts regarding the potential contributions of type 2 diabetes mellitus (T2DM), metabolic syndrome, and obesity to AD pathogenesis. Herein, we review the evidence that (1) T2DM causes brain insulin resistance, oxidative stress, and cognitive impairment, but its aggregate effects fall far short of mimicking AD; (2) extensive disturbances in brain insulin and insulin-like growth factor (IGF) signaling mechanisms represent early and progressive abnormalities and could account for the majority of molecular, biochemical, and histopathological lesions in AD; (3) experimental brain diabetes produced by intracerebral administration of streptozotocin shares many features with AD, including cognitive impairment and disturbances in acetylcholine homeostasis; and (4) experimental brain diabetes is treatable with insulin sensitizer agents, i.e., drugs currently used to treat T2DM. We conclude that the term “type 3 diabetes” accurately reflects the fact that AD represents a form of diabetes that selectively involves the brain and has molecular and biochemical features that overlap with both type 1 diabetes mellitus and T2DM.

Altogether, the results from these studies provide strong evidence in support of the hypothesis that AD represents a form of diabetes mellitus that selectively afflicts the brain

The human and experimental animal model studies also showed that CNS impairments in insulin/IGF signaling mechanisms can occur in the absence of T1DM or T2DM

Altogether, the data provide strong evidence that AD is intrinsically a neuroendocrine disease caused by selective impairments in insulin and IGF signaling mechanisms, including deficiencies in local insulin and IGF production.

At the same time, it is essential to recognize that T2DM and T3DM are not solely the end results of insulin/IGF resistance and/or deficiency, because these syndromes are unequivocally accompanied by significant activation of inflammatory mediators, oxidative stress, DNA damage, and mitochondrial dysfunction, which contribute to the degenerative cascade by exacerbating insulin/ IGF resistance.

Some of the most relevant data supporting this concept have emerged from clinical studies demonstrating cognitive improvement and/or stabilization of cognitive impairment in subjects with early AD following treatment with intranasal insulin or  a PPAR agonist

Repurposing Diabetes Drugs for Brain Insulin Resistance in Alzheimer Disease

 Although many classes of drugs are now approved for management of diabetes, a primary focus of efforts to treat insulin-signaling dysfunction in AD has been the administration of exogenous insulin. There is abundant anecdotal evidence that insulin administration in people with diabetes may acutely affect mood, behavior, and cognitive performance.

Results of recent pilot studies of intranasal insulin in mild cognitive impairment (MCI) and AD have been encouraging. The most notable of these studies was a doubleblind, randomized trial of 104 older adults with MCI or AD who received placebo, low-dose (20 IU), or high-dose (40 IU) intranasal insulin for 4 months

In 2012, the U.S. National Institutes of Health allocated $7.9 million for a pivotal trial of intranasal insulin called the Study of Nasal Insulin in the Fight Against Forgetfulness (SNIFF; ClinicalTrials identifier: NCT01767909). This multicenter phase 2/3 study will be conducted by the ADCS. It is expected to recruit 250 participants with AD or MCI and to randomize them for 12 months to intranasal insulin or placebo, followed by an open-label extension of 6 months in which all participants will receive intranasal insulin. The study should be completed in late 2014.  The Study of Nasal Insulin in the Fight Against Forgetfulness (SNIFF)

In preclinical studies, TZDs improved biomarkers of AD as well as memory and cognition (31). The first pilot studies in humans were also generally encouraging, including a study by Watson et al. (32) that showed improved memory and modulation of amyloid-b levels in CSF compared with placebo after 6 months of treatment with rosiglitazone. On the basis of these preliminary studies, the maker of rosiglitazone sponsored two adequately powered phase 3 studies of rosiglitazone in AD as monotherapy or as adjunctive therapy to acetylcholinesterase inhibitors in mild to-moderate AD. These larger trials failed to replicate the positive findings of the smaller pilot studies (33).

Many explanations have been proposed for why rosiglitazone does not appear to be effective as a treatment for AD in cognitively impaired adults. Perhaps the most convincing explanation is that rosiglitazone has only modest blood-brain barrier penetration, and in fact, rosiglitazone is actively pumped out of the brain by an endogenous efflux system (34). Therefore, rosiglitazone should be expected to have only a mild insulin-sensitizing effect in the human brain.



The type 2 diabetes drugs like Rosiglitazone/Pioglitazone have been trialed in both autism and Alzheimer’s.  The results in autism with pioglitazone were positive, in Alzheimer’s they used Rosiglitazone, due to the adverse side effects of pioglitazone, and the results were very mixed.  Rosiglitazone has only modest blood-brain barrier penetration so it looks a poor choice.

In the autism trial they measured "autism" rather than cognitive function.

Effect of pioglitazone treatment on behavioral symptoms in autistic children 

In a small cohort of autistic children, daily treatment with 30 or 60 mg p.o. pioglitazone for 3–4 months induced apparent clinical improvement without adverse events. There were no adverse effects noted and behavioral measurements revealed a significant decrease in 4 out of 5 subcategories (irritability, lethargy, stereotypy, and hyperactivity). Improved behaviors were inversely correlated with patient age, indicating stronger effects on the younger patients.
Conclusion  Pioglitazone should be considered for further testing of therapeutic potential in autistic patients.

One to watch is the effect of the standard type 2 diabetes treatment Metformin on cognition in Alzheimer’s.  Nobody really knows the mode of action of Metformin.

Intranasal insulin is very interesting and not just in Alzheimer’s.

Intranasal insulin improves memory in humans

Intranasal Insulin as a Treatment for Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence

I will add it to my growing list of therapies for mild cognitive impairment, in case I need it in the future.

·        Nerve growth factor (NGF) eye drops
·        Lions Mane Mushrooms (that increase NGF)
·        Cocoa Flavanols (increase cerebral blood flow)
·        Intranasal insulin or just Tangeritin/Sytrinol

I do not know if intranasal insulin would be a safe long-term therapy for children, but it would be a good diagnostic tool.  Once large numbers of older people start using intranasal insulin for cognition, we will find out how well it is tolerated.  Older people seem far more prone to side effects than younger people.

For now I think Tangeritin/Sytrinol is the best choice.