Showing posts with label Cholinergic. Show all posts
Showing posts with label Cholinergic. Show all posts

Monday 15 September 2014

Antabine (Anatabloc) and Autism - a Supplement or a Drug?

This is another post prompted by a comment received on this blog.

My 15 year-old daughter has classic regressive type ASD. I started her on an anti-inflammatory, Anatabloc, over a year ago and it allowed me to take her off atypical anti-psychotics ( she was on them for aggression) Do you know anyone else using this dietary supplement?  

I found this very interesting and so I did some quick research.

Anatabloc was until very recently sold in the US as a supplement, it was withdrawn from sale by the producer following a corruption trial and a dispute with the FDA over approvals.  Nobody is saying the supplement does not work, rather it is a drug.


Anatabloc was sold as an anti-inflammatory supplement based on a substance called Anatabine, found in tobacco and in lower concentrations in green tomatoes, green potatoes, ripe red peppers, tomatillos, and sundried tomatoes.

Anatabine has been studied in animal models and in cells to see if it might be useful for treating nicotine addiction and inflammation, and has been studied in models of diseases characterized by inflammation, such as Alzheimer's Disease, thyroiditis, and multiple sclerosis.

On a biochemical level, it appears to be active against certain nicotinic acetylcholine receptors.

Regular readers will recall extensive earlier posts on the cholinergic system and nicotinic acetylcholine receptors.

The conclusion of all those posts was that, most definitely, in some people’s autism, an effective strategy is to adjust the cholinergic system.  Possible methods include:-

·        Vagus nerve stimulation – still in development
·        Nicotine patches – cheap and effective in some people
·        Two Alzheimer's drugs Donepezil and Galantamine, that are acetylcholinesterase inhibitors

So at first it seemed that Anatabloc may be “just another” cholinergic drug.  However on analyzing the patent submitted by the producer, it seems there may be an alternative mode of action.

Patent for Antabine use in Autism

32| Anatabine is an alkaloid present in tobacco and, in lower concentrations, in a variety of foods, including green tomatoes, green potatoes, ripe red peppers, tomatillos, and sundried tomatoes. Without being bound by this explanation, data presented in Examples I and 2 below indicate that anatabine reduces transcription mediated by nuclear factor B (NFKB). NFKB is a transcription factor which operates in cells involved in inflammatory and immune reactions.

The nuclear factor NF-κB pathway

NF-κB is seen as being clinically significant in cancer and inflammation.

The NF-κB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-κB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules.  

NF-κB has long been considered the “holy grail” as a target for new anti-inflammatory drugs.

Because NF-κB controls many genes involved in inflammation, it is not surprising that NF-κB is found to be chronically active in many inflammatory diseases, such as inflammatory bowel disease, arthritis, sepsis, gastritis, asthma, atherosclerosis and others. It is important to note though, that elevation of some NF-κB inhibitors, such as osteoprotegerin (OPG), are associated with elevated mortality, especially from cardiovascular diseases.  Elevated NF-κB has also been associated with schizophrenia.

I take the, perhaps unconventional, view that schizophrenia is adult-onset autism.  It has already shown that in terms of genetics, there is a great overlap between these two conditions.


Schizophrenic patients showed activation of the cytokine system and immune disturbance. NF-kappaB activation may play a pivotal role in schizophrenia through interaction with cytokines

The nuclear factor NF-κB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-κB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. In this article, we describe how genetic evidence in mice has revealed complex roles for the NF-κB in inflammation that suggest both pro- and anti-inflammatory roles for this pathway. NF-κB has long been considered the “holy grail” as a target for new anti-inflammatory drugs; however, these recent studies suggest this pathway may prove a difficult target in the treatment of chronic disease. In this article, we discuss the role of NF-κB in inflammation in light of these recent studies.

Clinical trials using Anatabloc

The producer behind Anatabloc is well advanced with clinical trials, as you can see below.

I suspect that Anatabloc will disappear as a supplement and reappear a few years later on as an FDA approved drug for various conditions.


It is a pity that Anatabloc has been taken off the market.

It looks plausible that it could be effective in other people’s autism, not just the reader of this blog.

For the time-being, other than taking up smoking, a good source would be those tasty sun-dried tomatoes.


Having re-read this post and taken a closer look at the patent and the company, I wonder if the original comment is genuine.  The patent is not very convincing and in Table 1 on page 44 it is quoting Wakefield et al, as one of only two sources that link inflammation to autism.  I could have written a much better patent application myself.

Monday 16 December 2013

Comorbidities in Autism and the Curious Cleaning Lady

Regular readers will know that I believe in the value of investigating the comorbidities of autism. 

We have a cleaning lady who comes each week to help keep our house in order.  She also understands the value of comorbidities. She is one of my independent observers, in changes in the behaviour of Monty, aged 10 with ASD.  She has a friend, whose husband was diagnosed with early-onset Alzheimer’s.
Alzheimer’s is not autism, but they are both examples of brain damage.

Still in his early 50s, the husband does not recognize his children and cannot leave home.  The expert Professor, treating him privately, was not halting the rapid decline.
So the cleaning lady asks me about all my investigations and decides that she might as well tell her friend.  She decided to suggest the antioxidant NAC and the cholinergic stimulant nicotine.

Well, after NAC, the husband was able to make it to the WC and do his business.  A small step forward.
After a day with the nicotine patch, things really changed so much that the family decided that they should seek a second opinion, this time from a doctor, yet to publish a book.

Doctor number two decided that it is not Alzheimer’s after all, and the prescribed medicines of the last three years were only making things worse.  And the new therapy? Nicotine patches.

The conclusion is self-evident. 

The next related conditions I will be investigating are cluster headaches, febrile seizures and absence seizures.



Wednesday 30 October 2013

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:-

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

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:-

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.


Monday 21 October 2013

Piracetam for Autism, Comrades

Piracetam was first synthesized in 1964 by a Romanian scientist called Corneliu Giurgea, who was highly unusual.  He was educated in then communist Romania, followed by research in Russia and then at the University of Rochester in the US, before ending up in Belgium, eventually as the Head of Research at drug firm UCB and being a Professor at a Belgian university.  How this was possible under the strict form of communism followed in Romania,  I do not really understand.

Anyway, Giurgea was clearly very resourceful and he decided to invent a new class of drugs, to be called Nootropic.
He stated that Nootropic drugs should have the following characteristics:
1.     They should enhance learning and memory.
2.     They should enhance the resistance of learned behaviors/memories to conditions which tend to disrupt them (e.g. electroconvulsive shock, hypoxia).
3.     They should protect the brain against various physical or chemical injuries.
4.     They should increase the efficacy of the tonic cortical/subcortical control mechanisms.
5.     They should lack the usual pharmacology of other psychotropic drugs (e.g. sedation, motor stimulation) and possess very few side effects and extremely low toxicity.

Piracetam was soon followed by other drugs developed by competitors.
This class of drug seems never to have been licensed in the US, but was used widely in the Soviet Union, Eastern Europe and some western European countries.
As seems all too common in medicine, nobody knows for sure how Piracetam works.  There are many proposed mechanisms and I was attracted by one of them.

Autism in Ukraine
The internet does give the impression of giving you all the answers.  Often it gives you far too much information, much of it of dubious quality.  In reality, you are only seeing what is written in English, and although it is the international language of science and medicine, you will never see the majority of Russian, Japanese and Chinese knowledge/research.  Medical practice varies widely between Western medicine and the others.
In Japan for example, the MMR vaccination has been banned since 1993 and Prozac, the anti-depressant prescribed in huge quantities in the US, is a banned substance.  
So it was not a surprise to find only passing references to apparently widespread use of Piracetam for autism in the Ukraine, going back for decades.  I have no doubt if you could access the Russian research you would find studies on this.

Side Effects
There is no shortage of drugs prescribed in the US for autism, such as Ritalin, Prozac and Risperidone.  I have no doubt that they have some very good qualities; however they all have very real side effects, some of which are permanent.  Giurgea was very wise to only consider drugs with very few side effects and low toxicity.

In the 50 years since he synthesized Piracetam, one thing everyone seems to agree on, is that either it has no side effects, or it has very minor side effects.

Does Piracetam work?
In the 1970s there were numerous studies on Piracetam in a wide range of neurological conditions.  Today Piracetam is extensively used “off label” as a treatment for many of those conditions.  Does Piracetam work in autism?

I guess the doctors in the Ukraine must think it works.  Dr Akhondzadeh, a researcher into autism, ADHD, and other mental health conditions in Iran, found it to be effective.  Kelly Dorfman of the Development Delay Resources in Pittsburgh thinks it is effective for learning disabilities and dyspraxia, but less so for autism.
Olga Bogdashina, President of the Autism Society of Ukraine, notes that piracetam is widely used as an autism treatment in the Ukraine. Having conducted her own small-scale study, she found that piracetam improved the attention spans and mental capabilities in the majority of participating children. She also says that her autistic son became more sociable and flexible and less aggressive on the supplement. She does warn that during the initial phase of treatment, hyperactivity and tantrums may increase. However, researcher Stephen Fowkes notes that these side effects are only common with high doses, and asserts that they are rare with standard doses (both cited in “Letters to the Editor, Autism Research Review International, 1996).

I thought Bogdashina’s name was familiar.  I read her book on sensory issues in autism.  It is a good read, but it does not really tell you what to do.

Piracetam’s claimed possible methods of action
·        It is NOT a sedative or a stimulant

·        Piracetam is a positive allosteric modulator of the AMPA receptor.

·         It is hypothesized to act on ion channels or ion carriers; thus leading to increased neuron excitability

·         GABA brain metabolism and GABA receptors are not affected by piracetam.

·         Piracetam improves the function of the neurotransmitter acetylcholine via muscarinic cholinergic (ACh) receptors, which are implicated in memory processes

·        Furthermore, piracetam may have an effect on NMDA glutamate receptors, which are involved with learning and memory processes.

·        Piracetam is thought to increase cell membrane permeability

·        Piracetam may exert its global effect on brain neurotransmission via modulation of ion channels (i.e., Na+, K+).

·        It has been found to increase oxygen consumption in the brain, apparently in connection to ATP metabolism, and increases the activity of adenylate kinase in rat brains.

·        Piracetam, while in the brain, appears to increase the synthesis of cytochrome b5, which is a part of the electron transport mechanism in mitochondria.

·        But in the brain, it also increases the permeability of the mitochondria of some intermediaries of the Krebs cycle.

In 2005 there was an interesting review carried out in Poland; it is very readable.

"Piracetam is generally reported to have minimal or no side effects. It is interesting to note, however,  that piracetam is occasionally reported side effects of anxiety, insomnia, agitation, irritability  and tremor are identical to the symptoms of excessive acetylcholine/glutamate neuroactivity. In spite of these effects, piracetam is generally not considered to be a significant agonist or inhibitor of the synaptic action of most   neurotransmitters. The piracetam-type nootropic drugs might exert their
effect on some species of molecules present in the plasma membrane. It would seem that they act as potentiators of an already present activity, rather than possessing any neurotransmitter-like activity of  their own."

It would seem to me that we have come back to the vagus nerve and the Cholinergic system

I learnt in that post that there are two main classes of acetylcholine receptor (AChR), nicotinic acetylcholine receptors (nAChR) and muscarinic acetylcholine receptors (mAChR).  Mostly it seems to be the nicotinic type that is targeted by medical science, but piracetam has an effect on the other type of receptor.  This would explain excessive use of piracetam causing symptoms of too much acetylcholine.
If this is indeed the case, that would add yet another method of “correcting” the known biomarker of autism that is “diminished acetylcholine and nicotinic receptor activity”.  Of all the methods I have so far investigated, this might actually be the safest;  it is certainly inexpensive.

Effect on Comorbidities
My method of separating fact from fiction in autism now includes looking at the effect of therapies on the principal comorbidities of autism.  Most genuinely effective drugs seem to work across many comorbidities.  Epilepsy is the most prevalent comorbidity.

"CONCLUSIONS—This study provides further evidence that piracetam is an effective and safe medication in patients with Unverricht-Lundborg disease. In addition, it shows that a dose of 24 g is highly beneficial, more effective than lower doses and that a dose-effect relation exists. There is considerable variation in optimal individual dosage. "
Note:  Unverricht–Lundborg disease is the most common form of an uncommon group of epilepsy called the progressive myoclonus epilepsies.

Piracetam seems to be a safe supplement/drug that improves mood and reduces aggression (and SIBs).  I thought it was worthwhile testing and indeed I was not disappointed.  The dosage suggested is 50-100 mg/kg, but the optimal dose seems to vary by child.  If you follow my vagus nerve/neuroinflammation/ cholinergic way of thinking, then Piracetam would be acting (via acetylcholine) to reduce pro-inflammatory cytokines and hence reduce inflammation in the autistic brain.  This would mean that Piracetam would be a useful tool to control autism flare-ups, be they triggered by pollen allergy, intestinal inflammation, or even stress.  I shall use it as such.

As for why Piracetam seems more effective in the Ukraine than in Pittsburgh - that I can answer.  Much of what passes as autism in Pittsburgh, would be completely ignored in Kiev.  It would not be diagnosed as autism; only if it is disabling would it be called autism.  If you have "autism-lite", the symptoms are mild and you probably do not need Piracetam and it would likely have little effect.   The same would apply for the majority of ADHD/ADD cases, outside of the US they would not be diagnosed as such.
If you are on Ritalin for your severe ADHD, you might want to try Piracetam.  If you Google ADHD and Piracetam, you will find adults using Piracetam to avoid the side effects of Ritalin.
If your child suffers from SIBs (self-injurious behaviours) then Piracetam, along with nicotine patches, would be well worth investigating.




Thursday 17 October 2013

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.)