UA-45667900-1
Showing posts with label pioglitazone. Show all posts
Showing posts with label pioglitazone. Show all posts

Monday, 16 August 2021

Pioglitazone for Autism and Specifically Summertime Raging and Verapamil-responsive Autism?

 


Adult-sized people with autism can cause property damage and much worse.


I am told that summertime raging is a common problem encountered by neurologists, but it remains poorly understood and usually remains untreated.

The most common worry for parents of toddlers diagnosed with severe autism is their lack of speech.

By the time these children reach adulthood, the biggest worry for parents is often aggression and self-injury. Often it is the mother who faces the worst episodes of aggression, which is a really cruel turn of events.

Aggression is usually not present in young children with autism, in some people it never develops, but in others it later becomes established as a learned behavior and then you are stuck with how to deal with it.

One of my own therapy targets has long been to improve cognitive function; this can indeed be achieved and then you can improve important daily living skills (adaptive function). Some steps that you can take to improve cognition, and indeed speech, have a downside in that they increase anxiety, which may lead to aggression. Calcium Folinate (Leucovorin) does cause aggression in a significant minority of people.  I think that low dose Roflumilast (60mcg) is cognitive enhancing, as proposed by the researchers at 100mcg, but it does seem to increase edginess/anxiety. DMF (Dimethyl fumarate) increases alertness, which is a good thing, but too much alertness will make you anxious.

When dealing with a full sized adult, which is more important, increased cognition/speech or avoiding explosive aggression?

Clearly there is a need for a compromise.

In adults with severe autism, living at home, entirely extinguishing aggressive behavior looks like the number one treatment goal.

For children in mainstream school, following the regular curriculum, cognitive function has to be a top priority.  Fortunately, this is our case, but only after starting Bumetanide therapy in 2012.

It looks like you can potentially have the best of both worlds - increased IQ and adaptive function, but without aggressive behavior. That is my own experience, but it was not simple.

Pioglitazone has been covered quite extensively in this blog and it is again featuring in the research. Pioglitazone is an interesting old drug used to treat people with type 2 diabetes; the phase 2 trial for autism has been completed.  I doubt there will be a phase 3 trial due to the high costs. Pioglitazone is broadly anti-inflammatory; it reduces the pro-inflammatory cytokine IL-6 and increases the anti-inflammatory cytokine IL-10.

We have seen in early posts how important is IL-6 and that it plays a key role in both allergy and even how milk teeth roots “dissolve” and then permanent teeth erupt. This transition to permanent teeth is another common cause of raging in autism, in our case it was mostly wintertime raging. 

IL-6, either directly or indirectly, seems to negatively affect behavior.

 

PPAR gamma

In earlier posts there was a lot about the various PPARs. These are used in medicine as targets to treat conditions like high cholesterol and type 2 diabetes.

Resveratrol and Pterostilbene are the OTC supplements that some readers are using. Sytrinol is another such supplement, but its cognitive benefit unfortunately just lasts a few days.

Here is a relatively recent paper on the subject, for those seeking the details. 

 

Nuclear Peroxisome Proliferator-Activated Receptors (PPARs) as Therapeutic Targets of Resveratrol for Autism Spectrum Disorder

 

Or just look up the old posts in this blog:- 


https://epiphanyasd.blogspot.com/search/label/PPAR%CE%B3


PPARs are rather complicated, but do seem to be very relevant.  For example, the master regulator of mitochondrial biogenesis, something called PGC-1 alpha, is activated by PPAR gamma. If you have mitochondrial dysfunction that included a reduced number of mitochondria, you might want to make more mitochondria. A PPAR gamma agonist might be beneficial.

Dysregulation of PGC-1 alpha is associated with neurodegenerative and metabolic disorders including Parkinson's, Alzheimer's and Huntington's.

Outside this blog, there is some interest in PGC-1 alpha and autism, particularly in connection with oxidative stress and mitochondrial dysfunction.

 

“In conclusion, we demonstrated mitochondrial oxidative stress may affect a significant subgroup of ASD children and that the SIRT1/PGC-1α signaling pathway may be a promising medical treatment for ASD.”

Source: Role of SIRT1/PGC-1α in mitochondrial oxidative stress in autistic spectrum disorder


It does look like PPARs can be targeted and provide a benefit for at least some types of autism. My choice is Pioglitazone.

 

Dumber in the Summer

In parallel with summertime raging comes the phenomenon I called “Dumber in the Summer”, where cognitive function regresses.

Monty’s assistant told me recently there is no “Dumber in the Summer” this year, and I opened my medicine cupboard and explained why this is indeed the case.

At least in our case, when you resolve summertime raging, you also protect against cognitive regression. That therapy involves Verapamil, Pioglitazone and allergy therapies, Dymista spray (azelastine + fluticasone) plus Ceterizine and Clemastine. Clemastine also has the pro-myelination effect and stabilizes microglia.

 

Pioglitazone Side effects

In the stage 2 trials for autism doses of 0.25 mg/kg, 0.5 mg/kg and 0.75 mg/kg were all found to be safe and well tolerated.

As a summertime add-on therapy it appears very well tolerated.

In adults with type 2 diabetes, who will tend to be overweight and not so healthy, there are common side effects.  At one point, it was thought that there was an association between this drug and bladder cancer. Now this is thought not to be the case.

For adults with severe untreated autism, who are aggressive and self-injure, these behaviors very much limit where they can live and what they can do during the day. Life expectancy is also severely reduced. If Pioglitazone can help control these behaviors, some side effects are likely a price worth paying. 

 

Conclusion

Pioglitazone, by the standards of autism drugs, has plenty of evidence in the literature, regarding both mouse models and humans, to support an n=1 trial.  It addresses neuro-inflammation, one key feature of autism and it has beneficial effects on mitochondria.

Pioglitazone abolishes autistic-like behaviors via the IL-6 pathway

In a small cohort of autistic children, daily treatment with pioglitazone eased some autistic behaviors, such as irritability, lethargy, stereotypy, and hyperactivity, without significant side effects

 pioglitazone treatment inhibits the secretion of proinflammatory factors, such as nitric oxide and IL-6, and enhances the levels of the secretion of anti-inflammatory factors IL-4 and IL-10. Therefore, considering the results of Qiu and Li and our present findings, pioglitazone acted to benefit autistic-like behaviors possibly via the inhibition of IL-6 secretion in astrocytes stimulated by LPS, which inhibited the neuroinflammatory response.

 

I think for people whose child with autism has a behavioural or cognitive regression in summer, there is good reason to expect a benefit.  They very likely have allergies or other autoimmune conditions.

For people who deal with aggression and self-injury in a person who responds partially, but not 100%, to Verapamil, they may find that Pioglitazone helps to complete their anti-aggression therapy.

Our doctor reader Agnieszka did her best to collect case studies of people with autism responsive to Verapamil, but not enough parents wanted to participate.

Based on the comments section in this blog, it would look like our reader George in Romania has a son whose son’s aggression is reduced by Verapamil.  If some aggression persists in summer, I think there is a very good chance that Pioglitazone will help reduce it.  George did recently share with us the the anti-inflammatory Probiotic Lactobacillus Plantarum 299v, from the previous post and widely used for irritable bowel syndrome (IBS), improved his son's speech.  

Note that the research clearly shows that most autism has an "inflammatory" element, but the exact nature varies (for details read the work of Paul Ashwood at the MIND Institute).  There are very many different anti-inflammatory therapies that are reported to benefit specific people, but there are no unifying therapies that work for all. Some will inevitably make non-responders worse and potentially dramatically so, like L.reuteri ATCC PTA 6475, found in Biogaia Gastrus. Trial and error seems unavoidable if you want to find an effective therapy.

The research proposes Pioglitazone as a year round therapy for idiopathic autism.  In the phase 2 trial almost half of the children were deemed to be responders to the treatment; not a bad result. I think it also has potential as just a summertime add-on therapy. We used it last summer and now again this summer.

People with a diagnosis of mitochondrial disease, who also present with lethargy, might be another target group because of PGC-1 alpha.





Wednesday, 8 July 2020

Immune modulatory treatments for autism spectrum disorder


Need a wizard, or your local doctor?

I was intrigued to come across a recent paper on immune modulatory treatments for autism by a couple of doctors from Massachusetts General Hospital for Children.  The lead author has interests in:

·      Autism spectrum disorders
·      Psychopharmacology
·      Developmental Disabilities
·      Williams syndrome
·      Angelman syndrome
·      Down syndrome

Apparently, he is an internationally-recognized expert in the neurobiology and neuropsychopharmacology of childhood-onset neuropsychiatric disorders including autistic disorder.  Sounds promising, hopefully we will learn something new.

The paper is actually a review of existing drugs, with immunomodulatory properties, that have already been suggested to be repurposed for autism. The abstract was not very insightful, so I have highlighted the final conclusions and listed the drugs, by category, that they thought should be investigated further.

All the drugs have already been covered in this blog and have already been researched in autism.

One important point raised in the conclusion relates to when the drugs are used.  Autism is a progressive condition early in life and there are so-called “critical periods” when the developing brain is highly vulnerable.

For example, Pentoxifylline has been found to be most effective in very young children.  This does not mean do not give it to a teenager with autism, it just means the sooner you treat autism the better the result will be.  This is entirely logical.

Some very clever drugs clearly do not work if given too late, for example Rapamycin analogs used in people with TSC-type autism.

Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in Tsc-1-Suppressed Brain

Importantly, each of these developmental abnormalities that are caused by enhanced mTOR pathway has a specific window of opportunity to respond to rapamycin. Namely, dyslamination must be corrected during neurogenesis, and postnatal rapamycin treatment will not correct the cortical malformation. Similarly, exuberant branching of basal dendrites is rectifiable only during the first 2 weeks postnatally while an increase in spine density responds to rapamycin treatment thereafter.  

Back to today’s paper.


The identification of immune dysregulation in at least a subtype ASD has led to the hypothesis that immune modulatory treatments may be effective in treating the core and associated symptoms of ASD. In this article, we discussed how currently FDA-approved medications for ASD have immune modulatory properties.

“Risperidone also inhibited the expression of inflammatory signaling proteins, myelin basic protein isoform 3 (MBP1) and mitogen-activated kinase 1 (MAPK1), in a rat model of MIA. Similarly, aripiprazole has been demonstrated to inhibit expression of IL-6 and TNF-α in cultured primary human peripheral blood mononuclear cells from healthy adult donors.”

We then described emerging treatments for ASD which have been repurposed from nonpsychiatric fields of medicine including metabolic disease, infectious disease, gastroenterology, neurology, and regenerative medicine, all with immune modulatory potential. Although immune modulatory treatments are not currently the standard of care for ASD, remain experimental, and require further research to demonstrate clear safety, tolerability, and efficacy, the early positive results described above warrant further research in the context of IRB-approved clinical trials. Future research is needed to determine whether immune modulatory treatments will affect underlying pathophysiological processes affecting both the behavioral symptoms and the common immune-mediated medical co-morbidities of ASD. Identification of neuroimaging or inflammatory biomarkers that respond to immune modulatory treatment and correlate with treatment response would further support the hypothesis of an immune-mediated subtype of ASD and aid in measuring response to immune modulatory treatments. In addition, it will be important to determine if particular immune modulating treatments are best tolerated and most effective when administered at specific developmental time points across the lifespan of individuals with ASD.


Here are the drugs they listed:-

1.     Metabolic disease

Spironolactone
Pioglitazone
Pentoxifylline

Spironolactone is a cheap potassium sparing diuretic. It has secondary effects that include reducing the level of male hormones and some inflammatory cytokines.

Pioglitazone is drug for type 2 diabetes that improves insulin sensitivity.  It reduces certain inflammatory cytokines making it both an autism therapy and indeed a suggested Covid-19 therapy.

Pentoxifylline is a non-selective phosphodiesterase (PDEinhibitor, used to treat muscle pain.  PDE inhibitors are very interesting drugs with a great therapeutic potential for the treatment of immune-mediated and inflammatory diseases.  Roflumilast and Ibudilast are PDE4 inhibitors that also may improve some autism.  The limiting side effect can be nausea/vomiting, which can happen with non-selective PDE4 inhibitors.

I did try Spironolactone once; it did not seem to have any effect.  It is a good match for bumetanide because it increases potassium levels.

I do think that Pioglitazone has a helpful effect and there will be another post on that.

PDE inhibitors are used by readers of this blog. Maja is a fan of Pentoxifylline, without any side effects. Roflumilast at a low dose is supposed to raise IQ, but still makes some people want to vomit. The Japanese drug Ibudilast works for some, but nausea is listed as a possible side effect.


2.     Infectious disease

Minocycline
Vancomycin
Suramin

Minocycline is an antibiotic that crosses in to the brain.  It is known to stabilize activated microglia, the brain’s immune cells.  It is also known that tetracycline antibiotics are immunomodulatory.

Vancomycin is an antibiotic used to treat bacterial infections, if taken orally it does not go beyond the gut.  It will reduce the level of certain harmful bacteria including Clostridium difficile.

Suramin is an anti-parasite drug that Dr Naviaux is repurposing for autism, based on his theory of cell danger response.
  

3.     Neurology

Valproic acid

Valproic acid is an anti-epileptic drug.  It also has immunomodulatory and HDAC effects, these effects can both cause autism when taken by a pregnant mother and also improve autism in some people.

Valproic acid can have side effects. Low dose valproic acid seems to work for some people. 


4.     Gastroenterology

Fecal microbiota transplant (FMT)

FMT is currently used to treat recurrent Clostridium difficile infection and may also be of benefit for other GI conditions including IBD, obesity, metabolic syndrome, and functional GI disorders.

Altered gut bacteria (dysbiosis) is a feature of some autism which then impairs brain function.  Reversing the dysbiosis with FMT improves brain function.  


5.     Oncology

Lenalidomide
Romidepsin
  
Lenalidomide is an expensive anti-cancer drug that also has immunomodulatory effects.

Romidepsin is a potent HDAC inhibitor, making it a useful cancer therapy.  HDAC inhibitors are potential autism drugs, but only if given early enough not to miss the critical periods of brain development. 


6.     Pulmonology

N-acetylcysteine

Many people with autism respond well to NAC. You do need a lot of it, because it has a short half-life.


7.     Nutritional medicine and dietary supplements

Omega-3 fatty acids
Vitamin D
Flavonoids

Nutritional supplements can get very expensive.  In hot climates, like Egypt, some dark skinned people cover up and then lack vitamin D.  A lack of vitamin D will make autism worse.

Some people with mild brain disorders do seem to benefit from some omega-3 therapies.

Flavonoids are very good for general health, but seem to lack potency for treating brain disorders.  Quercetin and luteolin do have some benefits. 


8.     Rheumatology

Celecoxib
Corticosteroids
Intravenous immunoglobulin (IVIG)


Celecoxib is a common NSAID that is particularly well tolerated (it affects COX-2 and only marginally COX-1, hence its reduced GI side effects).

NSAIDS are used by many people with autism.

Steroids do improve some people’s autism, but are unsuitable for long term use.  A short course of steroids reduces Covid-19 deaths – a very cost effective therapy.

IVIG is extremely expensive, but it does provide a benefit in some cases. IVIG is used quite often to treat autism in the US, but rarely elsewhere other than for PANS/PANDAS that might occur with autism.


9.     Regenerative medicine

Stem cell therapy

I was surprised they gave stem cell therapy a mention. I think it is still early days for stem cell therapy.


Conclusion

I have observed the ongoing Covid-19 situation with interest and in particular what use has been made of the scientific literature.

There are all sorts of interesting snippets of data. You do not want to be deficient in Zinc or vitamin D, having high cholesterol will make it easier for the virus to enter your cells.  Potassium levels may plummet and blood becomes sticky, so may form dangerous clots. A long list of drugs may be at least partially effective, meaning they speed up recovery and reduce death rates. Polytherapy, meaning taking multiple drugs, is likely to be the best choice for Covid-19.

Potential side effects of some drugs have been grossly exaggerated, as with drugs repurposed for autism.  Even in published research, people cheat and falsify the data. In the case of hydroxychloroquine, the falsified papers were quickly retracted.

The media twist the facts, to suit their narrative, as with autism.  This happens even with Covid-19. Anti-Trump media (CNN, BBC etc) is automatically anti-hydroxychloroquine, and ignores all the published research and the results achieved in countries that widely use it (small countries like China and India). 

Shutting down entire economies when only 5-10% of the population have been infected and hopefully got some immunity, does not look so smart if you are then going to reopen and let young people loose.  They will inevitably catch the virus and then infect everyone else. Permanent lockdown restrictions, if followed by everyone, until a vaccine which everyone actually agreed to take, makes sense and living with the virus makes sense, but anything in between is not going to work. After 3 months without any broad lockdown, and allowing young people to socialize, most people would have had the virus and then those people choosing to shield could safely reemerge. The death rate with the current optimal, inexpensive treatment, as used in India or South Africa is very low, in people who are not frail to start with. Time to make a choice.  Poor people in poor countries cannot afford to keep going into lockdown, they need to eat.

What hope is there for treating a highly heterogeneous condition like autism, if it is not approached entirely rationally and without preconceptions and preconditions?  In a pandemic we see that science does not drive policy and translating science into therapy is highly variable.  The science is there for those who choose to read it.

I frequently see comments from parents who have seen some of the research showing that autism has an inflammatory/auto-immune component.  They ask why this has not been followed up on in the research.  It has been followed up on.  It just has not been acted upon.

Why has it not been acted on?

This missing stage is called “translation”.  Why don’t doctors translate scientific findings into therapy for their patients?

What is common sense to some, is “experimental” to others. “Experimental” is frowned upon in modern medicine, but innovation requires experimentation.

Many people’s severe autism is unique and experimental polytherapy/polypharmacy is their only hope.

The cookie cutter approach is not going to work for autism. 

Thankfully, for many common diseases the cookie cutter approach works just fine.

Do the authors of today’s paper, Dr McDougle and Dr Thom, actually prescribe to their young patients many of the drugs that they have written about?  I doubt it and therein lies the problem.  

Time for that wizard, perhaps? 

A few years ago I did add the following tag line, under the big Epiphany at the top of the page. 

An Alternative Reality for Classic Autism - Based on Today's Science

You can choose a different Autism reality, if you do not like your current one.  I am glad I did. I didn't even need a wizard.  

There are many immuno-modulatory therapies for autism that the Massachusetts doctor duo did not mention, but it is good that they made a start.








Sunday, 14 June 2020

Summertime Autism Raging and Dumber in the Summer


By far the most read post in this blog is one about histamine and allergies, which means many people are searching on Google for “histamine, allergy and autism”.

Our reader Kei recently commented that his daughter, without allergy, was again showing signs of summertime raging and that his neurologist confirmed that summertime raging does indeed happen and nobody knows why.

I did figure out how to deal with our version of “summertime raging” and the post-bumetanide “dumber in the summer” phenomena.  There were several posts on this subject.  The lasting solution was to treat the raging as if it was caused by inflammation driven by pollen allergy and to note that inflammation will further worsen the KCC2/NKCC1 imbalance in Bumetanide-responsive autism, making those people appear “dumber in the summer”.  This also accounts for the “Bumetanide has stopped working” phenomenon, reported by some parents.  You need to minimize inflammation from allergy and increase Bumetanide (or add Azosemide).  My discovery was that Verapamil was actually more effective than anti-histamines and actual mast cell stabilizers. Mast cells degranulate via a process dependent of the L-type calcium channels that Verapamil blocks. Mast cells release histamine and inflammatory cytokines like IL-6.

This spring when Monty’s brother asked why Monty was acting dumber, it was time to implement the “dumber in the summer” therapies.  Add a morning tablet of cetirizine (Zyrtec) and a nasal spray of Dymista (Azelastine + Fluticasone).

Dymista is inexpensive and OTC where we live, but I see in the US it is quite an expensive prescription drug.  It is a favourite of Monty’s pediatrician and his ENT doctor. 



Summertime Regression in the Research Literature

I recently came across two very relevant papers on this subject by a proactive American immunologist called Dr Marvin Boris.  If you live in New York, he looks like a useful person to know.

In his first study he investigated whether the onset of the allergy season caused a deterioration in behavior of children with autism or ADHD; in more than half of the trial subjects, it did.

In his second study he went on to make a double‐blind crossover study with nasal inhalation of a pollen extract or placebo on alternate weeks during the winter.  This was his way to recreate the pollen season during winter.

Sixteen of 29 (55%) children with ASD and 12 of 18 (67%) children with ADHD or a total of 28 of 47 (60%) children regressed significantly from their baseline. Nasal pollen challenge produced significant neurobehavioral regression in these children. This regression occurred in both allergic and non‐allergic children and was not associated with respiratory symptoms.

In other words, half of children with autism regress when exposed to pollen, even though they may not show any symptoms of allergy, or test positive for allergy.  This should be of interest to Kei and his neurologist.



Purpose: To determine whether children with autistic spectrum disorders (ASD) or attention deficit hyperactive disorder (ADHD) exhibit neurobehavioral regressive changes during pollen seasons.
Design: A behavioral questionnaire‐based survey, with results matched to pollen counts; an uncontrolled, open non‐intervention study.
Materials and Methods: Twenty‐nine children identified with ASD and 18 children with ADHD comprised the study population. The parents of the study children completed the Allergic Symptom Screen for 2 weeks during the winter prior to the pollen allergy season under investigation. The parents of the ASD children also completed the Aberrant Behavior Checklist and the parents of the ADHD children completed Conners' Revised Parent Short Form for the same periods. The parents completed the respective forms weekly from 1 March to 31 October 2002. Pollen counts from the geographical area of study were recorded on a daily basis during this period.
Results: During natural pollen exposure, 15 of 29 (52%) children with ASD and 10 of 18 (56%) children with ADHD demonstrated neurobehavioral regression. There was no correlation with the child's allergic status (IgE, skin tests and RAST) or allergy symptoms.
Conclusions: Pollen exposure can produce neurobehavioral regression in the majority of children with ASD or ADHD on a non‐IgE‐mediated mechanism. Psychological dysfunction can be potentiated by environmental exposures. 


Pollen Exposure as a Cause for the Deterioration of Neurobehavioral Function in Children with Autism and Attention Deficit Hyperactive Disorder: Nasal Pollen Challenge 

Purpose: In a previous study it was established that children with attention deficit hyperactive disorder (ADHD) and autistic spectrum disorders (ASD) had regressed during pollen seasons. The purpose of this study was to determine if these children regressed on direct nasal pollen challenge. 

Design: A double‐blind crossover placebo‐controlled nasal challenge study. Materials and Methods: Twenty‐nine children with ASD and 18 with ADHD comprised the population. The study was a double‐blind crossover with nasal instillation of a pollen extract or placebo on alternate weeks during the winter. The pollens used were oak tree, timothy grass and ragweed. The dose insufflated into each nostril was 25 mg (±15%) of each pollen. 

Results: Sixteen of 29 (55%) children with ASD and 12 of 18 (67%) children with ADHD or a total of 28 of 47 (60%) children regressed significantly from their baseline. 

Nasal pollen challenge produced significant neurobehavioral regression in these children. This regression occurred in both allergic and non‐allergic children and was not associated with respiratory symptoms. There was no correlation to the child's IgE level, positive RAST pollen tests, or skin tests.


Conclusion

When I was figuring out Monty’s summertime raging and cognitive decline, several years ago, there were no significant signs of allergy present.  Nowadays there are far more visible signs of allergy.

Dr Boris does not suggest any therapy for summertime raging, but he did show that it can be driven by pollen in half of those with autism, even children who have no signs of having any allergy.

His studies were published more than a decade ago and seem to have been forgotten.  This seems a pity, but it says a lot.

I only stumbled upon his papers because I was reading another of his decade old papers.  That paper is based on his early use of Pioglitazone in autism, which resulted in several hundred children being successfully prescribed this drug.  Pioglitazone selectively stimulates the peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α.

There was a bladder cancer scare, lots of hungry lawyers and I suppose people stopped prescribing Pioglitazone for autism a decade ago.  The numerous subsequent safety studies and meta-analysis show either a small increased risk, or no increased risk, very much dependent on who financed the research.  Pioglitazone is given to people with type 2 diabetes, and they are already at an increased risk of bladder cancer.  In those people, that risk increases between 0 and about 20%, depending on the study.  We are talking about 0.07% to 0.1% of people with T2 diabetes taking Pioglitazone later developing bladder cancer.

A decade later and Pioglitazone is again back in fashion with trials in humans with autism and studies in mouse models of autism. The current autism research does not see cancer risk as reason not to use Pioglitazone.  I agree with them. 

It looks like a minority of people taking Pioglitazone are more likely to suffer upper respiratory tract infections.  That is the risk that I consider relevant.  I also note that in trials even the placebo can appear to cause upper respiratory tract infections.

Pioglitazone was covered in earlier posts, 


but there will soon be a new post.  For most people I think histamine, allergy and summertime raging will continue to be of more interest.






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. 




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.

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.