Pregnenolone - an effective OTC anti-inflammatory therapy for autism?

Pregnenolone is the true mother hormone, being derived from cholesterol and the precursor of all steroid hormones. 

It is a potent anti-inflammatory agent.  It is  also claimed that supplementing with Pregnenolone will increase IGF-1, which I found interesting, given my very recent post on IGF-1 therapy in autism.  

In the late 1940’s and 1950’s successful studies were carried out into the use of Pregnenolone in the inflammatory condition of arthritis. 

As we found in recent posts regarding the vagus nerve, all inflammatory conditions (autism included) share much in common.  A treatment that is effective against neuroinflammation in one condition should be tested in the others.

Interest was high in Pregnenolone because it was cheap and free of troubling side effects.  Alternative steroid treatments, for example with Prednisone, can have major side effects.

In an earlier post I referred to the successful use of the steroid Prednisone in ASD in the US.  Wider adoption, and the lack of clinical trials, are held back by the fear of side effects.

Promoting Speech in a 7 year old Non-verbal Child with Autism

"... Dr Michael Chez, of the Pediatric Neurology and Autism Neurodevelopmental Program, Sutter Neuroscience Institute in Sacramento California.  He wrote a paper I have already referred to in this blog called:-

Immune Therapy in Autism: Historical Experience and Future Directions with Immunomodulatory Therapy

In that paper he talks of his knowledge of the effects of prednisone on children with autism and he mentions the dosage used.

Treatment was usually prescribed with daily prednisone doses of 2 mg/kg/day for 3 to 6 months. Limitations to therapy were usually Cushingoid side effects. As in other chronic conditions requiring steroids, pulse dosing was tried with steroids in the form of prednisone or prednisolone at 5 to 10 mg/kg twice per week.

Long-term success with no dependence or minimal Cushingoid effects has been noted in several hundred patients treated in this manner (Chez, unpublished data, personal communication).

In all, 17 of 32 patients showed response to prednisone after 2 to 4 months of treatment (53%). Improvements were seen on EEG and in language skills of the patients. Other steroid treatment series of regressed language in autistic spectrum patients diagnosed with LKS variant showed improved language with pulse-dose steroids."

 Pregnenolone Studies

Pregnenolone in the Treatment of Rheumatoid Arthritis

Pregnenolone in Rheumatoid Arthritis

If effect, Pregnenolone seems to be a weaker, but much safer, alternative to Prednisone.  Some people with arthritis currently take it. 

Pregnenolone is indeed already one of hundreds of fringe treatments for autism.  There are some very good reasons why it should be effective. 

Stanford University are currently running a clinical trial of Pregnenolone on adults with autism. It is the same researcher that worked on their study on NAC in children with autism.  It is nice to know that the adults with ASD have not been forgotten; after all, children have a habit of growing up.

A Study of Pregnenolone in the Treatment of Individuals With Autism

Conclusion

The next time I receive a question on this blog asking for a potentially effective OTC anti-neuroinflammatory “supplement” for autism, I will know what to suggest trying.

The Vagus Nerve and Autism

It is good to know that there are some brilliant minds out there, willing to cross disciplines.  A case in point is Professor Stephen Porges, a neuroscientist with particular interests in understanding the neurobiology of social behavior.  He is a Professor in the Department of Psychiatry and the Director of the Brain-Body Center in the College of Medicine at the University of Illinois at Chicago.  He has an equally clever wife who is a world leader in the role of neuropeptides oxytocin and vasopressin in social cognition.
You would want to think twice before inviting this couple round for dinner, unless you had spent the day before boning up on your science. 

Porges is best known for his Polyvagal Theory.  The Wikipedia article does not really do justice to the theory.  Here are two highly cited papers:-

The polyvagal theory: phylogenetic substrates of a social nervous system (2001)

The Polyvagal Theory: phylogenetic contributions to social behavior (2003)

He has only written one paper on autism, it is certainly not a light read but it shows a brilliant mind.

The vagus: A mediator of behavioural and visceral features associated with autism 

This paper is actually a chapter in a book and can be accessed via Google Books.

His paper explains odd autistic behaviours in terms of the functioning of the vagus nerve.  For example, the neural mechanism for making eye contact is shared with those needed to listen to the human voice.  So if you struggle to make eye contact, you will struggle to listen to what somebody is saying to you.  We can infer that if your ABA program trains you to make eye contact, you will likely become a better listener in the process.  Also, don’t talk to somebody unless you are facing them.

He comments on the regulation of the gut, the vagus and the immune system, vagal regulation of the HPA axis, all with reference to ASD.

Having read his paper you really will need no more convincing to go tune up your child’s vagus nerve. 

Tuning up the Vagus Nerve

Unlike Professor Porges, I like to simplify things so you do not read them more than once.  Clearly Kevin Tracey and Porges are the experts on the vagus nerve, but they do not go as far as telling you what you really want to know – how to improve its function using today's technology.  Fortunately, there is plenty of research on the Cholinergic System, of which the vagus nerve is part.  The following paper is a good example:-

Cholinergic Activity in Autism: Abnormalities in the Cerebral Cortex and Basal Forebrain

You may recall from my earlier post Biomarkers in Autism: The Cholinergic system, that there are two types of cholinergeric receptors, nicotinic and muscarinic.  This paper is telling us how in autism these receptors are fewer in number than normal and the ones that are there, are not working (binding) as they should.

So this goes some way to perhaps explain why so many odd behaviours can be tracked back to the autistic vagus nerve; it is damaged.

In his paper, Porges is basically telling you to go try a vagus nerve stimulator, of the kind that already exists for epilepsy (see photo above) and Kevin Tracey is developing for arthritis (another inflammatory condition).  Right now this is not very feasible, but chemical stimulation of the vagus nerve does not look beyond the wit of man, using currently available technology.


 

Monty’s First Joke

Today at 6.30 in the morning something very unexpected happened;  Monty, aged 10 with ASD, made his first joke.  For a boy of few words this is quite a big step.

“I hit my head and now I can see birdies”

Elder brother Ted, when he finally arose, was impressed. It was very much his kind of humour, making a joke about your own weaknesses.

Regular readers will know that we are currently investigating the role of the vagus nerve in autism; all I can say is that nobody mentioned that the vagus nerve also mediates your sense of humour.  It may just be a happy coincidence, but this happened within 24 hours of our latest little experiment.  


 

Cytokine Theory of Disease & the Vagus Nerve

If you are a regular reader of this blog you will know that the key to controlling autism is reducing oxidative stress and neuroinflammation.  One of the key drivers of the on-going neuroinflammation are signalling molecules called cytokines; if you can limit the release of harmful cytokines you can reduce neuroinflammation.  This appears to be easier said than done.  I learnt that some statins limit the release of pro-inflammatory cytokines and neuroscientists in the US are researching their use, but not yet in autism.  I did some home research and found a positive effect within 24 hours.

It turns out there is an entire field of neuroscience relating to cytokines as a mediator of disease and this is all channelled through the Vagus nerve.  There is an eminent  neuroscientist, Kevin Tracey, who dominates this field; he is credited with discovering that vagus nerve stimulation inhibits inflammation by suppressing pro-inflammatory cytokine production.   Tracey is also an inventor, he is seeking to apply the science and has an interesting start-up company.  So I have found a kindred spirit and if you read his papers, you will find that often missing element, a sense of humour.

Tracy has even written a book, which explains his discoveries.

Fatal Sequence: The Killer Within

For those scientists among you, a very readable paper is:- 

Physiology and immunology of the cholinergic  Anti-inflammatory pathway

For those in a hurry, here is summary

The cytokine theory of disease is a concept that cytokines produced by the immune system can cause the signs, symptoms, and damaging aftereffects of disease.

One example is the case of TNF, a cytokine implicated as a necessary and sufficient mediator of lethal septic shock. Administration of TNF to healthy humans reproduces the metabolic, immunological, and pathological manifestations of the disease and the gene knockout or pharmacological blockade of TNF activity prevents the development of lethal septic shock. Other pathophysiological activities ascribed to TNF are the capacity to cause fever and localized inflammation. Clinical successes in the 1990s using drugs that specifically inhibit TNF for patients with inflammatory bowel disease or rheumatoid arthritis directly implicated a pathogenic role of this cytokine in other diseases and validated in humans the fundamental premise of the cytokine theory of disease.

 

 

The cholinergic anti-inflammatory pathway

Tracey reasoned that, since the CNS coordinates major physiological responses via innervated circuits, it might also use neural input to control a potentially deadly cytokine response. In classical physiological systems, the sensory projections of the autonomic nervous system provide input to brain networks about essential bodily functions. These elicit a coordinated neural output from the CNS to maintain homeostasis for parameters as varied as heart rate, blood pressure, digestion, body temperature, organ perfusion, and blood glucose levels. Accordingly, it seemed possible to posit the existence of a comparable mechanism to control cytokine release that could, at least in theory, function as an extremely fast, reflex-like anti-inflammatory pathway controlled by brain networks.  Stimulation of vagus nerve signals was shown to significantly inhibit TNF release in animals receiving lethal amounts of endotoxin. Subsequent work established that vagus nerve signaling inhibits cytokine activities and improves disease endpoints in experimental models of sepsis, schemia/reperfusion, hemorrhagic shock, myocardial ischemia, ileus, experimental arthritis, and pancreatitis. The cellular molecular mechanism for inhibition of cytokine synthesis is attributable to acetylcholine (ACh), the major vagus nerve neurotransmitter. Macrophages and other cytokine-producing cells express acetylcholine receptors (AChRs), which transduce an intracellular signal that inhibits cytokine synthesis. The best characterized of these cholinergic receptors that suppress cytokines is the α7 subunit of the nicotinic AChR (α7 nAChR).

 

 

It takes nerve to restrain cytokines: anatomy of an innervated cytokine system

Recent studies of the physiology, functional anatomy, and cellular molecular mechanisms of the cholinergic anti-inflammatory pathway indicate that the principal components for cytokine suppression by the vagus nerve converge in the spleen. Endotoxin localizes to macrophages primarily in the spleen and liver, thereby activating an immediate early cytokine response. The spleen is the major source of both hepatic and systemic TNF during endotoxemia; it releases newly synthesized TNF into the splenic vein, which drains into the liver, and from there, TNF crosses into the systemic circulation.

 Vagus nerve stimulation, or administration of α7 nAChR agonists, inhibits not only TNF but also IL-1, IL-6, IL-8, and high mobility group box 1 (HMGB1)

 

Preclinical efficacy of experimental therapeutics

Preclinical studies are in progress to determine whether it may be possible to develop therapeutics based upon either devices that stimulate vagus nerve activity or drugs that activate the cholinergic anti-inflammatory pathway to suppress cytokine damage. A significant number of studies indicate that the cholinergic anti-inflammatory pathway is a robust regulator of cytokine-mediated damage in local and systemic experimental disease.

The role of exercise

Exercise reduces levels of TNF and other cytokines, confers protection against cardiovascular disease and type 2 diabetes, increases vagus nerve activity, and confers protection against the development of atherosclerosis. It is possible that the mechanism of these exercise effects is at least in part attributable to exercise-induced increases in cholinergic anti-inflammatory pathway activity. Obesity, on the other hand, is characterized by diminished vagus nerve output and elevated cytokine levels, which have been implicated in mediating insulin resistance and atherosclerosis. Since weight loss and exercise are each associated with increasing vagus nerve activity, one can consider whether enhanced activity in the cholinergic anti-inflammatory pathway might decrease cytokine production and reduce the damage and metabolic derangements mediated by chronic, low-grade systemic inflammation that is characteristic of the metabolic syndrome

His conclusion:-

“It is bemusing to think that one of the fundamental premises of the ancient Greeks was that dietary manipulation controlled humoral balances. This concept is now, at least in principle, supported by new evidence of a direct link between dietary composition and the regulation of cytokines by the cholinergic anti-inflammatory pathway. Modern clinical studies have advocated supplementing diet with fish oil, soy oil, olive oil, and other fats to significantly increase vagus nerve activity, reduce inflammatory markers, and improve disease severity in inflammatory bowel disease, rheumatoid arthritis, and cardiovascular disease. These clinical anti-inflammatory responses may be linked to the fat-induced stimulation of the cholinergic anti-inflammatory pathway, as is the case in rats. And now it appears that a major source of systemic TNF during lethal challenges is the spleen, the source of Galen’s black bile. One can’t help but wonder: How did the ancient Greeks know?”

 

Anti-inflammatory activities of vagus nerve stimulation

The discovery by Tracey that vagus nerve stimulation inhibits inflammation by suppressing pro-inflammatory cytokine production has led to significant interest in the potential to use this approach for treating inflammatory diseases ranging from arthritis to colitis, ischemia, myocardial infarction, and congestive heart failure. Action potentials transmitted in the vagus nerve activate the efferent arm of the Inflammatory Reflex, the neural circuit that converges on the spleen to inhibit the production of TNF and other pro-inflammatory cytokines by macrophages there. This efferent arc is also known as the Cholinergic anti-inflammatory pathway Because this strategy targets the release of TNF and other pro-inflammatory cytokines, it may be possible to use vagus nerve stimulation instead of anti-inflammatory antibodies (e.g., Remicade or Enbrel) to treat inflammation. SetPoint Medical, Inc. is an early-stage medical device company, set up by Tracey, developing an implantable  neurostimulation platform for the treatment of inflammatory diseases.

Remicade and Enbrel are ultra-expensive drugs, costing about $20,000 per year.  Not surprisingly, some US autism doctors are wondering what they would do in autism.

My Conclusion

I was wondering if Kevin Tracey might be related to Jeff Tracy, in which case, can Brains please make Monty, aged 10 with ASD,  a vagus nerve stimulation device, preferably with a built-in nuclear power pack.  (I refer to a cult British TV series from the 1960s called Thunderbirds, a favourite of both Monty and his big brother, Ted.)  

 

 

IBS, IBD and Autism, leading to Cholinergic Signaling and the Vagus Nerve

This post is all about those stomach problems typical of many kids with ASD and some of their neuro-typical close relatives. Since Monty, aged 10 with ASD, does not have any of these problems, it is not something I have looked into earlier.  As you will see later in this post, by understanding the underlying science, we can move another step towards inhibiting systemic inflammation, which affects all people with ASD.
 

Irritable bowel syndrome (IBS) and Inflammatory Bowel Disease (IBD),

First of all we need to differentiate two common conditions with very similar symptoms.  IBS is the less serious condition, though it causes lots of discomfort.
 

Irritable Bowel syndrome - IBS

Irritable bowel syndrome (IBS) sufferers show no sign of disease or abnormalities when the colon is examined.

IBS does not produce the destructive inflammation found in IBD. It does not result in permanent harm to the intestines, intestinal bleeding, or the harmful complications often occurring with IBD. People with IBS are not at higher risk for colon cancer, nor are they more likely to develop IBD or other gastrointestinal diseases

The exact cause of IBS is unknown.   The most common theory is that IBS is a disorder of the interaction between the brain and the gastrointestinal tract, although there may also be abnormalities in the gut flora and immune system.

Inflammatory Bowel Disease -  IBD

Inflammatory bowel disease is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis

Crohn’s disease has a strong genetic component and is far more prevalent among smokers.  The usual onset is between 15 and 30 years old.

Ulcerative colitis is an auto-immune disease with no known cause.  The symptoms are very similar to Crohn’s disease, but there are some stark differences.  Ulcerative colitis is far less prevalent among smokers

Autistic Colitis / Ulcerative Colitis

The Inflammatory Bowel Disease (IBD) that seems to be relevant in Autism is ulcerative colitis, so much so that Wakefield and Krigsman sought to name a sub-type Autistic Enterocolitis.  Due to all the furore about vaccinations and autism, the research of these two gastroenterologists has been blacklisted.

Dr Krigsman has an informative website and has published some interesting research.

If you spend all day looking via the endoscope  at children with ASD, you are bound to notice a thing or two.  Ignoring what Krigsman observes is bizarre.

In case you are wondering what he does, he is going through the mouth to do an Upper Endoscopy; for the Colonoscopy he goes in from below.  He does both procedures under general anaesthetic.  That will be painless; I once had an endoscopy under general anaesthetic and you have no bad effects.  I had the misfortune to have another one without any anaesthetic, which was one of the most unpleasant experiences of my life.

Ulcerative colitis looks like a nasty condition but Krigsman finds it is generally treatable with some combination of anti-inflammatory medication, antimicrobials, probiotics, digestive enzymes and dietary restriction.

One thing he does not mention is nicotine, more of that later.

GERD

Gastroesophageal reflux disease (GERD) is a very common disease.  The acid within the stomach rises up into the esophagus and in doing so, damages its lining.

Most children will outgrow their reflux by their first birthday. However, a small but significant number of them will not outgrow the condition. This is particularly true when a family history of GERD is present.   It is estimated that 15% of adults of adults are affected by GERD.

Krigsman find that in kids with ASD and their siblings, GERD is relatively common.

 

Mechanisms linking IBS and IBD to Autism

I have already written about the link between food allergies, autism and behaviour.  In those posts it was histamine released from mast cells (along with cytokines and other nasties) that was the culprit.  The treatments included antihistamines and mast cell stabilizers (Ketotifen, Intal etc).  I would presume this would fall into the IBS category.

When it comes to IBD, things get interesting.

In 1936 the Nobel Prize for Physiology was awarded to Sir Henry Dale and Otto Loewi.  One had identified the neurotransmitter acetylcholine and the other had shown how the vagus nerve releases acetylcholine to control heartbeat.

It later became apparent how important the vagus nerve is.  The vagus nerve is a modulator of inflammation throughout the body.  Acetylcholine, the principle neurotransmitter released by the vagus nerve, can exert its anti-inflammatory effect via binding to nicotinic acetylcholine receptors (nAChRs), which are expressed on macrophages and other immune cells.

 
In a recent post I showed that autistic brain samples have diminished acetylcholine and nicotinic receptor activity.  I showed how this could be corrected either by drugs that mimic acetylcholine (eg nicotine or acetylcholine) or with an acetylcholinesterase inhibitor (Galantamine or Donepezil).

I found it very interesting that IBD can be successfully treated by mild smoking (3 cigarettes a day) or with nicotine patches. 

This then connects various comorbidities in a very useful way and opens up therapeutic directions.  The vagus nerve is also key to epilepsy.  Vagus nerve stimulation is currently used to treat epilepsy and depression.

Experimentally, vagus nerve stimulation is already used in autism.  

Vagus nerve stimulation therapy inpatients with autism spectrum disorder and intractable epilepsy: results fromthe vagus nerve stimulation therapy patient outcome registry.

CONCLUSIONS:

Patients with ASD and intractable epilepsy respond as favorably as all other patients receiving VNS therapy. In addition, they may experience a number of QOL improvements, some of which exceed those classically observed following placement of a VNS device.

 

Kevin J. Tracey

A neurosurgeon and inventor, Kevin Tracey, is the man behind the inflammatory reflex.  The inflammatory reflex is a neural circuit that regulates the immune response to injury and invasion. All reflexes have an afferent and efferent arc. The Inflammatory reflex has a sensory, afferent arc, which is activated by cytokines, and a motor, or efferent arc, which transmits action potentials in the vagus nerve to suppress cytokine production. Increased signaling in the efferent arc inhibits inflammation and prevents organ damage.

We will be looking at his research and the Cholinergic anti-inflammatory pathway, in later posts