Is a Subtype of Autism an Allergy of the Brain?

 

 

I am actually in the middle of writing up my ideas about autism and the various human growth factors, but I just came across a paper worthy of its own post.  It is by one of those researchers already on my Dean's List, Dr Theoharis Theoharides from Tuft's University.

Is a Subtype of Autism an Allergy of the Brain?

You may recall that Theoharides works in the very small world of the mast cell.  These cells play a key role in allergies.  They contain histamine, serotonin and various other inflammatory agents.

The allergy causes the mast cells to "degranulate" and all the contents is released into the blood supply.  This then starts a chain reaction of events all over the body.

I was just reading about Nerve Growth Factor (NGF) which appears to behave strangely in autism.  It turns out that mast cells synthesise, store and release NGF.

NGF is very important for the brain, but it can also be highly neuro-inflammatory.  In autism NGF levels are elevated, just like Serotonin levels usually are.

What is the connection between NGF, Serotonin and Autism?  The degranulation of the mast cell.

Well, Theoharides knows everything about mast cell stabilizers.  These are agents that stop the mast cells emptying their contents into the blood stream.

But perhaps he has actually missed a connection.  In my forthcoming post on Human Growth Factors, we will find out about palmitoylethanolamide (PEA), a natural substance found in body that counters the inflammatory effect of NGF.  According to the Nobel Laureate who discovered TNF, PEA itself has mast cell stabilzing properties.

And one other strange thing, in people with autism and ADHD, they have low levels of PEA.

Put all the pieces together and then reconsider:-

        Is a subtype of autism an allergy of the brain?

I think the answer is of course yes; but more than that, I think it may well affect all subtypes of autism, just not all the time.

In some people they may have this "allergy" and nothing else.  In other people there are other issues like ion channel dysfunctions, but when their autism suddenly flares up, think over-activated immune system in Peter-speak or allergy of the brain in Theoharis-speak.

I think we are in effect speaking the same language.



 

 

Catecholamines and Autism

 

 

 

 

 

 

Source: Wikipedia

 

As I mentioned a few posts back, it looks like endocrinology of the brain holds the key to treating autism and indeed most other psychiatric and neurological conditions.

Today’s post is about one group of hormones/neurotransmitters called  catecholamines.  Due to the inter-relationships between hormones, neurotransmitters and electrolytes it is helpful to group them together.  Catecholamines include three well known hormones: - epinephrine (adrenaline), norepinephrine (noradrenaline) and dopamine.

For those of you that did chemistry at school, the reason for the odd sounding name, catecholamines, is that these hormones contain a benzene ring with two OHs attached.

Catecholamines are very important hormones and also form the basis of several well-known drugs.  In chemistry when you take molecule like a hormone and make a tiny change to it, it then is referred to as an analogue (or an analog).   Some successful drugs are catecholamine analogs.

 
Dopamine

In the brain dopamine acts as a neurotransmitter; it appears to several distinct functions, some better known than others.

·        It controls the release of several hormones in the brain.  This may be the most important role in autism.

·        Motor control

·        Reward motivated behavior

Dysfunctions of the dopamine system are known to lead to:

Parkinson’s disease.  Loss of dopamine-secreting neurons in the midbrain disrupts motor control.

Schizophrenia involves altered levels of dopamine activity.

Attention deficit hyperactivity disorder(ADHD) and restless legs syndrome (RLS) are also believed to be associated with decreased dopamine activity.

Given that until recently autism was sometimes diagnosed as childhood schizophrenia and ADHD is evidently a case of autism-lite, it looks like dopamine plays a key role in Autism.

Dopamine does not cross the blood brain barrier (BBB) and its function outside the brain appears to be completely different.  Dopamine exerts its effects by binding to receptors on the surface of cells; so far 5 types of receptors have been identified.

Dopamine in ADHD

In ADHD it appears that genetic differences lead to altered dopaminergic neurotransmission. 

Catecholaminergic Gene Variants: Contribution in ADHD and Associated Comorbid Attributes in the Eastern Indian Probands

This part of science is only just emerging, but for many years some of the most effective therapeutic agents for ADHD have been psychostimulants such as methylphenidate (Ritalin) and amphetamine, drugs that increase both dopamine and norepinephrine levels in brain.

Very recently a study was published by Cambridge University, which would appear to contradict all this:-

Imaging study shows dopamine dysfunction is not the main cause of Attention Deficit Hyperactivity Disorder (ADHD) 

Professor Barbara Sahakian who led the study at the BCNI said: “We feel these results are extremely important since they show that people who have poor concentration improve with methylphenidate(Ritalin) treatment whether they have a diagnosis of adult ADHD or not. These novel findings demonstrate that poor performers, including healthy volunteers, were helped by the treatment and this was related to increases in dopamine in the brain in an area of the striatum called the caudate nucleus.”

Professor Trevor Robbins, co-author and Director of the BCNI, said: “These findings question the previously accepted view of major abnormalities in dopamine function as the main cause of adult ADHD patients. While the results show that Ritalin has a 'therapeutic' effect to improve performance it does not appear to be related to fundamental underlying impairments in the dopamine system in ADHD.”

I find all this quite odd.  The researchers are surprised to find that Ritalin helps people without ADHD concentrate better.  Are they not aware that for many years students and “cognitive enhancers” have been taking Ritalin to improve their exam grades? These people do not have ADHD.  If the researchers spent half an hour on Google, they could have saved a lot of money. 

The study showed that Ritalin helps you concentrate and it also showed that using a combination of positron emission tomography (PET) and magnetic resonance imaging (MRI) to measure grey matter that in ADHD there are structural differences in the brain’s grey matter.  I wonder how this comes as a surprise to anyone.

It looks like the ADHD researchers in India are far more advanced than their Cambridge counterparts.

Affecting Dopamine Levels in the Brain

After synthesis, dopamine is transported from the cytosol into synaptic vesicles by the vesicular monoamine transporter 2 (VMAT2). Dopamine is stored in and remains in these vesicles until an action potential  occurs and causes the contents of the vesicles to be ejected into the synaptic cleft.

Once in the synapse, dopamine binds to and activates dopamine receptors.

After an action potential, the dopamine molecules quickly become unbound from their receptors. They are then absorbed back into the presynaptic cell, via reuptake mediated either by the high-affinity dopamine transporter (DAT) or by the low-affinity plasma membrane monoamine transporter (PMAT). Once back in the cytosol, dopamine is subsequently repackaged into vesicles by VMAT2, making it available for future release.

Dopamine is broken down into inactive metabolites by a set of enzymes, monoamine oxidase (MAO), aldehyde dehydrogenase (ALDH), and catechol-O-methyl transferase (COMT), acting in sequence. Both isoforms of MAO, MAO-A and MAO-B, are equally effective.

The level of dopamine circulating is there for a function of:-

·        How much is synthesized in the first place

·        How much is held in storage in the vesicles

·        How much is “recycled” via re-uptake

·        How much is degraded by MAOs

·        Presence of any Dopamine analog drugs acting as agonists

 

The release of Dopamine from the vesicles will be influenced by the factors maintaining central homeostasis; this includes hormones, electrolytes and other neurotransmitters.

Effect of Ritalin (Methylphenidate)

Recent research has shown that prolonged use of Ritalin increases dopamine transporter (DAT) levels and therefore amplifies the effect of amphetamines.

Long-Term Stimulant Treatment Affects Brain Dopamine Transporter Level in Patients with Attention Deficit Hyperactive Disorder 

In the end this means that once on Ritalin, it will be very difficult to come off it, or in the words of the researchers:-

Upregulation of dopamine transporter availability during long-term treatment with methylphenidate may decrease treatment efficacy and exacerbate symptoms while not under the effects of the medication.

Methylphenidate amplifiesthe potency and reinforcing effects of amphetamines by increasing dopamine transporter expression

All in all, Ritalin does not look a good idea for children with ADHD or autism. 

Epinephrine

Epinephrine is a hormone and neurotransmitter that poorly crosses the blood brain barrier (BBB).

Regulation

The major physiologic triggers of adrenaline release centre upon stresses, such as physical threat, excitement, noise, bright lights, and high ambient temperature. All of these stimuli are processed in the CNS

Adrenocorticotropic hormone (ACTH) and the sympathetic nervous system stimulate the synthesis of adrenaline precursors by enhancing the activity of tyrosine hydroxylase and dopamine-β-hydroxylase, two key enzymes involved in catecholamine synthesis ACTH also stimulates the adrenal cortex to release cotisol, which increases the expression of PNMT in chromaffin cells, enhancing adrenaline synthesis. This is most often done in response to stress. The sympathetic nervous system, acting via splanchnic nerves to the adrenal medulla, stimulates the release of adrenaline. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing cell depolarization and an influx of calcium through voltage-gated calcium channels. Calcium triggers the exocytosis of chromaffin granules and, thus, the release of adrenaline (and noradrenaline) into the bloodstream^]

Unlike many other hormones, adrenaline and the other catecholamines do not exert negative feedback to down regulate their own synthesis. Their action is terminated with reuptake into nerve terminal endings, some minute dilution, and metabolism by MAO and catechol-O-methyl transferase. 

Norepinephrine

Norepinephrine is a hormone and neurotransmitter responsible for vigilant concentration.  As a stress hormone, norepinephrine affects parts of the brain, such as the amygdala, where attention and responses are controlled. Norepinephrine also underlies the fight-or-flight response, along with epinephrine, directly increasing heart, triggering the release of glucose from energy stores. It increases the brain's oxygen supply. Norepinephrine can also suppress neuroinflammation when released diffusely in the brain from the locus coeruleus.

Norepinephrine is synthesied from dopamine. It is released from the adrenal medulla into the blood as a hormone, and is also a neurotransmitter in the central nervous system (CNS).   The actions of norepinephrine are carried out via the binding to adrenergic receptors.
 

Clinical uses

Norepinephrine may be used for the indications attention deficit hyperactivity disorder (ADHD), depression, and hypotension. Norepinephrine, as with other catecholamines, cannot cross the blood–brain barrier, so drugs such as amphetamines are necessary to increase brain levels.

Attention-deficit/hyperactivity disorder

Norepinephrine, like dopamine, has come to be recognized as playing a large role in attention. For people with ADHD, psychostimulant medications such as amphetamines (Adderall, Desoxyn,) are prescribed to increase both levels of norepinephrine and dopamine.  Methylphenidate (Ritalin/Concerta), a dopamine reuptake inhibitor, and Atomoxetine (Strattera), a selective norepinephrine reuptake inhibitor (SNRI), increase both norepinephrine and dopamine in the prefrontal cortex equally but only dopamine and norepinephrine, respectively, elsewhere in other parts of the brain. Other SNRIs, currently approved as antidepressants, have also been used off-label for treatment of ADHD

Depression

Differences in the norepinephrine system are implicated in depression. Serotonin-norepinephrine reuptake inhibitors are antidepressants that treat depression by increasing the amount of serotonin and norepinephrine available to cells in the brain. There is some recent evidence implying that SNRIs may also increase dopamine transmission. This is because SNRIs work by inhibiting reuptake, i.e. inhibiting the serotonin and norepinephrine transporters from taking their respective neurotransmitters back to their storage vesicles for later use. If the norepinephrine normally recycles some dopamine too, then SNRIs will also enhance dopamine transmission. Therefore, the antidepressant effects associated with increasing norepinephrine levels may also be partly or largely due to the concurrent increase in dopamine.

Tricyclic antidepressants (TCAs) increase norepinephrine activity as well. Most of them also increase serotonin activity, but tend to produce unwanted side-effects due to the nonspecific inactivation of histamine, acetylcholine and alpha-1 adrenergic receptors. Common side-effects include sedation, dry mouth, constipation, sinus tachycardia, memory impairment, orthostatic hypotension, blurred vision, and weight gain.  For this reason, they have largely been replaced by newer selective reuptake drugs. These include the SSRIs, e.g. fluoxetine (Prozac), which however have little or no effect on norepinephrine, and the newer SNRIs, such as venlafaxine (Effexor) and duloxetine (Cymbalta).


Release modulators
 

Inhibitors of norepinephrine release
Substance	Receptor
acetylcholine	muscarinic receptor
norepinephrine (itself)/epinephrine	α2 receptor
5-HT	5-HT receptor
adenosine	P1 receptor
PGE	EP receptor
histamine	H2 receptor
enkephalin	δ receptor
dopamine	D2 receptor
ATP	P2 receptor

 

Anti-inflammatory agent role in Alzheimer’s disease

The norepinephrine from locus ceruleus cells in addition to its neurotransmitter role locally diffuses from "varicosities". As such, it provides an endogenous anti-inflammatory agent in the microenvironment around the neurons,  glial cells, and blood vessels in the neocortex and hippocampus. Up to 70% of norepinephrine projecting cells are lost in Alzheimer’s disease.

Timothy Syndrome

Timothy Syndrome is a rare genetic condition that is generally accompanied by autism.  Researchers at Stanford University found that this type of autism is caused by defective calcium channels in the  brain and that the defect could be reversed with  a drug.  Note that in this syndrome there is OVER-production of  dopamine and norepinephrine. 

Scientists identify defect in brain cell channel that may cause autism-like syndrome 

In this study, the scientists suggest that the autism in Timothy syndrome patients is caused by a gene mutation that makes calcium channels in neuron membranes defective, interfering with how those neurons communicate and develop. The flow of calcium into neurons enables them to fire, and the way that the calcium flow is regulated is a pivotal factor in how our brains function.

The researchers also found brain cells grown from individuals with Timothy syndrome resulted in fewer of the kind of cells that connect both halves of the brain, as well as an overproduction of two of the brain’s chemical messengers, dopamine and norepinephrine. Furthermore, they found they could reverse these effects by chemically blocking the faulty channels.

Conclusion

This post was a short biology lesson.  Its relevance will become apparent in later posts as we look at the inter-relationships between hormones/neurotransmitters and ion channels/transporters. 

Then we can investigate therapeutic avenues.


 

 

 

Clonidine, ADHD and Autism

Clonidine has been used for more than half a century as an antihypertensive drug, to lower blood pressure.

It later found favour as a treatment for ADHD, drug withdrawal treatment, tobacco withdrawal treatment and a wide range of psychiatric disorders.  Off label usage of Clonidine includes autism.

Until recently it appeared to researchers to be a centrally acting α₂ adrenergic agonist, but recent research indicates than instead it is a centrally as an imidazoline receptor agonist.  This would account for its actions other than lowering blood pressure. Maybe it is both.  The good thing is that it is centrally acting (i.e. acting on the brain and the CNS) and it does appear to work. 

Adrenergic Agonist

As a centrally-acting α-adrenergic receptor agonist, Clonidine has more affinity for α₂ than α₁. It selectively stimulates receptors in the brain that monitor catecholamine (epinephrine, norepinephrine and dopamine) levels in the blood. These receptors close a negative feedback loop that begins with descending sympathetic nerves from the brain that controls the production of catecholamines.  By fooling the brain into believing that catecholamine levels are higher than they really are, clonidine causes the brain to reduce its signals to the adrenal medulla, which in turn lowers catecholamine production and blood levels. The result is a lowered heart rate and blood pressure.

Imidazoline Receptors

There are three classes of imidazoline receptors:

• I₁ receptor – mediates the sympatho-inhibitory actions of imidazolines to lower blood pressure
• I₂ receptor – an allosteric binding site of monoamine oxidase and is involved in pain modulation and neuroprotection.
• I₃ receptor – regulates insulin secretion from pancreatic beta cells

L-Monoamine oxidases (MAO)

MAOs are enzymes that act as catalysts.  There are two types of MAO: MAO-A and MAO-B

MAO- A is an enzyme that degrades amine neurotransmitters such as dopamine (DA), norepinephrine (NE), and serotonin (5-HT).

MAO-B is an enzyme that catalyzes the oxidation of arylalkylamine neurotransmitters, including dopamine (DA).

The differences between the selectivity of the two enzymes are utilized clinically.  MAO- A inhibitors have been used in the treatment of depression, and MAO-B inhibitors are used in the treatment of Parkinson's disease

Selective MAO-B inhibitors preferentially inhibit MAO-B, which mostly metabolizes DA. If MAO-B is inhibited, then more DA is available for proper neuronal function, especially in Parkinson's Disease. 

Clinical significance

Because of the vital role that MAOs play in the inactivation of neurotransmitters, MAO dysfunction (too much or too little MAO activity) is thought to be responsible for a number of psychiatric and neurological disorders. For example, unusually high or low levels of MAOs in the body have been associated with schizophrenia, depression, attention deficit disorder, substance abuse, migraines, and irregular sexual maturation.

MAO inhibitors are one of the major classes of drug prescribed for the treatment of depression, although they are often last-line treatment due to risk of the drug's interaction with diet or other drugs. Excessive levels epinephrine, norepinephrine or dopamine may lead to a hypertensive crisis, and excessive levels of serotonin may lead to serotonin syndrome.

MAO-A inhibitors act as antidepressant and antianxiety agents, whereas MAO-B inhibitors are used to treat Alzheimer’s and Parkinson’s diseases.

Clonidine in ADHD

In the US, the FDA has licensed clonidine for use in children with ADHD.

Pediatric doses of clonidine are calculated based on the child's body weight. Clonidine dosage for ADHD in children is 5 micrograms per kilogram of body weight per day orally in four divided doses. Children who require a daily dosage of 0.2 mg usually can use the 0.3 mg trans-dermal patch. If ADHD is associated with sleep disturbances, low to moderate doses of clonidine can be taken at bedtime.

Clonidine in Autism

Not surprisingly, since clonidine is effective in ADHD, it also shows promise in autism. 

Other ADHD drugs, like Ritalin, have problematic side effects.  The US Center for Disease Control reported in 2012 that an estimated 6.4 million children ages 4 to 17 had been diagnosed with ADHD at some point, a 53 percent increase over the past decade. Approximately two-thirds of those currently diagnosed have been prescribed drugs such as Ritalin or Adderall. Those drugs can help patients with both mild and severe symptoms, but they can also cause addiction, anxiety and psychosis.  In the UK, it is suggested that about 3% of children may have ADHD.  Drug use is far lower than in the US, but 657,000 prescriptions were written by doctors for drugs like Ritalin in 2012.

Use of ADHD drugs 'increases by 50% in six years'

There have been studies of clonidine in autism; here a fairly recent one:-

Use of clonidine in children with autism spectrum disorders

Perhaps even more interesting is a lively debate among parents who have tried it:-

Clonidine for autism?

It does seem to work, but nobody seems to be following it up.

Clonidine Stimulation Test

Regular readers will know my interest in TRH and GH.  At least there is no doubt about Clonidine’s effect on GH (growth hormone).  If you want to test pituitary function to see how well GH is being produced, the standard test is the:-

Clonidine GH stimulation Test

For those interested in GH, if you were to take Clonidine, smoke a cigarette and then have your GH measured, the Endocrinologist would have a surprise.

Nicotine from cigarette smoking enhances clonidine-induced increase of serum growth hormone concentrations in men

“These findings suggest that in man nicotinic cholinergic and adrenergic mechanisms might interact in the stimulation of GH secretion.”
 

Interestingly, one of the milder side effects of the ADHD drug Ritalin is growth retardation. According to Professor Tim Kendal, who created the national guidelines in the UK for treating ADHD: - “In children, without doubt, if you take Ritalin for a year, it's likely to reduce your growth by about three-quarters of an inch.

Conclusion

Clonidine looks like another old drug that has been stumbled upon by somebody doing some off label experimentation.  It does seem to have good results in ADHD and Autism.  The good thing is that it is FDA approved and is available in both oral and time release transdermal forms.

I do not think anybody really understands how it works in ADHD or other psychiatric disorders; undoubtedly, there is another, as yet unidentified, mode of action.

 

For those who want more info:- 

The Clinical Utility of Clonidine

Note ulcerative colitis, ADD and even growth delay.

 

Clonidine treatment for short stature