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

Monday 14 October 2013

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.  

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


 

Thursday 3 October 2013

Biomarkers in Autism : The Cholinergic system – In need of caffeine & nicotine or maybe just choline

Strange as it may sound, but if you have ASD a strong cup of coffee and a cigarette may actually do you some good.  Following on from my earlier post about Serotonin, showing that LSD was seen as an effective therapy in the 1960s, you might be wondering where my blog is taking us.  I just follow the science, wherever it takes us.

First of all what is the Cholinergeric system.

Cholinergic system (a summary from Wikipedia)
Cholinergic typically refers to acetylcholine in the neurological sense.  The parasympathetic nervous system, which uses acetylcholine almost exclusively to send its messages, is said to be almost entirely cholinergic. Neuromuscular junctions, preganglionic neurons of the sympathetic nervous system, the basal forebrain, and brain stem complexes are also cholinergic

In neuroscience and related fields, the term cholinergic is used in the following related contexts:
  • A substance (or ligand) is cholinergic if it is capable of producing, altering, or releasing acetylcholine ("indirect-acting") or mimicking its behaviour at one or more of the body's acetylcholine receptor types ("direct-acting").
  • A receptor is cholinergic if it uses acetylcholine as its neurotransmitter.[2]
  • A synapse is cholinergic if it uses acetylcholine as its neurotransmitter.

Acetylcholine is one of many neurotransmitters in the autonomic nervous system (ANS). It acts on both the peripheral nervous system (PNS) and central nervous system (CNS) and is the only neurotransmitter used in the motor division of the somatic nervous system.

In the central nervous system, acetylcholine and the associated neurons form a neurotransmitter system, the cholinergic system, which tends to cause anti-excitatory actions.
Damage to the cholinergic (acetylcholine-producing) system in the brain has been shown to be plausibly associated with the memory deficits associated with Alzheimer's disease.

Synthesis and degradation


Acetylcholine is synthesized in certain neurons by the enzyme choline acetyltransferase from the compounds choline and acetyl-CoA. Cholinergic neurons are capable of producing Ach.

Receptors


There are two main classes of acetylcholine receptor (AChR), nicotinic acetylcholine receptors (nAChR) and muscarinic acetylcholine receptors (mAChR). They are named for the ligands used to activate the receptors.

Nicotinic


Nicotinic AChRs are ionotropic receptors permeable to sodium, potassium, and calcium ions. They are stimulated by nicotine and acetylcholine. They are of two main types, muscle-type and neuronal-type. The former can be selectively blocked by curare and the latter by hexamethonium. The main location of nicotinic AChRs is on muscle end plates, on autonomic ganglia (both sympathetic and parasympathetic), and in the CNS.[32]

Muscarinic


Muscarinic receptors are metabotropic, and affect neurons over a longer time frame. They are stimulated by muscarine and acetylcholine, and blocked by atropine. Muscarinic receptors are found in both the central nervous system and the peripheral nervous system, in heart, lungs, upper GI tract and sweat glands. Extracts from the plant Deadly night shade included this compound (atropine), and the blocking of the muscarinic AChRs increases pupil size as used for attractiveness in many European cultures in the past

--- end of wikipedia ---
 
The Research Showing Abnormality in ASD
The following study was carried out in the UK in 2002 on post mortem brain tissue from “Brain banks” in the US.  It is extensively referred to in the later research.




 






An earlier paper on the same subject:-



CONCLUSIONS: These neurochemical abnormalities implicate the cholinergic system in developmental disorders such as autism and suggest the potential for intervention based on cholinergic receptor modulation.

If the low level of cortical nicotinic receptors is consistently observed and clinically relevant, therapeutic strategies could include receptor agonists, such as nicotine, which has already been applied in Tourette’s disorder with amelioration of symptoms. Such treatment could also be disease modifying.
 

Other studies on autistic brain samples have shown diminished acetylcholine and nicotinic receptor activity.

Implications 10 years on remain the same
A recent study by neuroscientists at Ohio State University, concludes that neuronal nicotinic acetylcholine receptor (nAChR) alterations are biomarkers for ASD and that specific nAChRs subtypes are likely to be useful therapeutic targets for the treatment of core deficits. They claim a case can be made for the use of  α7 nAChRs to reduce neuroinflammation in the brain in those ASD individuals with such clinical pathology. The ultimate hope is that these agents, when administered early in development, by their presumed ability to modulate a number of different neurotransmitter systems and associated signaling pathways, could help correct core deficits associated with ASD.

Interventions

Just by spending 5 minutes on Wikipedia, you can find logical interventions that could have been tested since 2002.  Some have indeed been tested, others have not.  Here below is a copy-paste from Wikipedia, with interesting drugs highlighted.

 

Reversibel acetylcholinesterase inhibitor (often abbreviated AChEI)


Compounds which function as reversible competitive or noncompetitive inhibitors of cholinesterase are those most likely to have therapeutic uses. These include:


Natural Compounds



ACh receptor agonists/antagonists


Acetylcholine receptor agonists and antagonists can either have an effect directly on the receptors or exert their effects indirectly, e.g., by affecting the enzyme acetylcholinesterase, which degrades the receptor ligand. Agonists increase the level of receptor activation, antagonists reduce it.

Drugs acting on the cholinergic system


Blocking, hindering or mimicking the action of acetylcholine has many uses in medicine. Drugs acting on the acetylcholine system are either agonists to the receptors, stimulating the system, or antagonists, inhibiting it.

ACh and its receptors
Drug
Nm
Nn
M1
M2
M3
+
+
+
+
+
+
+
+/-
-
+
-
+
+
+
-
-
-
+
-
-
-

Direct acting


These are drugs that mimic acetylcholine on the receptor. In low doses, they stimulate the receptors, in high doses they numb them due to depolarisation block.



------- end of Wikipedia ---------
 
Evidence based approach
The web is full of commentators telling you to only pay attention to evidence-based treatments.  This sound great in principle, but it assumes there are copious amounts of well-constructed clinical trials.  Moreover, is assumes that there is just one type of autism, or that clinical trials are sophisticatedly constructed to test individual sub-types, one at a time (which they are not).

So, in reality, the evidence is generally poor quality and so applying a pure evidence-based approach will leave you exactly back where you started.
I have gathered together what I think is a remarkable amount of evidence from multiple imperfect trials and anecdotal case studies.


Use Of Donepzil
Following on two earlier trials, Chez et Al carried out a double-blind study  of Donepezil hydrochloride, an acetylcholinesterase inhibitor  to confirm those findings. 

 

 The trial concluded:-

Expressive and receptive speech gains, as well as decreases in severity of overall autistic behavior, were documented after 6-weeks for the treatment group. These improvements were statistically significant when compared to placebo, and were clinically meaningful as assessed over time. Donepezil hydrochloride appears to improve expressive and receptive language as well as overall autistic features, consistent with the hypothesis of acetylcholinergic enhancement

 Here is a more recent case study from India


A woman consulted psychiatric Out-Patient Department (OPD) for her 5-year and 2-month-old son presenting with typical autistic symptoms like social, behavioural, and communicational ineptitudeness. Subsequent treatment with Donepezil resulted in marked improvement in the aforementioned symptomatology. Recent studies in autistic child have shown diminished acetylcholine and nicotinic receptor activity, thus an acetylcholinergic enhancer, Donepezil, likely accounts for improvement in autistic symptoms. Evidently, the case report consolidates Donepezil role as a potentially useful agent in the treatment of cognitive and behavioural symptoms observed in this disorder.

 Mecamylamine
There was a recent trial of Mecamylamine, with mixed results, but the researcher is already planning a follow trial of a similar drug called varenicline, that was previously suggested by other researchers.

RESULTS:

Eighteen participants (10 mecamylamine, 8 placebo) completed the study. All doses were well tolerated; the only side effect of note was constipation (50% compared with 25% of placebo group). Three children had clinically nonsignificant electrocardiographic QT prolongation. Both groups showed modest to moderate improvement, but differences between groups were negligible. On the primary outcome measure, the Ohio Autism Clinical Impressions Scale, 90% of the active treatment group showed improvement at some point (but only 40% sustained it), compared with 62% on placebo. Of the four in active treatment that sustained improvement, three had a maximum dose of 0.13-0.15 mg/kg/day, while those who regressed had doses ≥0.18 mg/kg/day. Graphed means suggested better outcome with lower mg/kg and longer medication duration. Four parents spontaneously reported reduced hyperactivity and irritability and better verbalization and continued mecamylamine at their own expense.

CONCLUSION:

Mecamylamine appeared to be safe, but not very effective in autism. The suggestion of better results at lower doses and longer exposure warrants consideration for future trials. The next step would be exploration of a more specific α4β2 nAChR agonist, such as varenicline.

Varenicline is a drug developed to help people to stop smoking.  It is widely used and looks set to be trialed in autism


Galantamine
Galantamine was successfully trialed and I am surprised we do not hear more about it.  In fact, it was developed in the Soviet Union in the 1950s and is now used for Alzheimer's.  It is based on snowdrop flowers.  It is available as a drug and as a supplement, depending on where you live.

RESULTS:

Patients showed a significant reduction in parent-rated irritability and social withdrawal on the ABC as well as significant improvements in emotional lability and inattention on the Conners' Parent Rating Scale--Revised. Similarly, clinician ratings showed reductions in the anger subscale of the Children's Psychiatric Rating Scale. Eight of 13 participants were rated as responders on the basis of their improvement scores on the Clinical Global Impressions scale. Overall, galantamine was well-tolerated, with no significant adverse effects apart from headaches in one patient.

CONCLUSION:

In this open trial, galantamine was well-tolerated and appeared to be beneficial for the treatment of interfering behaviors in children with autism, particularly aggression, behavioral dyscontrol, and inattention. Further controlled trials are warranted


The missing evidence
You will have noticed caffeine and nicotine in the title of this post.  You may have noted that back in 2001/2 the original researchers suggested the logical next step was to trial nicotine patches.

All I can find is one case report in ADHD, which to me is just ASD-lite.


If you look in internet forums you will see that DAN doctors in the US are using nicotine patches.  You will also find people giving small doses of caffeine.
Having reviewed “the evidence” I think it is entirely logical to trial SMALL doses of nicotine and caffeine.  The research indeed tells us that only SMALL does may have the desired effect.
One report I read was a DAN Doctor giving her own child a quarter of 7mg nicotine patch.  By my research, that equals the nicotine of a single cigarette.
You will also see older kids with HFA (high functioning autism) writing on the web how they feel it easier to (pretend to) be more NT (neuro-typical) after drinking coffee and/or smoking. (Maybe they just look more NT, or maybe there is some truth in it).  They do not talk about alcohol.
The other “obvious” thing that has not been trialed is acetylcholine or choline itself.  It is known to be deficient in autism.  It is sometimes included in multivitamin pills in small amounts. Choline is widely available as a supplement.  It is also used for its nootropic properties and there are claims it reduces neuroinflammation.  It is used in depression, memory loss, Alzheimer’s and schizophrenia  It also lower cholesterol. Most surprisingly, choline is prescribed to control asthma, a comorbidity of ASD.  
Choline is used by people trying to boost their brainpower by combining it with other nootropic drugs.  Their favourite drug appear to be Piracetam, which is the same drug used for ASD in Ukraine and subject of a clinical trial in Iran, that I wrote about recently.

It is remarkable how many drugs I am writing about are either (ab)used by body builders or now IQ builders.

Conclusion
This post has really surprised me.  Firstly, there more drugs that look like they actually do work in autism (Donepezil and Galantamine).  There is an interesting phase 4 trial underway using Donepzil + Choline. Phase 4 is the final phase.

Nicotine may set alarm bells ringing, but if you check it out, you will see that very small amounts are apparently harmless.  Thanks to smokers, there exists a perfect transdermal delivery system.  Just why nobody trials it in autism (Glaxo produce Nicorette patches) is inexplicable.
Small amounts of coffee are given to even young children in many strong coffee drinking countries (like the Balkans). Coca Cola and even Ice Tea are caffeine-rich.

Choline is probably the simplest, cheapest and safest intervention;  but that does not mean it is will be effective.  Nobody has made a controlled trial with it, probably because there is no money in it.
For a change in my posts, it looks like there is something for everyone.