Ketones and Autism Part 6 - Capric Acid (C10) for Mitochondrial Disease, in Particular Complex 1, plus more on Metformin

Capric Acid (C10) is so named because it smells like a goat (Goat in Latin = Caper)

Photographer: Armin Kübelbeck, CC-BY-SA, Wikimedia Commons

Rather than Goaty acid, C10 is called Capric acid, or indeed Decanoic acid (after its 10 carbon atoms). Today’s post is indirectly again about ketones, because if you eat a Ketogenic Diet (KD) you are likely to consume a fair amount of Capric acid (C10).

I have written a lot in this blog about mitochondria, even though I do not think my son has mitochondrial dysfunction. Clearly many people with autism do have a lack of one or more of the critical mitochondrial enzyme complexes that allow glucose to be converted to ATP (usable energy), by the clever process OXPHOS (Oxidative phosphorylation).

The “rate limiting” enzyme is usually Complex 1, meaning that is the one it is most important not to be short of.

Another favourite, but obscure, subject of this blog is PPAR gamma.

Peroxisome proliferator-activated receptors (PPARs) are a group of proteins that function as transcription factors regulating the expression of certain genes. Transcription factors are particularly important because they trigger numerous effects.

PPAR gamma plays a key role in fat storage and glucose metabolism, but has other functions. 

Activation of PPAR-gamma by Capric acid (C10) has been shown to increase the number of mitochondria, increase the mitochondrial enzyme citrate synthase, increase complex I activity in mitochondria, and increase activity of the antioxidant enzyme catalase. 

So, if you have autism and impaired mitochondrial function, C10 may well give a benefit because it can increase the peak power available to your brain.

The ketogenic diet component decanoic acid increases mitochondrial citrate synthase and complex I activity in neuronal cells

The Ketogenic diet (KD) is an effective treatment with regards to treating pharmaco-resistant epilepsy. However, there are difficulties around compliance and tolerability. Consequently, there is a need for refined/simpler formulations that could replicate the efficacy of the KD. One of the proposed hypotheses is that the KD increases cellular mitochondrial content which results in elevation of the seizure threshold. Here, we have focussed on the medium-chain triglyceride form of the diet and the observation that plasma octanoic acid (C8) and decanoic acid (C10) levels are elevated in patients on the medium-chain triglyceride KD. Using a neuronal cell line (SH-SY5Y), we demonstrated that 250-μM C10, but not C8, caused, over a 6-day period, a marked increase in the mitochondrial enzyme, citrate synthase along with complex I activity and catalase activity. Increased mitochondrial number was also indicated by electron microscopy. C10 is a reported peroxisome proliferator activator receptor γ agonist, and the use of a peroxisome proliferator activator receptor γ antagonist was shown to prevent the C10-mediated increase in mitochondrial content and catalase. C10 may mimic the mitochondrial proliferation associated with the KD and raises the possibility that formulations based on this fatty acid could replace a more complex diet. We propose that decanoic acid (C10) results in increased mitochondrial number. Our data suggest that this may occur via the activation of the PPARγ receptor and its target genes involved in mitochondrial biogenesis. This finding could be of significant benefit to epilepsy patients who are currently on a strict ketogenic diet. Evidence that C10 on its own can modulate mitochondrial number raises the possibility that a simplified and less stringent C10-based diet could be developed.

Capric Acid (C10) as a PPARγ agonist

As shown in the above study the mechanism by which C10 benefits the mitochondria is via PPARγ agonism.

Here is another study confirming that C10 is indeed a PPARγ agonist.

Identification and Mechanism of 10-Carbon Fatty Acid as Modulating Ligand of Peroxisome Proliferator-activated Receptors

Background: Mechanism of action of medium chain fatty acid remains unknown.

Results: Our results show that decanoic acid (C10) binds and activates PPARγ.

Conclusion: Decanoic acid acts as a modulator of PPARγ and reduces blood glucose levels with no weight gain.

Significance: This study could lead to design of better type 2 diabetes drugs.

Other PPARγ agonists

PPARγ agonists have been covered previously in this blog and we know that glitazones, a class of drugs for diabetes, do improve some types of autism. Glitazones are PPARγ agonists.

Metformin, a very widely used drug for type 2 diabetes, works differently to Glitazones, but I did suggest a while back it should help some types of autism. Last year it was indeed found to be beneficial in Fragile X.

Diabetes drug may help symptoms of autism-associated condition

 "Basically, it's something like a wonder drug," Sonenberg said.

The study suggests that metformin might also be used to treat other autism spectrum disorders, said Ilse Gantois, a research associate in Sonenberg's lab at McGill.

"We mostly looked at the autistic form of behaviour in the Fragile X mouse model," explained Gantois, who is co-lead author with McGill researchers Arkady Khoutorsky and Jelena Popic. "We want to start testing other mouse models to see if the drug could also have benefits for other types of autism."

Metformin is very cheap and has been used in humans for 60 years. It is another example of re-purposing a drug from Grandpa’s medicine cabinet to treat Grandson’s autism. 

Metformin has been trialled to combat obesity in idiopathic autism caused by antipsychotics. It did help with weight gain, but no comments were made about behavioural improvements, but then those studied were on antipsychotic drugs, which might mask such effects. 

Glitazone-type drugs appear more problematic than Metformin.

There are natural PPAR gamma agonists and they are often used to lower cholesterol, lower blood sugar and improve insulin sensitivity.

Sytrinol, a product containing flavanols tangeretin and nobiletin does indeed have a positive effect on some people’s autism, but for most people (but not all) the effect is lost after a few days.

Our doctor reader Maja, did suggest combining it with a PPARα agonist to see if the effect might be maintained.

This combination has indeed been researched for type 2 diabetes.               

The effect of dual PPAR alpha/gamma stimulation with combination of rosiglitazone and fenofibrate on metabolic parameters in type 2 diabetic patients.

There actually is another natural substance that is an agonist of both PPARγ and PPARα, Berberine, the alkaloid long used in Chinese medicine.

In the research it is suggested that “BRB localizes in mitochondria, inhibits respiratory electron chain and activates AMPK”, which is not what you would want. But this may not be correct.

People who like supplements might want to follow up on Berberine.

Berberine is used by many people with diabetes and a few with autism, for all kinds of reasons, from mercury to GI problems.

Berberine is a potent agonist of peroxisome proliferator activated receptor alpha.

Although berberine has hypolipidemic effects with a high affinity to nuclear proteins, the underlying molecular mechanism for this effect remains unclear. Here, we determine whether berberine is an agonist of peroxisome proliferator-activated receptor alpha (PPARalpha), with a lipid-lowering effect. The cell-based reporter gene analysis showed that berberine selectively activates PPARalpha (EC50 =0.58 mM, Emax =102.4). The radioligand binding assay shows that berberine binds directly to the ligand-binding domain of PPARalpha (Ki=0.73 mM) with similar affinity to fenofibrate. The mRNA and protein levels of CPT-Ialpha gene from HepG2 cells and hyperlipidemic rat liver are remarkably up-regulated by berberine, and this effect can be blocked by MK886, a non-competitive antagonist of PPARalpha. A comparison assay in which berberine and fenofibrate were used to treat hyperlipidaemic rats for three months shows that these drugs produce similar lipid-lowering effects, except that berberine increases high-density lipoprotein cholesterol more effectively than fenofibrate. These findings provide the first evidence that berberine is a potent agonist of PPARalpha and seems to be superior to fenofibrate for treating hyperlipidemia.

Berberine activates peroxisome proliferator-activated receptor gamma to increase atherosclerotic plaque stability in Apoe^-/- mice with hyperhomocysteinemia.

                                                                                                                                     

Sources of Capric Acid (C10)

Goat milk is a good source of capric acid.

Capric acid is 8-10% of coconut oil and 4% of palm kernel oil

Capric acid is a large component (about 40%) of the less expensive MCT oil supplements.

http://cdn.intechopen.com/pdfs/39464/InTech-The_effect_of_fatty_acids_in_goat_milk_on_health.pdf

1.2. Fatty acid composition in goat milk fat Average goat milk fat differs in contents of its fatty acids significantly from average cow milk fat, being much higher in butyric (C4:0), caproic (C6:0), caprylic (C8:0), capric (C10:0), lauric (C12:0), myristic (C14:0), palmitic (C16:0), linoleic (C18:2), but lower in stearic (C18:0), and oleic acid (C18:1) (Table 1). Three of the medium chain fatty acids (caproic, caprylic, and capric) have actually been named after goats, due to their predominance in goat milk. They contribute to 15% of the total fatty acid content in goat milk in comparison to 5% in cow milk (Haenlein, 1993). The presence of relatively high levels of medium chain fatty acids (C6:0 to C10:0) in goat milk fat could be responsible for its inferior flavour (Skjevdal, 1979). 

             

Conclusion

If someone responds well to coconut oil or cheaper MCT oil the reason may have more to do with PPAR gamma and improved mitochondrial function than anything to do with ketones and what they do.

Cheaper MCT oils are mainly a mixture of C8 and C10. To maximize the production of the ketone BHB you really want just C8, but if what you really need is a PPAR gamma agonist, to perk up your mitochondria, it is the C10 you need.

You may indeed benefit from both ketones and agonizing PPAR gamma, in which case you either follow the Ketogenic Diet, or supplement BHB, C8 and C10.

I think this explains why some people with autism reportedly respond well to teaspoon-sized doses of cheaper MCT oil or small amounts of coconut oil.

If you have Complex 1 mitochondrial dysfunction then a dose of Capric acid (C10) is likely to help.

Berberine may, or may not be, as effective as C10. I doubt we will ever know. I think C10 is the better option. 

I wonder when the Canadian researchers will publish their results showing whether Metformin is beneficial beyond Fragile X syndrome. They do not really know why it helps, but that is a repeating theme in medicine.  It is a cheap safe drug, so it would be a pity to waste time finding out if it could be repurposed for some autism.

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.  

Mitochondrial Disease and Autism

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.

Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis

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).

PPAR delta, but not PPAR alpha,activates PGC-l alpha gene transcription in muscle

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.

Palmitoylethanolamide:A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and 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. 

Berberine Is a Potent Agonist of Peroxisome Proliferator Activated Receptor Alpha

Berberine activates peroxisome proliferator-activated receptor gamma to increase atherosclerotic plaque stability in Apoe-/- mice with hyperhomocysteinemia. 

Effect of berberine on PPAR alpha/delta/gamma expression in type 2 diabetic rat retinae.

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. 

Telmisartan increases lipoprotein lipase expression via peroxisome proliferator-activated receptor-alpha in HepG2 cells.

Telmisartan is a promising cardiometabolic sartan due to its unique PPAR-gamma-inducing property

Angiotensin II receptor blockertelmisartan enhances running endurance of skeletal muscle through activation of the PPAR-δ/AMPK pathway.

AICAR

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

AICAR Protects against High Palmitate/High Insulin-Induced Intramyocellular Lipid Accumulation and Insulin Resistance in HL-1 Cardiac Cells by Inducing PPAR-Target Gene Expression

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

Conclusion

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.

Angiotensin II in the Brain & Therapeutic Considerations

In a previous post I suggested that another cheap generic drug (an ACE inhibitor) could potentially be repurposed to treat schizophrenia and some autism. The original idea was related more to modifying the immune/inflammatory response in the body, rather than the brain.  There is however plenty of research regarding Angiotensin within the brain and the numerous roles it plays.

Juggling - maximizing effects, while minimizing
drug interventions

You may recall in the earlier post that in both schizophrenia and autism there is elevated angiotensin II.

In the brain there are two types of angiotensin receptor, AT1 and AT2.  Their actions are opposing each other.

In many kinds of disease we would want to stimulate AT2, but inhibit AT1.

AT2 is thought to be important for cognitive function and is now a target for Alzheimer’s research.

Using an ACE inhibitor you reduce the amount of angiotensin II and so in effect inhibit both AT1 and AT2.

In theory angiotensin II should not cross the blood brain barrier (BBB), so we should be dealing with centrally produced (i.e. inside the brain) angiotensin II.  In practical terms it seems that people with high levels of angiotensin II may have a permeable BBB.

This is relevant because most ACE inhibitors do not cross the BBB, but the original ACE inhibitor called Captopril does cross the BBB.  So if a centrally acting ACE inhibitor were found to be required, it was discovered 40 years ago.

A therapy would ideally be targeted selectively at AT1 or AT2 receptors.  An AT1 blocker might treat for stress-induced disorders.  An experimental AT2 receptor agonist, called compound 21, is now available and is expected to reduce inflammation and oxidative stress.

Compound 21, a selective agonist of angiotensin AT2 receptors, prevents endothelial inflammation and leukocyte adhesion in vitro and in vivo.

Angiotensin II receptor AT1 antagonists are widely used drugs indicated for hypertension, diabetic nephropathy and congestive heart failure. They block effect of Angiotensin on AT1 and might be good in the brain.

We would like to increase the effect on AT2, we could do that with more Angiotensin II, but then we would make things worse with AT1.

                          Do nothing  ACE inhibitor    AT1 antagonist      AT2 agonist

Effect on AT1               none                            good                                     good                          none

Effect on AT2               none                            bad                                       none                          good

AT1 antagonists are widely available and seen as well tolerated.

AT1 antagonists appear to protect against Alzheimer’s.

The only AT2 agonist is an experimental drug called Compound 21.

The only ACE inhibitor that should affect AT2 in the brain is Captopril and so may be an unwise choice. It will reduce Angiotensin II in the brain and in the rest of the body.


Why were we interested in Angiotensin?

Targeting Angiotensin in Schizophrenia and Some Autism

In the original Angiotensin post in this blog we saw that in schizophrenia and some autism, that Angiotensin II is elevated.  We also saw that:-

·        Blocking angiotensin-converting enzyme (ACE) induces those potent regulatory T cells that are lacking in autism and modulates Th1 and Th17 mediated autoimmunity.  See my last post on Th1, Th2 and Th17. 

·        In addition, Angiotensin II affects the function of the NKCC1/2 chloride cotransporters that are dysfunctional in much autism and at least some schizophrenia.

·        It should also reduce any troubling high levels of leptin, which we saw in another post is an issue in most autism

So the idea was that many broadly anti-inflammatory effects of reducing Angiotensin II might be helpful in autism.

But what about inside the brain?

Angiotensin in the Brain

Here we do get to the science, but I will start with the conclusion. We actually want more effect from the Angiotensin AT2 receptor, which should give numerous benefits, but have no means of achieving this. What we can do is make sure we do not reduce AT2 activity, this means better to use and AT1 antagonist, rather than an ACE inhibitor.

The science supporting the use of an AT agonist follows:-

In the text you will see ARB and compound 21. Both are doing good things. The suggestion is that by doing all these good things there should be improved cognitive function; this has yet to be proved in human tests.

ARB = Angiotensin Receptor AT1 Blocker

Compound 21 = Angiotensin Receptor AT2 agonist

Roles of Brain Angiotensin II in Cognitive Function and Dementia

The brain renin-angiotensin system (RAS) has been highlighted as having a pathological role in stroke, dementia, and neurodegenerative disease. Particularly, in dementia, epidemiological studies indicate a preventive effect of RAS blockade on cognitive impairment in Alzheimer disease (AD). Moreover, basic experiments suggest a role of brain angiotensin II in neural injury, neuroinflammation, and cognitive function and that RAS blockade attenuates cognitive impairment in rodent dementia models of AD. Therefore, RAS regulation is expected to have therapeutic potential for AD. Here, we discuss the role of angiotensin II in cognitive impairment and AD. Angiotensin II binds to the type 2 receptor (AT₂) and works mainly by binding with the type 1 receptor (AT₁). AT₂ receptor signaling plays a role in protection against multiple-organ damage. A direct AT₂ receptor agonist is now available and is expected to reduce inflammation and oxidative stress and enhance cell differentiation. We and other groups reported that AT₂ receptor activation enhances neuronal differentiation and neurite outgrowth in the brain. Here, we also review the effect of the AT₂ receptor on cognitive function. RAS modulation may be a new therapeutic option for dementia including AD in the future.

Figure 1: Possible effect of angiotensin II on neurovascular unit. AT₂: angiotensin II type 2 receptor, AchR: acetylcholine receptor, BBB: blood brain barrier, and TGF-β: transforming growth factor β.

Figure 2: Effect of angiotensin II type 2 receptor signaling on cognitive function. AT₂: angiotensin II type 2 receptor, ATIP: AT₂ receptor-interacting protein, Id1: inhibitor of DNA binding protein 1, MMS2: methyl methanesulfonate-sensitive 2, NO: nitric oxide, SHP-1: Src homology 2 domain-containing protein-tyrosine phosphatase 1, and Ubc-13: ubiquitin conjugating enzyme 13.

Figure 3: Effect of angiotensin II on cognitive function. ACE: angiotensin converting enzyme inhibitor, AT₁: angiotensin II type 1 receptor, AT₂: angiotensin II type 2 receptor, and ARB: angiotensin II type 1 receptor blocker.

Continuous stimulation with angiotensin II may damage neurons via multiple cascades through AT₁ receptor stimulation. On the other hand, stimulation of the AT₂ receptor is expected to prevent neural damage and cognitive impairment (Figure 3). However, it is difficult to perform clinical intervention studies to confirm the results of animal studies because of the long-term progression of cognitive impairment. Moreover, in clinical practice, it is not possible to exclude the antihypertensive effect of RAS blockade on cognition in patients with hypertension. However, RAS modulation may be a new therapeutic option for dementia including AD in the future. Therefore, the hypothesis that RAS regulation affects future cognitive function should be confirmed with carefully designed clinical studies.

Which ARB (Angiotensin Receptor Blocker) for Autism?

Very many biological markers are disturbed in autism and many of them seem to be best ignored, you cannot “correct” them all.

However, there will be an underlying reason behind each one of them being disturbed.

As we saw in the recent post on metabolic syndrome, it is not uncommon to find a cascade of downstream problems that might seem to indicate a huge list of drugs.  A different approach is required, it is necessary to treat the underlying (upstream) problems and have a much shorter list of therapies.

We saw in the post on leptin that the elevated levels in autism are treatable, but is there any point?

We have a long list of other things that might be useful in autism and it would be nice to have a single therapy that might address many of them.

It appears that selecting the optimal ARB might give the opportunity to address numerous issues at once.

Telmisartan seems to have numerous potentially useful additional effects:

·        Acts as a PPAR gamma agonist, like the glitazone drugs shown effective in autism trials

·        Acts as a PPAR delta agonist, which should activate the impaired PPARδ  PGC-1α signaling pathway, and enhance mitochondrial biogenesis. This should help people with mitochondrial disease and should be evident by increased exercise endurance and, in theory, improved cognitive function.

·        Telmisartan regulates the Bcl-2 cancer gene, implicated in autism

BDNF-Akt-Bcl2 antiapoptotic signaling pathway is compromised in the brain of autistic subjects

While the effect in autism is complex, Telmisartan is already seen as a potent target for prevention and treatment in human prostate cancer

·        Telmisartan and other ARBs appear to give protection from Alzheimer’s Disease (suggested to be via its effect on PPAR gamma). Perhaps useful for young adults with Down Syndrome, where early onset Alzheimer’s is expected?

·       Telmisartan and other ARBs have a tendency to increase the level of potassium in blood. Up to 10% of people would experience mild hyperkalemia.  For people with autism taking bumetanide, this effect on potassium might actually be helpful. They would need to reduce their potassium supplementation, or might need none at all.

Telmisartan in clinical trials related to autism

As is repeatedly the case, schizophrenia research is again more advanced than autism research. A quick check showed this:-

Telmisartan Completed Phase 4 Trials for Schizoaffective Disorders / Schizophrenia Treatment

This is a 12-week, randomized, double-blinded, placebo-controlled trial of telmisartan 80 mg/day as an adjunctive to clozapine or olanzapine therapy, in 70 schizophrenia subjects to examine telmisartan's effect on glucose metabolism, weight, food intake, resting energy expenditure, and body composition. In addition, the study will examine insulin's effects on psychopathology and cognition.

Conclusion

We currently have no possibility of something like Compound 21, but Telmisartan looks very interesting and it would nice if those psychiatrists who have trialed it in schizophrenia would do the same in autism.  

It looks like the beneficial effects should come at a lower dose than that used to lower blood pressure. In the schizophrenia trial I think they used a higher dose (80mg) than necessary, I suppose they wanted to maximize their chance of success.  In order to minimize any possible negative effects, I would suggest the psychiatrists trial 20mg in youth with autism.

There will be a post on PPAR delta and mitochondrial disease, because there are at least two other ways to target mitochondrial disease in this way, if you do not like Telmisartan.  There is the cheap drug Bezafibrate and the supplement berberine.

Metabolic Syndrome & Autism

Today’s post is not just about autism.

Having written 370 posts in this autism blog, I sometimes feel that I am becoming a bit of an expert on diabetes (and COPD), which you might think has nothing to do with autism.

I was talking to a friend of mine who has type 2 diabetes; he was telling me about all the other things that are going wrong with him, because he actually has “metabolic syndrome”.

What exactly is metabolic syndrome?  It really is not a very good name. Sure you can have a metabolic system, but there are going to be many different ones.  It looks like in the world of medicine there is just one.

The common problem is that in late middle age many people get overweight around their waist, they also have increased blood pressure, high blood sugar and abnormal cholesterol, or triglyceride levels. This combination of symptoms is called metabolic syndrome and it increases your risk of heart disease, stroke, diabetes and much more. (see chart above, even high uric acid/gout is there)

The clever way to treat metabolic syndrome would be to treat the underlying molecular biology, rather than each symptom one by one.  This is not as hard as it may sound, just from reading about the biology of autism, I was telling my friend lots of things he could suggest to his doctor.

If you are going to take a drug to lower blood pressure, why not take the one that also protects your beta cells, the ones that produce insulin, from dying? If you are going to take an ACE inhibitor, why not take the one that will also improve your insulin sensitivity. Instead of taking a glitazone drug that is effective at lowering blood glucose, but has not been shown to reduce the long-term complications of diabetes (such as heart disease and stroke), why not take a single drug that does all three?

Metabolic Syndrome & Autism

It is not surprising to me that research shows that parents who develop metabolic syndrome have an increased likelihood of already having children with autism.

Nor is it a surprise that people with autism, or schizophrenia, have themselves a tendency to various kinds of metabolic syndrome; in fact I would suggest that autism is a metabolic syndrome, just not always the same kind.

It is not a surprise that the drugs produced to treat the classic metabolic syndrome seem to provide such a good hunting ground for autism drugs.

We know that glitazone drugs, being PPAR gamma agonists, should help some kinds of autism and also that PPAR delta agonists may help some with mitochondrial disease. The issue I have with glitazone drugs is their safety in long term use.  Another glitazone autism trial is underway in Canada. Glitazone drugs are used to improve insulin sensitivity in type 2 diabetics.

Bezafibrate is getting a well-deserved trial for mitochondrial disease. Through its action on PPAR, where it is a “pan-agonist”, it is thought that Bezafibrate should trigger biogenesis of mitochondria. Bezafibrate is an old drug to lower cholesterol.

One very interesting candidate drug for autism is Telmisartan which will be covered in a coming post on Angiotensin II in the brain.  Telmisartan is an Angiotensin AT1 agonist, which means it will lower blood pressure, but it does numerous other things. It happens also to be a PPAR gamma/delta agonist.  It improves insulin sensitivity and lower blood glucose levels.  It also modifies the immune system by reducing Il-17a, an important inflammatory cytokine found elevated in both autism and schizophrenia. It also reduces leptin release and prevents leptin resistance. Leptin levels are high in autism and leptin resistance is feature of obesity.

One of the drugs often prescribed to people with metabolic syndrome is Atorvastatin, which some readers of this blog have found improves the application of cognitive ability in their case of autism.

If I had metabolic syndrome, after losing weight, I would choose Atorvastatin, Verapamil and Telmisartan as my top three drugs; none of which are prescribed to that friend of mine. I would also add a glass of beetroot juice which is vasodilating; it is not a drug, but should do plenty of good. I would use an antioxidant like ALA (alpha-lipoic acid) and use sulforaphane to activate the body’s antioxidant genes via Nrf2; many side effects of metabolic syndrome are caused/aggravated by oxidative stress.