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Wednesday, 15 January 2014

4G and Autism - Glutamine, Glutamate, GABA & GAD


This post is not about your IPad, it’s still about autism.

There are a few important substances that I have not fully addressed yet in this blog; as is often the case in biology, the names do all rather look alike.  A complete understanding of these 4 Gs will definitely help to understand the literature and hopefully separate science from pseudoscience and the voodoo.
We know for a fact that in autism some strange things are going on here, but it remains to be proved exactly what is going on, and whether all types of autism are similarly affected.  So it may be premature to visit the supplement shop.
 
The 4 Gs
Glutamine, like Creatine, is one of those chemicals that is widely used by body builders and sometimes given to children with autism.  It is an amino acid.

Glutamine is a precursor chemical to Glutamate.  Glutamate is a major excitatory neurotransmitter in the brain.
Glutamate is a precursor chemical to GABA, another very important neurotransmitter.

Glutamate is converted to GABA by the neuronal enzyme glutamate decarboxylase (GAD).
Glutamate is synthesized from glutamine via glutaminase, but after release in the synapse, glutamate is converted back into glutamine in glial cells, by glutamine synthetase.

 
Some Facts

Glutamine
Glutamine is known to help heal injuries and recover from abdominal surgery.  It was thought that this would extend to helping maintain the gut barrier, which is sometimes implicated in autism.  DAN type doctors use glutamine to “heal the gut”; however, when trials were made in Crohn’s disease, an inflammatory bowel disease similar to the type sometimes implicated in autism, supplementing with glutamine had no effect.
 

Glutamate

Glutamine + H2O
Glu + NH3

 
Glu is actually glutamic acid, the salts and esters of glutamic acid are called glutamates.  Often the literature mixes the terms glutamate and glutamic acid.

NH3 is ammonia, which is also important and plays a role in some people’s autism theories.
Excessive glumate release is implicated in autism.  Glutamic acid is implicated in epilepsy, which is highly comorbid with autism.
Glutamate decarboxylase (GAD) is an enzyme that catalyzes the conversion  of glutamate  to GABA and CO2.

HOOC-CH2-CH2-CH(NH2)-COOH → CO2 + HOOC-CH2-CH2-CH2NH2

Where HOOC-CH2-CH2-CH2NH2  is GABA (Gamma-Aminobutyric acid)
 
GABA

GABA is another amino acid and important neurotransmitter.  It is also known to regulate muscle tone, which is often affected in autism.
GABA works by binding at receptors, this binding causes the opening of ion channels to allow the flow of either negatively charged chloride ions into the cell or positively charged potassium ions out of the cell.
There are two classes of GABA receptor : GABAA and GABAB
The drug Baclofen is an agonist for the GABAB receptors. A version of this drug called Arbaclofen is being developed as a treatment for autism and Fragile X.
Baclofen is a drug to treat spasticity, which is a condition where there can be strange effects on the muscles like spasms, stiffness and tightness.  Some people with ASD have a tendency to clasp their hands and fingers in a strange tight claw-like fashion and indeed some walk with an odd gait.  That would appear to me to be a form of spasticity.  Baclofen was stumbled upon by accident as a possible autism drug, where it would treat a form of mental spasticity.
Baclofen also has a long forgotten secondary effect that interested me; it stimulates the production of GH (Growth Hormone).  GH does appear to be implicated in autism along with IGF-1 and its analogues.
An antagonist of the GABAA receptor, bumetanide, works by blocking the NKCC1 cation-chloride co-transporter, and thus decreases internal chloride concentration in neurons. In turn, this concentration change makes the action of GABA in some people with autism, returning it from excitory to inhibitory, where is should be.

I think it is clear that GABA plays a major role in some types of autism.

Recent Studies
As noted in previous posts, some very practical research comes out of Iran these days.


"2.1. Glutamate

Glutamate is a major excitatory neurotransmitter in the brain. The high level of plasma glutamate level especially in children with normal IQ is supposed to be a diagnostic screening test. The increased plasma level in adults with autism is also reported. Higher glutamate level is not limited to plasma, and some studies confirmed its higher level in some brain regions (amygdala-hippocampal regions but not in parietal region) of patients with autism compared to the controls. The increased plasma glutamic acid is not limited to patients with autism, but its level is increased in their siblings and parents. "

"2.2. Glutamine

The low level of plasma glutamine level is suggested as a screening test for detecting autism in children especially those with normal IQ. The decreased level has been reported before in all children with autism."

A very recent study by King's College London looked at the level of glutamate and glutamine in adults with ASD using clever proton magnetic resonance spectroscopy in two brain regions. 
They found reduced levels of the combined signal of glutamate and glutamine in autism versus the control group.  It all sounds very clever until you get to the discussion part, where they say:-
"Hence, it could be that serotonergic abnormalities underlie the differences in Glx we observed—either indirectly via influences on neurodevelopment or through direct action on glutamate metabolism."

This may be the case of over-analyzing certain variables, because the technology exists, even though you can only understand 20% of the problem.  The end result is lots of complicated looking data and analysis that may actually lead nowhere.
A reality check is required.  We have to come back to definitive facts otherwise the research is just generating confusion.

We already know serotonergic abnormalities are present in autism.  We know that drugs that increase brain serotonin, such as LSD and Prozac, improve autistic behaviours.  So the researchers at Kings College have very likely just measured a consequence of these abnormalities.  As a result, the glutamate/glutamine issue may indeed join the long list of consequences, rather than causes of autism.
 
The fever effect (again)
Another reason for this post is that both Glutamine and Glutamate have been put forward as possible explanations for the fever effect in autism; that is a reduction in autistic behaviour when person is sick, with a high temperature.

The fever effect is so dramatic in some people, that it would be ever so easy to validate a hypothesis.  In doing so, you would open the door to a very useful therapy for many people.
 
This paper was published in the Journal Medical Hypotheses, but the full version is not always available free, the first link is to the author’s own site.  It is a very thorough analysis and worth a read, but in the end the author seems to disprove his own hypothesis.

A preliminary version of this paper was sent to several hundred ASD practitioners (DAN Doctors) formerly listed on the ARI site, for feedback. Fourteen replies suggest ASD practitioners commonly give oral glutamine to heal the intestines, from 250 mg to 8 g/day, with few side effects (some hyperactivity) but few notable improvements in behavior.

So now on to the next candidate, glutamate.
The second hypothesis is by Ghanizadeh, the Iranian author of the paper I referred to earlier.

Could fever and neuroinflammation play a role in the neurobiology of autism? A subject worthy of more research.


Abstract

Autism is neuropsychiatric disorder in which a hyperglutamate state may play a role. It is suggested here that fever or hyperthermia may be able to alter glutamate levels in the brain and may therefore be able to impact on the symptoms of autism. More study on this possibility is clearly warranted.


Conclusion
Of the 4 Gs, I am sticking with GABA as the key one, but I will not be buying any GABA supplements, even though they do exist.  Some DAN-type doctors favour Glutamine supplements, even though some well-known “holistic” type doctors like Dr Mercola say specifically not to give it to kids with ASD and ADHD.

I have no doubt that glutamate plays an important role in autism, but as with GABA it is not just a matter of swallowing some.
There is a line to be drawn between science, pseudoscience and pure voodoo. For the time being, you have to find this line yourself.

3 comments:

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  2. Still thinking about GABAA receptors, my son has had a positive calming response to an herbal concoction for parasites, whose biggest ingredient is wormwood. Eventually it wears off and once more he becomes physically restless, with intense rocking, jaw tensing, vocalizing, and facial grimacing. But for the first frew days, there is noticeable improvement According to wikopedia, wormwood is a GABAA antagonist. I'm not sure I know what that might indicate in terms of other therapuetic agents that might work.
    Thanks.

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    1. Hi Nancy, your discovery is very interesting.

      It appears that the active substance is something called Thujone.
      It affects both GABA and 5-HT3 receptors in the brain. It is found in essentials oils, perfume and even the drink Absinthe. It is found in wormwood and some species of mint.

      As a GABAa antagonist it should shift the excitatory/inhibitory balance towards excitatory and thus can cause convulsions at high doses.
      It is the opposite of valium, and can be used to counter its effects.
      The other effects are not surprisingly sleeplessness and anxiety.

      The fact that valium works as it should does not rule out a GABA dysfunction, since there are different types. There is no way of knowing for sure what will help, but there are certainly things well worth trying.
      I would try the GABAa drugs Bumetanide and low dose Clonazepam. This would mainly affect cognition and, by consequence, other behavior.

      These have both proved effective by readers of this blog and have a sound scientific basis for their use.

      I would also try the GABAb drugs like Baclofen. Baclofen is often used for spasticity and so it could well help with jaw tensing/contraction etc which may just be symptoms of the underlying dysfunction. Baclofen does seem to help people with Asperger’s for anxiety, and a smaller number of people with classic autism and Fragile X.

      GABAb has a connection to growth hormones and I think that in people whose growth patterns are unusual this may be a pointer as to why. In autism you often have extremes, so you have big heads, small heads, large stature, small stature and also people who start out big for their age and end up small for their age.

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