The Kynurenine Pathway in Autism and its modification using Sulforaphane or the probiotic Lactobacillus Plantarum 299v

 

 A pathway to somewhere, hopefully

Today’s post was prompted by our reader George’s observation that the probiotic Lactobacillus Plantarum 299v increased speech in his adult son.  This widely available probiotic is commonly used to treat IBS (Irritable Bowel Syndrome) and I did mention it in a recent post about Eubiotics.

Eubiotics for GI Dysfunction and some Autism

Increased speech is a target for many people treating autism and this probiotic is known to be safely used long term - so it is interesting.

Since I already had this probiotic at home, I made a trial and I observed a very similar effect to what happened several years ago when Monty started to use Sulforaphane / broccoli sprout powder. 

The effect of broccoli powder was a brief period of euphoria about 20 minutes later and a then a marked increase in verbalization.  The effect on mood was seen by some other readers, but not the majority. I recall back then a very happy parent who was feeding broccoli powder to his child via a G-tube. A gastrostomy tube, often called a G-tube, is a surgically placed device used to give direct access to your child's stomach for supplemental feeding, hydration or medication.  Some children with autism will not eat and so are fed via a G-tube.

Broccoli powder tastes pretty bad, but this is one problem you will not experience when taking it via a G tube.

I was surprised that even some people with mild autism found broccoli powder beneficial. In diabetics it improves insulin sensitivity and so reduces the amount of insulin they need to inject.

This post is about the science, but before reading all the science, I made my trial of Lactobacillus Plantarum 299v.  One capsule a day works very nicely. The science is optional.

I wondered what might be the shared effect of these two very different therapies - broccoli and L.P. 299v.  There is indeed a plausible explanation, the Kynurenine pathway.

 

Click on the graphic, to enlarge

This may all look rather complicated, but there are some terms we are already very familiar with. We know that Serotonin is the happy hormone and we know that Melatonin is the sleep hormone.

It all starts with Tryptophan, one of those amino acids. It is essential in humans, meaning that the body cannot synthesize it and it must be obtained from the diet. Good sources include milk, turkey and bananas. If you take bumetanide, you likely already eat a lot of bananas due to their potassium content.

95% of tryptophan is metabolized to Kynurenine, a very odd sounding word. So it must be that less than 5% becomes Serotonin and Melatonin. Two enzymes, namely indoleamine 2,3-dioxygenase (IDO) in the immune system and the brain, and tryptophan dioxygenase (TDO) in the liver, are responsible for the synthesis of kynurenine from tryptophan.

The so-called kynurenine pathway of tryptophan is altered in several diseases, including psychiatric disorders such as autism, schizophrenia, major depressive disorder and bipolar disorder.

The supplements Tryptophan and 5-hydroxytryptophan (5-HTP) are widely used for many conditions ranging from depression to autism.

 

The kynurenine pathway is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide (NAD⁺).

 

NAD⁺ is very important.

 

Increasing the level of NAD is itself an autism therapy in the research. 

New Preclinical Study Finds Niagen® Corrects Social Deficits in Mouse Model of Autism

First-of-its-kind preclinical study shows that Niagen® (nicotinamide riboside) resolves social deficits and anxiety-like behaviors in male mice

The amount of Tryptophan that ends up as the cute-sounding Picolinic acid is determined by how much of the enzyme ACMSD is present.

Quinolinic acid (QUIN) and Kynurenic acid (KYNA) are two neuroactive KP metabolites that have received considerable attention for their modulation of the NMDA receptor. While QUIN shows neurotoxic effects by over activation of the NMDA receptor, KYNA offers neuro-protection by blocking receptor function. Emphasis has been placed upon the importance of maintaining a balanced ratio between these two metabolites.

Picolinic acid (PIC) also shows antagonistic properties towards the toxic effects of QUIN via an unknown mechanism.  There are a number of biological factors that can potentially affect PIC levels and synthesis in the CNS including age, circadian rhythms and hormonal and nutritional factors.

 

 Source: The Physiological Action of Picolinic Acid in the Human Brain

Anthranilic acid (AA), once thought to be vitamin L, is very elevated in schizophrenia, and also in type-1 diabetes and arthritis.  AA is seen as a treatment target in these conditions. 

Now for the interesting part, the effect of the probiotic Lactobacillus Plantarum 299v on the Kynurenine pathway:

 

Probiotic Lactobacillus Plantarum 299v decreases kynurenine concentration and improves cognitive functions in patients with major depression: A double-blind, randomized, placebo controlled study

Highlights

· There was an improvement in cognitive functions in group of depressed patients receiving probiotic Lactobacillus Plantarum 299v (LP299v) compared to the placebo group.

 · There was a significant decrease in kynurenine concentration in the LP299v group compared to the placebo group.

 · There was a significant increase in 3-hydroxykynurenine : kynurenine ratio in the LP299v group compared with the placebo group.

· Decreased kynurenine concentration due to probiotic could contribute to the improvement of cognitive functions in the LP299v group compared to the placebo group.

  

And, the effect of Sulforaphane on the Kynurenine pathway: 

 

Altered kynurenine pathway metabolism in autism:Implication for immune-induced glutamatergic activity

Dysfunction of the serotoninergic and glutamatergic systems is implicated in the pathogenesis of autism spectrum disorder (ASD) together with various neuroinflammatory mediators. As the kynurenine pathway (KP) of tryptophan degradation is activated in neuroinflammatory states, we hypothesized that there may be a link between inflammation in ASD and enhanced KP activation resulting in reduced serotonin synthesis from tryptophan and production of KP metabolites capable of modulating glutamatergic activity. A cross-sectional study of 15 different Omani families with newly diagnosed children with ASD (n = 15) and their age-matched healthy siblings (n = 12) was designed. Immunological profile and the KP metabolic signature were characterized in the study participants. Our data indicated that there were alterations to the KP in ASD. Specifically, increased production of the downstream metabolite, Quinolinic acid, which is capable of enhancing glutamatergic neurotransmission was noted. Correlation studies also demonstrated that the presence of inflammation induced KP activation in ASD. Until now, previous studies have failed to establish a link between inflammation, glutamatergic activity, and the KP. Our findings also suggest that increased Quinolinic acid may be linked to 16p11.2 mutations leading to abnormal glutamatergic activity associated with ASD pathogenesis and may help rationalize the efficacy of sulforaphane treatment in ASD.

 

QA = Quinolinic Acid

KP = Kynurenine Pathway

 

The increased concentration of QA in ASD is also likely to be associated with increased oxidative stress. We previously showed that QA can significantly potentiate oxidative stress in human primary neuron cultures and that oxidative stress markers are increased in children with ASD.  Recently, a clinical study effectively used sulforaphane derived from the broccoli sprout to treat ASD resulting in improved behaviour.  Interestingly, sulforaphane was shown to attenuate the effect of QA-induced toxicity in rat brain by enhancing the antioxidant, glutathione. This study is coherent with our current finding of increased QA in children with ASD and our previous work showing decreased glutathione in the children with ASD.  Hence, the possibility that sulforaphane may act by attenuating QA-induce oxidative stress in ASD warrants further investigation.

 

Conclusion

Too much Quinolinic Acid (QA) does appear to be a damaging feature of autism and is produced by a malfunctioning Kynurenine pathway (KP).

The exact relevance of each part of the KP in diseases of the brain is still a work in progress, but it is clearly disturbed in a specific way in each particular CNS disorder, autism being just one.

Modifying the KP does look like a useful therapeutic avenue to follow, but it is not so simple to understand all of it.

It appears that Lactobacillus Plantarum 299v may improve some people’s autism via a mechanism that includes modification of the Kynurenine pathway (KP). It may also be the case that sulforaphane / broccoli powder has an effect that counters the disturbed KP. For whatever biological reason, the visible/audible effects of the two therapies appear to be remarkably similar.

As usual, you do not have to fully understand biological pathways, like the KP, to benefit from them.  In effect, it is all a question of where all the Tryptophan from your diet ends up – and for some people it does seem to matter.

Lactobacillus Plantarum 299v and sulforaphane / broccoli are not wonder autism therapies for most responders, but if there is an incremental benefit available, you may want to take it.

Another low hanging fruit? 

 

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.

Eubiotics for GI Dysfunction and some Autism

  

Today’s post is about some drugs/supplements that have already been discussed in earlier posts.  Rifaximin, used in cycles, is an effective part of our reader Maja’s therapy, while Sodium Butyrate was highlighted long ago by our reader in Switzerland, Alli.

I had a consultation with a gastroenterologist last week and came away with a prescription for Rifaximin, microencapsulated Sodium Butyrate and Lactobacillus Plantarum 299v. Where we live, these are all inexpensive. Rifaximin is an antibiotic with extra benefits and costs about 7 euros (9 dollars). 

A course of Rifaximin can cost $2,000 in the United States.

I was pleased to read that the private equity owners of a pharmaceutical company that raised the price of a common thyroid drug by 6000% have just been fined $140 million in the UK.

Advanz Pharma and former private equity owners were fined £100m by markets watchdog

Perhaps some of our US readers should query the crazy price of drugs in the US with their congressman? Very many cheap old drugs are ultra expensive in the US, even insulin is over-priced. Not a good model of a market economy. 

 

Eubiotics – a big business

You may very well never have come across the term eubiotic before, but it is already a multi-billion dollar business.  A eubiotic is something that changes the gut microbiome to improve health. The big business to date are additives to animal feed, rather than products for human health.

Eubiotics work for humans as well. Rifaximin is an antibiotic but it also has the additional properties of a eubiotic. 

“These include: modulation of the microflora of the gastrointestinal tract by promoting the growth of Lactobacilli and Bifidobacteria strains (the so-called “eubiotic” effect) as well as modulation of bacterial metabolism, including inhibition of the hydrocarbon-derived pathways.  This drug is also capable of reducing the virulence of enteropathogenic Escherichia coli strains by inhibiting the expression of enterotoxins or adhesive factors. Interestingly, Rifaximin is distinguished by several anti-inflammatory activities mainly exerted by the pregnane X receptor (PXR), expressed primarily in the gastrointestinal tract, the small intestine, and the colon. Due to the activity described above, Rifaximin is called a eubiotic, not an antibiotic.”

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497137/

Rifaximin, like vancomycin, is usually thought of as a GI antibiotic; it stays in your gut and almost none ends up in your blood.  Both drugs are used to kill off bacteria in your gut. This is all vancomycin does, so it is not classed as a eubiotic. Rifaximin, however, goes on to perform further functions as a eubiotic, so it models your gut flora in a beneficial way.

Rifaximin is almost a wonder drug for IBS-D (irritable bowel syndrome with diarrhea).  It is also a common therapy for SIBO (small intestinal bacterial overgrowth), but while it works well for some, it actually makes things worse for some others.

Rifaximin is used both as a therapy for an acute GI problem and preventatively. It can be used in cycles, like a few days every month.

Maja is in a good position, because where she lives Rifaximin costs a few euros/dollars.

People with IBS-D in the United States often cannot afford monthly cycles of Rifaximin.

Other kinds of eubiotics include prebiotics, other probiotics, all kinds of clever fiber, inulin, fructooligosaccharides (FOS), galactooligosaccharides (GOS) etc.  I did cover psychobiotics in an earlier post, these are probiotic bacteria that are used to reduce anxiety, ADHD and other psychiatric symptoms.

Psychobiotics (PS128) for Autism, Stereotypy and Sometimes Effective Therapies for what might be SIBO (Rifaximin and Herbal)

  

Sodium Butyrate

Sodium buyrate produces butyric acid when you swallow it.  Butyric acid is what gives rancid butter its smell.  Butyric acid is one of the big eubiotics used in the animal feed industry. I did cover the very old Japanese probiotic MIYAIRI 588 (full name is Clostridium butyricum MIYAIRI 588) a long time ago in this blog.  This probiotic, in use since the Second World War, produces butyric acid in your gut by fermentation.  In Japan this probiotic is used in humans and more recently as an additive to animal feed, to produce healthier, bigger, chickens and pigs. 

Our reader MG in Hong Kong recently reported that MIYAIRI 588 was beneficial in his case. 

My gastroenterologist prescribed me Microencapsulated Sodium Butyrate, which is covered in the research and has encouraging results. When you see the word microencapsulated, you might start feeling some pain developing in your wallet, rather than in your gut, but again, this product called Integra and made in Poland,  was not so pricey - about EUR 10 ($12) for 60 capsules. One capsule contains 150 mg of sodium butyrate in tiny particles covered in triglycerides.  I have no idea if it is going to do me any good, but the research suggests it is beneficial for certain types of GI dysfunction and will strengthen the intestinal gut barrier (the equivalent of the blood brain barrier). 

Butyric acid has several different modes of action, one is as an HDAC inhibitor, which was covered in earlier posts. HDAC inhibitors can change gene transcription, which is potentially very useful, including in the prevention and treatment of some cancers. The potent HDAC inhibitors from cancer therapy show effect in some types of single gene autism.

Autism-Like Social Deficits Reversed by Epigenetic Drug 

There are different classes of HDAC inhibitor and you would need to match the type of autism with the appropriate type of HDAC inhibitor.  Valproic acid is another common HDAC inhibitor sitting on the shelf of many people with autism plus epilepsy. 

Lactobacillus Plantarum 299v 

Lactobacillus plantarum 299v has been shown to improve symptoms of IBS (Irritable Bowel Syndrome).  It prevents Clostridium difficile-associated diarrhea among patients receiving antibiotic treatment.  It is also known to be immunomodulatory, shifting the balance away from pro-inflammatory cytokines.

The role of Lactobacillus plantarum 299v in supporting treatment of selected diseases 

Alterations in composition of human gut microbiome can lead to its dysbiosis. It is associated with gastrointestinal side effects during anti-cancer treatment, antibiotics administration, or infectious agents. There are studies confirming positive effect of consuming Lactobacillus plantarum 299v on intestinal microflora. This review summarizes the current knowledge about the role of L. plantarum 299v in supporting treatment of selected diseases, such as cancer, irritable bowel syndrome (IBS), and Clostridium difficile infection. The immunomodulating properties of L. plantarum 299v include an increase in the level of anti-inflammatory cytokines, which reduce the risk of cancer and improve the efficacy of regimens. The intake of L. plantarum 299v provides benefits for IBS patients, mainly due to normalization of stool and relief of abdominal pain, which significantly improves the quality of life of IBS patients. In addition, the intake of L. plantarum 299v prevents C. difficile-associated diarrhea among patients receiving antibiotic treatment. Due to the limited possibilities of treating these diseases and numerous complications of cancer treatment, there is a need for new therapeutic strategies. The administration of L. plantarum 299v seems to be useful in these cases. 

 

Bacteria could aid autistics

Might a daily dose of friendly bacteria help treat autism? UK researchers hope probiotics will soothe the gut problems linked to autism and may even ease psychological symptoms. They are planning a clinical trial to test the idea.

The proposed health benefits of probiotic bacteria are well known. The beneficial bugs are thought to out-compete other gut bacteria that can cause diarrhoea and ill health.

Children with autism are known to have higher levels of one group of 'bad' bacteria, Clostridia, in their guts, explains Glenn Gibson from the University of Reading. So he hopes probiotic food supplements that lower levels of Clostridia will allay some symptoms of autism.

He is not suggesting that the bad bacteria cause autism: genetic and environmental factors are both likely to contribute to the complex disorder, the cause of which is unknown. But toxic by-products of the bacteria may be absorbed into the blood and travel to the brain, where they may play a role in ill health.

At present, the researchers are honing their choice of bacteria. There are many different types of good bacteria, so it is important to choose one that can compete effectively against Clostridia.

One candidate, called Lactobacillus plantarum 299v, looks especially promising. The bacterium binds to the gut lining and stimulates its growth. As well as out-competing other bacteria, it also lowers gut pH, which helps the digestive tract to fight infection. It stays in the gut for days and has never been associated with any health problems.

 

Conclusion

I am always surprised how many common drugs that you come across have potential to be repurposed to benefit  some people with autism.

It really shows how effective therapy, for at least some people with autism, is already in the medicine cabinet at home, or more likely over at the grandparents’ house.

(statins, calcium channel blockers, asthma/COPD drugs, other blood pressure drugs, diuretics, type 2 diabetes drugs)

I thought my gastroenterologist’s therapy was quite enlightened. I hope his diagnosis is accurate; I am not entirely convinced, but time will tell.  The diagnosis from doctor number one was kidney stones and now I am on doctor number three. An accurate diagnosis is not always a simple matter, as autism parents know only too well.

I did meet Dr Federico Balzola a while back. He is an Italian gastroenterologist with a keen interest in autism. He is an associate of Dr Arthur Krigsman, a US gastroenterologist heavily involved with autistic patients. In some countries the connection between GI problems and autism is still a taboo subject, seemingly because Dr Andrew Wakefield was a gastroenterologist.  

 

I am always surprised how many young Aspies have symptoms of IBS or IBD. I would actually like to know if this is mainly a problem in childhood and adolescence, which I suspect is the case. 

One of my most popular posts was another one about gastroenterology, which really surprised me.

Eosinophilic Esophagitis – another Granulocyte Disorder Associated with Autism

 

Google is discontinuing subscribe by email feature

 

Many readers have been receiving new posts automatically by email.

This was a free service provided by Feedburner, part of Google.  This service is about to be discontinued by Google.

I have added a new service provided by a company called Follow.it, which should provide the follow by email service.

In theory, the people who subscribed to the Google service should be migrated over to the new service.  

If it does not work, you can just subscribe again in the top right corner of the Web version of the blog. 

The smart phone version of the blog may not display this feature, because of the small screen size.

 

 

Leaky ATP from either Mitochondria or Neurons in Fragile X and Autism

 

 

For leaky ATP, Popeye might want to try Dexpramipexole and

Suramin, or even the already approved Mirapex

If you are old enough to be a parent, you will have encountered problems with some kind of leak.  A leaky roof, a leaky pipe, a leaky washing machine, an air-conditioning unit... The list goes on, the older you get.

I have been preoccupied by fixing a leak recently.  We have a large roof terrace and, in the winter, water started leaking from the ceiling in the floor below.  I improvised a system to catch all the water, but still I had to find the source of the leak.

I did finally find the source of the problem and most importantly without digging up 95% of the terrace.  Now I have to put the 5% back together again.

Leaks are often extremely difficult to locate, because water always finds the easiest path and the dripping you see might have originated from a leak far away.  Nobody wants to fix leaks, because it can be a pretty thankless task and you can cause plenty of damage in the process, without solving the problem.  So, as with fixing autism, I ended up doing much of the fixing myself.  The damage had actually been there since the house was built, hidden under ceramic tiles.

I recently read about leaky ATP in Fragile-X, where ATP leaks from the mitochondria into the cell.

This fits neatly into Professor Naviaux’s belief that ATP is leaking from the cell into the extracellular space, as the basis for his concept of the cell danger response, as a unifying and treatable feature of most autism.

Sounds complicated?

Just think of it as bunch of leaks you need to fix.

 

 What is ATP? 

ATP has many functions:- 

·        It is the fuel your cells need to function.

·        It is a signalling molecule within a cell and importantly between different cells.

·        It is used to make your DNA

  

Mitochondria

Each cell in your brain contains many mitochondria and these are where ATP is produced. Mitochondria die and are replaced, whereas if the host brain cell dies, it is lost forever. Cell death in the brain is bad news.

The ATP – ADP Cycle 

You can think of ATP as a fully charged battery.  Once the energy has been used up the flat battery is called ADP and it goes back for recharging in the mitochondria.  It is a continuous cycle.

ADP is powered back to ATP through the process of releasing the chemical energy available in food; this is constantly performed via aerobic respiration in the mitochondria. This process is also called OXPHOS and has been covered in previous posts.  In most mitochondrial disease the problem is that one of the four mitochondrial enzyme complexes is insufficient; this means that the ATP-ADP cycle is restricted.  There is then insufficient energy to power the brain in times of peak energy requirement.  This can cause loss of myelination and ultimately cell death.

 

  

ATP in Fragile X

It looks like in Fragile X the mitochondria in the brain do not work properly. ATP is leaking from the mitochondria and this stops synapses from maturing. 

A synapse is just the junction between one neuron and its neighbour.

The immature synapse manifests as autistic behavior.  When you plug the leak with Dexpramipexole, a drug trialed for ALS and now asthma, dendritic spines mature and autistic behavior is reduced.

To what extent this leakage occurs in idiopathic autism is unknown, but we know that impaired dendritic spine formation/morphology is a key feature of most autism and that it can be modified, although the sooner you start the better the result will be.

It looks to me that some people diagnosed with mitochondrial disease based on blood tests may actually have leaking ATP which then affects metabolic pathways and shows up with odd blood test results, that is then misdiagnosed as mitochondrial disease.  Note that many people diagnosed with mitochondrial disease show no response to therapy.

In Professor Naviaux’s theory, the ATP leak is from the cell membrane, like the outer wall of the cell.  He thinks that ATP is leaking and this then sends a false danger signal to the rest of your brain.  This is his Cell Danger Response (CDR).  Because the brain thinks it is under attack it is set in a permanent pro-inflammatory state, this gets in the way of basic functions the developing brain needs to complete.  This might explain why the microglia (the brain’s immune cells) are found to be permanently activated in autism; this then means that they do not carry out their regular brain housekeeping activities very well, like pruning synapses.

Naviaux wants to plug the leaks in the cell wall using Suramin, which is an old anti-parasite drug made by Bayer, the giant German company.

The link between the Fragile X research from Yale and Naviaux’s work at UCSD is that ATP needs to be kept in the right place for the brain to function correctly.

Leaky ATP will cause you big problems.

 

 

Now for the supporting research

 

Leaky ATP in Fragile X

 

Fragile X syndrome traits may stem from leaky mitochondria

The persistent leak influences which metabolic pathway the cell uses to generate energy, the team discovered by using a technique called mass spectrometry. For example, fragile X neurons produce more enzymes associated with glycolysis — a pathway commonly used by immature cells — than do typical neurons. Previous studies have shown altered mitochondrial metabolism in people with other forms of autism2.

Adding dexpramipexole to the cells of fragile X mice decreased production of lactate dehydrogenase and other enzymes linked to glycolysis, suggesting that closing the leak causes the neurons to start to use different, more mature metabolic pathways.

Giving injections of dexpramipexole to fragile X model mice lessened their hyperactivity, repetitive behaviors and excessive grooming — traits that are reminiscent of those seen in people with autism and in those with fragile X syndrome. Mice that received the dexpramipexole injections also had neurons with more mature dendritic spines and decreased levels of protein synthesis.

Dexpramipexole has been tested in people with the neurological disease amyotrophic lateral sclerosis and found safe, but it is unclear how it would affect young people if taken over sustained periods of time.

 

ATP Synthase c-Subunit Leak Causes Aberrant Cellular Metabolism in Fragile X Syndrome

Loss of the gene (Fmr1) encoding Fragile X mental retardation protein (FMRP) causes increased mRNA translation and aberrant synaptic development. We find neurons of the Fmr1^-/y mouse have a mitochondrial inner membrane leak contributing to a "leak metabolism." In human Fragile X syndrome (FXS) fibroblasts and in Fmr1^-/y mouse neurons, closure of the ATP synthase leak channel by mild depletion of its c-subunit or pharmacological inhibition normalizes stimulus-induced and constitutive mRNA translation rate, decreases lactate and key glycolytic and tricarboxylic acid (TCA) cycle enzyme levels, and triggers synapse maturation. FMRP regulates leak closure in wild-type (WT), but not FX synapses, by stimulus-dependent ATP synthase β subunit translation; this increases the ratio of ATP synthase enzyme to its c-subunit, enhancing ATP production efficiency and synaptic growth. In contrast, in FXS, inability to close developmental c-subunit leak prevents stimulus-dependent synaptic maturation. Therefore, ATP synthase c-subunit leak closure encourages development and attenuates autistic behaviors.

 

Highlights 

·        ATP synthase c-subunit leak in Fragile X causes aberrant metabolism

·        Changes in ATP synthase component stoichiometry regulate protein synthesis rate

·        Inhibition of the leak normalizes synaptic spine morphology and Fragile X behavior

 

In Brief

Lack of FMRP in Fragile X neurons is associated with a leak in the ATP synthase, the blockade of which normalizes cellular and behavioral disease phenotypes.

 

Now they fix the leak using Dexpramipexole (Dex) and cyclosporine A (CsA)

 

 

We have found that the mitochondrial inner membrane leak of FX neurons and cells is caused by abnormal levels of ATP synthase c-subunit. The c-subunit leak causes persistence of a mitochondrial leak metabolic phenotype characterized by high glycolytic flux, high lactate levels, and increased levels of glycolytic and TCA enzymes. The leak also aberrantly elevates overall and specific protein synthesis; a decrease in c-subunit level or pharmacological inhibition of the ATP synthase leak reduces protein synthesis rates and decreases the levels of leak metabolism enzymes. In Fmr1/y synapses, stimulation-dependent protein synthesis is absent. This is correlated with a lack of stimulus induced EF2 phosphorylation and a lack of synthesis of the ATP synthase b-subunit. These abnormalities are readily reversed by ATP synthase leak inhibitors, suggesting that leak closure is required for the ATP-dependent phosphorylation of EF2 adjacent to mitochondria. EF2 phosphorylation may regulate the change in subsets of proteins synthesized and may be correlated with- the overabundant synthesis of enzymes supporting a high flux glycolytic/TCA cycle ‘‘leak’’ metabolism indicative of metabolic immaturity. Consistent with the hypothesis that the c-subunit leak is also a major cause of synapse immaturity, we find that inhibition of the ATP synthase leak allows the maturation of synapses and normalizes autistic behaviors.

 

 

 

Closing Leaky Mitochondria Halts Behavioral Problems in Fragile X, Study Suggests

“In Fragile X neurons, the synapses fail to mature during development. The synapses remain in an immature state and this seems to be related to their immature metabolism,” she said.

The investigators tested whether closing the leak to boost the efficiency of ATP production would lessen behavioral abnormalities.

They first saw that nerve cells treated with an ATP synthase inhibitor named dexpramipexole (Dex) — a form of the common Parkinson’s therapy Mirapex ER (pramipexole) and previously tested as a treatment for amyotrophic lateral sclerosis — increased the levels of ATP.

Two-day treatment with Dex also reversed autistic-like behaviors, namely excessive time spent grooming and compulsive shredding of the animals’ nests. The treatment also reduced hyperactivate behaviors.

“We find that inhibition of the ATP synthase leak allows for the maturation of synapses and normalizes autistic behaviors in a mouse model of [fragile X],” the team wrote.

Jonas and her team now intend to further test the effectiveness of this and other leak-closing therapies for improving learning.

The lab is conducting a study assessing the role of leaky membranes in memory formation. Findings could pave the way for novel therapeutics for fragile X and autism, as well as for Alzheimer’s disease.

 

 

 

Dr Naviaux and Suramin for Autism

 

I have covered Suramin in previous posts.  There is a presentation below by Prof Naviaux that is for lay people, it is good to hear directly from the man himself.

 

Autism Treatment, the cell danger response and the SAT1 trial

https://youtu.be/pqd_BoCeRUw

In essence he says that when cells are stressed, they leak ATP and this creates the cell danger response.  If you have suramin in your bloodstream, it plugs the ATP channels and stops it leaking out of the cell and so blocks the cell danger response.

It is the cell danger response that is causing the symptoms we see as autism.

  

Conclusion

Who to call to fix an ATP leak?

If it is a case of Fragile X, there looks to be potential solution, but you will definitely not find it at your local doctor’s office.

For a mouse with Fragile X, you might choose Dexpramipexole.  Dexpramipexole was developed as a therapy for ALS (motor neuron disease), but failed in phase 3 trials and is now being developed for asthma.

For a human, the logical place to start would be the already approved Mirapex, which is currently used to treat Parkinson's disease and restless legs syndrome.

Mirapex - a miracle for Fragile X?

Clearly somebody should make a clinical trial of the existing drug.

I expect what will happen is that the Yale researchers will come up will a new drug that can be patented as a novel therapy for Fragile X.  This way they get to make some money, but a decade is wasted.

Is leaky ATP from mitochondria an issue in broader autism, beyond Fragile X? That is still unknown, but the Yale researchers seem to think their work has potential application in both autism and Alzheimer’s.

In the case of broader autism, Dr Naviaux and his partner Kuzani have some competition from Paxmedica.  Both groups seek to monetize Dr Naviaux’s published research.

It looks like the German giant Bayer does not want to help either group.  Instead of just tapping into Bayer’s existing production of Suramin, Kuzani and Paxmedica will have to figure out how to produce Suramin.

This all helps us to understand why there still are no approved therapies for core Autism or indeed Fragile X and yet there is a mountain of research.  Too many barriers and interests to overcome.

If you want to fix leaky ATP any time soon, you will be doing it mainly by yourself.  This has been my experience with most other kinds of leak!