UA-45667900-1
Showing posts sorted by relevance for query potassium. Sort by date Show all posts
Showing posts sorted by relevance for query potassium. Sort by date Show all posts

Wednesday, 28 August 2013

Potassium may play an important role in Autistic Behaviours

This is not the kind of post that I expected to be writing.  How can the effect of something so simple as a mineral, not have been noticed by others and researched in depth?

Potassium (K+),  is one of several electrolytes that occur in humans, the others being sodium(Na+), calcium (Ca2+), magnesium (Mg2+), chloride (Cl), hydrogen phosphate (HPO42−), and hydrogen carbonate (HCO3)

Electrolyte balance or homeostasis is regulated by specific hormones.  These electrolytes are used to control many aspects of your body.  The concentration of each electrolyte varies across the boundary of each cell.  Electrolytes pass through the cell wall/membrane through so called ion channels.  These are like special valves that open and close based on particular pre-programmed circumstances.  When these ion channels malfunction, often due to a genetic fault, disease occurs.  Ion channel diseases have a special name - channelopathies.  This is still an emerging area of science.

In autism the brain has developed in an unusual way and although it is thankfully not a degenerative disease, the biological equilibrium it has evolved to is not the one originally intended.  There are both channelopathies and hormonal irregularities; indeed the two are interrelated.

Many hormones are interrelated and have multiple functions and therefore a change in one may have a cascading effect on others.  The same applies to the electrolytes, for example a deficiency in magnesium will trigger a deficiency in potassium.

Choride (Cl-)

I started my blog when I read about a successful clinical trial that set out to prove whether an imbalance in chloride between the extra/intra cellular fluid could cause one of the brain’s main neurotransmitters (GABA) to malfunction.  A clever Frenchman called Ben-Ari, had been researching neonatal seizures and proposed to trial the drug Bumetanide.    Bumetanide is known to block the NKCC1 cation-chloride co-transporter, and thus decreases internal chloride concentration in neurons. In turn, this concentration change makes the action of GABA more hyperpolarizing.  Do not be put off if this does not make sense to you.

The trial showed the positive effect on autistic behaviours of this long established and inexpensive drug.
 
A randomised controlled trial of bumetanide in the treatment of autism inchildren


Potassium (K+)

Not long after making a trial of bumetanide on Monty, then aged 9 years, I started this blog and my own research.  I soon came across a condition called Hypokalemic Sensory Overstimulation.  In this condition, the subject becomes overwhelmed by his senses of sound, light, smell etc.  After taking oral potassium, the symptoms disappear within 20 minutes.  It is claimed that this is also a characteristic of ADHD (attention deficit hyperactivity disorder).  Well sensory overload is pretty common in autism, and, as I have learnt, ADHD is really just a light case of autism.

There is almost no research into this condition, which is odd since it is linked to the very common ADHD condition.  The paper below  was only ever cited 3 times in other research, and only once in English.

I then did my own experiment using a small dose of K+  supplement (equivalent to one banana) to see if by any chance I could see a reduction in sensory overload.  I tested both my sons, and only in the ASD son did the potassium have any impact; and it was a marked impact.  I wrote this up in a blog post.

I kept potassium and channelopathy on my list of things to research and left it at that.

 
Ion Channels & Ion Channel Diseases (Channelopathies)

Ion channels are an emerging area of science all about how signals are sent throughout your body to control it.  It gets very complicated and is still far from fully understood.  So you may want to skip this part.

So far 300 types of ion channel have been identified.  The main types are:-

·         Chloride (Cl-) channels

·         Potassium channels

·         Sodium channels

·         Calcium channels

·         Proton channels

·         Non-selective cation channels

 Then there are differing ways in which the channels open and close such as:-

·         Voltage gated

·         Ligand gated

And odd ones like
 
·         Light gated

·         Temperature gated

·         Calcium activated potassium channels

When the ion channel and/or its gating does not work properly then a disease called a channelopathy may result.  Examples of well know disease are cystic fibrosis, various types of epilepsy and ataxia.

 
Puberty and Epilepsy  

As a result of the changes in hormones triggered by puberty it is therefore not surprising that around this time other changes occur in the body.  In some children with asthma, their symptoms become more mild or even appear to disappear.  In autism the hormonal changes often trigger an improvement, but may be the trigger of the onset of epilepsy.  When you consider the importance of all these electrolyte levels, and the variation of each across one each cell boundary in the body and how this is intertwined with how the neurotransmitters function, it is not surprising that a shift in Homeostatis occurs.

That shift in Homeostatis could be reflected in a mellowing of autistic characteristics.  But if you can now make some small adjustments in these levels via diet and mild drugs, why not investigate it?  You will not be able to achieve perfection, but you might be able to shift from one stable equilibrium to another one, with milder autism and no troubling side effects.

This would also imply that those children developing epilepsy during puberty might be able to treat it using the diuretic bumetanide.  By blocking the NKCC1 transporter, the level of Cl- is blocked and GABA becomes more inhibitory and thus the risk of an epileptic attack might be reduced, or perhaps eliminated.  This is surely worth some research?

 
K+ ion channel disease – Epilepsy & Autism

There is existing research linking potassium ion channels to both epilepsy and autism





ADHD & Ritalin

I read some research about a stimulant drug used to calm children with ADHD.  It seemed odd to use a stimulant to produce calm.  Here again potassium (K+) and sodium (Na+) levels are at the centre of argument.
 
Then I noted a very recent article (July 2013) reporting a study of Ritalin on children with ASD and/or ADHD.

In the world of alternative medicine there is talk of Ritalin helping in ADHD due to it altering the level of potassium:-


This inverted ratio of Na/K may be helpful in explaining why a stimulant drug like Ritalin would have a calming effect on hyperactive children and adolescents. Ritalin does, indeed, have a stimulating effect on these children, but its stimulating mechanism is neuroendocrine and biochemical, not behavioural. More specifically, its stimulating effect is on the adrenal glands and the retention of sodium in the tissues relative to potassium. It is critical for normal cellular functioning that sodium and potassium (Na and K) be in balance for the optimal operation of the Na/K pump at the cellular level. It is also critical for efficient neurotransmissions that there be a proper balance between sodium and potassium (Na and K) for neuronal conductance.

 
Measuring electrolyte (Ka, Na, Mg, Cl etc.) levels

I would have expected that it was easy to check the level of electrolytes and indeed to check the levels in blood is very easy.  I have done this and all was normal.  When you read further in the literature, you will realize that the level of electrolytes at the extra/intra cellular level is not so easy to measure.  A whole business has been created by people analyzing hair samples for clues as to the balance or imbalance of various minerals in the body.

Hair analysis is used in forensic toxicology and  drug testing to detect the presence of various chemicals in the body.  The method has been adopted by the complementary and alternative medicine (CAM) community to try to predict food intolerance and dietary deficiency.  It is viewed by the scientific community that much of the CAM use of the technology is not valid and potentially fraudulent,

So there is no certain way of checking the cellular level of electrolytes.  You can only measure what you eat and you can measure what is in your blood.


Other suspected electrolyte imbalances in Autism

There have been several studies regarding Magnesium and autism, but the peer reviews of these studies are highly critical of the methodologies used and conclude that nothing has been proven.

Vitamin B6-magnesium treatment for autism: the current status of the research

Calcium has also been put forward as an intervention.  One mother spent a great deal of time collecting supporting information in her paper below.


 
DAN doctors and Spironolactone

Having come across a “bible” of therapies proposed by DAN (Defeat Autism Now) doctors I noted the use of a potassium-sparing diuretic called Spironolactone.  For a change, there is actually a published paper setting out their case for this drug.  The case made has nothing to do with potassium, even though the intended purpose of the drug is to raise potassium levels.

Bradstreet et al wrote a paper on this in 2006.  It has been cited only 7 times up until 2013 and two of these times by the authors themselves.  This tells you that other researchers were either skeptical or just disinterested.
 


Potassium Supplements
 
There are many hundreds of types of mineral and vitamin supplements; these days many contain far more than recommended daily amount (RDA).  This is not the case with potassium.  Even though the RDA for adults is 3,500 – 4,700 mg, in the US supplements by law may not contain more than 100 mg of potassium.  In Europe potassium supplements with 500mg are common.

A typical banana contains over 400mg of potassium, which would seem to make a 100mg supplement pretty pointless.

In the US it seems that there is a perceived fear of potassium poisoning.  It is indeed the home of the lethal injection.  Potassium chloride in a very high dose will stop your heart.

You will even find people debating whether you can poison yourself with bananasIt would seem that while you can reduce your high blood pressure with bananas, it does not kill you.  One person was even eating 30 bananas a day!!

The fear of potassium though remains and it is all over the American internet.
 
But, in the UK, the National Health Service advises:-

You should be able to get all the potassium you need by eating a varied and balanced diet. If you take potassium supplements, do not take too much because this could be harmful.

Taking 3,700mg or less of potassium supplements a day is unlikely to cause any harm.

That amount of potassium would require 37 American supplement tablets each and every day!

In reality, a concentrated dose of potassium may indeed upset your stomach and this is why it is better to get it from a healthy mix of fruit and vegetables.  The average American apparently consumes about 1,000mg of potassium per day.

Internet Chatter

If, like me, you use Google to see what other people are up to, you will come across talk of potassium and autism.  The discussions in forums never get far, because someone starts talking about lethal injections, and then fear prevails.

Sodium Potassium Pump  (Na+/K+-ATPase)

The sodium-potassium pump was discovered in the 1957 by a Danish Scientist, who later went on to win a Nobel prize for his discovery in 1997.  Its main application has been in the understanding and treatment of heart disease, but it is now thought to be directly involved in a critical part of the brain already known to be damaged in autism. 


As I have already mentioned in my blog, the comorbidities of autism (asthma, high cholesterol etc.) mean that much of the work has already been done by others.

Those many people with hypertension (high blood pressure) are suffering due the way the sodium potassium pump works.  They eat too much sodium and far too little potassium and the end result is high blood pressure.

An author and researcher, Dr Richard Moore, has a simple explanation on his website and a link to his book showing how diet can indeed control your blood pressure.  If you check the book on Amazon you will see many very favourable comments from people who have indeed lowered their blood pressure with bananas.

His book is called: The High Blood Pressure Solution: A Scientifically Proven Program for Preventing Strokes and Heart Disease.

 
Sodium Potassium Pump and Autism

I was looking for evidence (other than my own) that potassium levels affect the autistic brain.  Potassium plays a key role in how most ion channels function, but I was looking for something really tangible.  I think I have found it.

In my earlier posts I introduced readers to a part of the cerebellum called the Purkinje Cell Layer (PCL).  This is a critical part of the brain and unfortunately in autism, half of the cells are dead and this then manifests itself in altered brain functioning and hence behaviour.  

As recently as 2012, scientists in England showed that the neurons in the PCL are controlled by the Sodium Potassium Pump.


The paper’s summary concludes “We propose that Na+/K+ pump activity controls the intrinsic firing mode of cerebellar Purkinje cells”
 
Our new friend Dr Richard Moore puts it very simply:-

For the Na-K-pump to operate normally, the diet must have a ratio of potassium to sodium ratio (the K/Na ratio, or "K Factor") that is above a threshold that is somewhere between 2 and 4. Our ancestors ate a diet with a K/Na ratio ranging between 12 and 16. However, the average American white eats a diet with a K/Na ratio of less than 1 - about 0.6 - and the average American black eats a diet with an average K/Na ratio of about only 0.38! Obviously, the American diet generally has a very deficient K/Na ratio.

A low dietary K/Na ratio causes a low K/Na ratio in each and every cell in your body. This has been known since the end of World War II when whole body radio-active counters were used to determine the amount of potassium (a small part of which is naturally radioactive) in the human body. Almost universally, to their surprise, it was found that people with hypertension have a deficient amount of potassium in their body.

By 1983, several scientists including myself had worked out the vital role of the Na-K-pump in cell function to the point where our understanding predicted that other dysfunctions, or disease states, of the body's cells would occur. Not until the mid 1990's did anyone bother to look for these other conditions. Since then, it has become well established that in the U.S., our typical diet with its low K/Na ratio is the cause of:

About 95% of the cases of high blood pressure.
At least 90% of strokes whether or not high blood pressure is involved.
Much of the osteoporosis and kidney stones.
An increased likelihood of h-pylori infection with resulting stomach ulcer and stomach cancer.
An increase in the severity of asthma.
An increased likelihood of mental decline with aging.

In addition, there is some evidence that this low K/Na ratio in the American diet contributes to insulin resistance, to obesity, and to adult diabetes

  
So since in autism a critical part of the brain is already damaged and has been shown to be subject to oxidative attack and neuroinflammation, it is not surprising that it is particularly susceptible to further interference.  As a result whereas, in a typical childlike Ted, aged 13 with an aversion to fruit and vegetables, can function perfectly well and additional potassium made no measurable difference to his sensory behaviour, the same was not true of Monty, aged 10 with ASD, and with a diet full of fruits and vegetables.  The additional potassium actually changed his sensory behavoiur.  Now I have a plausible explanation

Electrolytes etc.

 If you really want to go into the biology and understand intercellular/extra cellular fluid, role of hormones vasopressin and aldosterone and all about sodium and potassium balance, then take 10 minutes to carefully read the following link:-
 

 
Autism and Heart Disease, Diabetes and Cancer

On this blog I have already shown that several strategies for cardiac health also help autism.  Since in autism there is proven high cholesterol and high neuroinflammation and most likely also hypertension, it would make great sense reduce these risks regardless of the fact that those steps may likely also reduce autistic behaviours and improve functioning.

I made a study into omega 3 and conclude “eat fish”, it is cheaper than omega 3 oil, and it definitely will help cardiac health, but probably will do little to nothing for the autism.


A high potassium diet, particularly if it is based on food rather than supplements, will protect your child from heart disease later in life.  He/she is already in an at risk group.

 So there are two very good reasons increase potassium and reduce sodium in his/her diet.  If you are not aware of the health issues surrounding autism, take a look at this:-


Without intervention, adults with autism spectrum disorder appear to be at significant risk for developing diabetes, coronary heart disease, and cancer by midlife.

For a general discussion on these and other health issues, there is a well-researched paper called:
 

  
Conclusion

In the case of Monty, aged 10 with ASD, incremental potassium in diet and via an over the counter potassium supplement (that also contains magnesium and B vitamins) has a positive effect on autistic behaviours.  The total daily potassium ingested (1g as supplement, plus banana, orange juice, potato etc.) is still probably below the adult RDA of 3.5g, but much higher than most 10 year olds with ASD.

There is a scientific logic to show why potassium might produce beneficial effects due to better functioning of the sodium-potassium pump, particularly in the Purkinje cell layer of the brain, which is a known to be damaged in ASD.

It may also be that the magnesium, that is also present in the potassium supplement, is having a beneficial effect.  This could easily be investigated by some further research, should anyone be so inclined.

In any case, a relatively high potassium diet is well established to be very healthy and, along with strategies to lower cholesterol, will promote a healthy heart.  The literature shows that autistic people have elevated cardiac risk and so already have a good reason to be following this kind of diet;  I have just added another good reason.

 

Monday, 28 October 2013

Epsom salts, Autism and Hypokalemic Sensory Overload


Early on in this blog I wrote about a supposedly rare condition, where somebody suffers from sensory overload, usually from sound, but it could be light or even smell.  That condition has fancy sounding name, Hypokalemic Sensory Overload.  The cure is very simple, just to give oral potassium and within 20 minutes there is a full recovery.  Here is one research study.
 
I felt it odd that nobody had compared this to sensory overload in autism.  I did my own experiment at home and found to my surprise that sensory overload in autism could also be treated with oral potassium.

In the last few weeks I received two very thoughtful comments on this blog, from adult sufferers who have found the same remedy as I have.  So at least I am no longer in a minority of one.
The interesting thing about potassium in the human body is that it relies on another electrolyte, magnesium.  Without sufficient magnesium, the body cannot maintain an adequate level of potassium.  This is why supplements normally contain both potassium and magnesium.  A problem with both potassium and magnesium is that they very easily upset the stomach, indeed some laxatives are based on magnesium.

Epsom salts
I have noted that the long list of autism interventions used in the US, frequently includes having a bath in Epsom salts.  Epsom salts are named after a town near London, England, from which they were originally mined.  Epsom salts are just magnesium sulphate (MgSO4).
In the “biomedical” community it is proposed that magnesium does great things for autism and/or sulphur does.
The sulphur part at least has a scientific explanation.  It was long ago shown that there is an apparent abnormality in the sulphur metabolism in autism. 

In effect there is greater loss than normal of sulphur in the urine, resulting in lower plasma levels than in typical people.

So people are dipping their kids in Epsom salts on that basis that either the magnesium or the sulphur will do some good, not sure of which.
Interestingly, on the web, I found one mother writing about the Epsom salts baths she gives her child; she says she know when it is time for another one, where her child starts to cover her ears (sound sensory overload).

Trans-dermal Magnesium
Since magnesium supplements are in-effect laxatives, other ways have been sought to administer this electrolyte.  There are several transdermal creams and sprays that do indeed seem to work, but they can irritate the skin.  Interestingly, also on the web, some autistic adults talk about using such supplements and benefiting. 
 

Making the Connection
Well I hope this is all obvious to you, at least one of the things that is going on is an ion channel disease, the result of which is sensory overload in autism.  By chance, some people have stumbled upon magnesium supplementation as a therapy.  The extra magnesium is making whatever potassium there is in that person’s diet more effective, and hence reducing their symptoms.  Since the condition is actually Hypokalemic Sensory Overload, they would do even better to add some extra potassium as well.

The sulphur part may, or may not be, a red herring.  Sadly there are many of them in autism.

Conclusion
I have completed this part of my autism investigation.  If you want to treat autistic sensory overload, that seems to affect almost all people with ASD and most with ADHD, the options are:-

1.     Reduce the body’s daily loss of potassium and magnesium, with a potassium sparing diuretic, like Spironolactone
2.     Increase consumption of potassium and magnesium in diet.  Bananas, oranges and kiwis are rich in potassium, for example.

3.     Use small doses of oral potassium and magnesium supplements throughout the day

4.     Use expensive transdermal magnesium treatments.  Nobody seems to make a potassium version.

5.     Take a soak in the bath with an added cup of Epsom salts.

There should be a second reason to try option (1).  For entirely unrelated reasons, this drug is proposed to help in autism due to its secondary anti-inflammatory and hormonal effects.
Spironolactone might be a desirable immunologic and hormonal intervention in autism spectrum disorders
 I have to say that, having done my field research, I will be sticking with (2), (3) and the occasional (5)

 

Wednesday, 27 May 2015

Diamox & Bumetanide, Ion Channels Nav1.4 and Cav1.1, HypoPP, Autism and Seizures









Today’s post links together subjects that have been covered previously.

It does suggest that there are multiple therapies that may be effective in the large sub-group of autism that is characterized by the neurotransmitter GABA being excitatory (E) rather than inhibitory (I).  The science was covered in the earlier very complicated post:-



The growing list of potential therapies is:-

·        Bumetanide (awaiting funding for Stage 3 clinical trials in humans)
·        Micro-dose Clonazepam (trials in mouse models of autism)
·        Diamox (off-label use in autism)
·        Potassium Bromide  - to be covered in a later post (in use for 150 years)


Not surprisingly, all of these drugs also have an effect on certain types of seizure.

The optimal therapy in people with this E/I imbalance will likely be a combination of some of the above.



Periodic paralysis

Periodic paralysis (Hypokalemic periodic paralysis or HypoPP) is a rare condition that causes temporary paralysis that can be reversed by taking potassium.  A similar condition is hypokalemic sensory overload, when someone becomes overwhelmed by lights or sounds, but after taking potassium all goes back to normal. Autistic sensory overload, experienced by most people with autism, can also be reduced by potassium.

Though rare, we know that HypoPP is caused by dysfunction in the ion channels Nav1.4 and/or Cav1.1.

For decades one of the treatments for HypoPP has been a diuretic called Diamox/Acetazolamide.

Other treatments include raising potassium levels using supplements or potassium sparing diuretics.

Bumetanide is a diuretic, but rather than raising potassium levels, it does the opposite.  So I always thought it was odd that bumetanide would have a positive effect on HypoPP.  But the research showed a benefit.


Autism and Channelopathies

We know that autism and epilepsy are associated with various ion channel and transporter dysfunctions (channelopathies).  In a recent post I was talking about Cav1.1 to Cav1.4.

Today we are talking about Cav1.1 and Nav1.4.

We know that Nav1.1 is associated with epilepsy and some autism (Dravet syndrome).


Nav1.4 is expressed at high levels in adult skeletal muscle, at low levels in neonatal skeletal muscle, and not at all in brain

Nav1.1 expression increases during the third postnatal week and peaks at the end of the first postnatal month, after which levels decrease by about 50% in the adult.

We saw with calcium channels that a dysfunction in one of Cav1.1 to Cav1.4 can cause a dysfunction in another dysfunction in another one of Cav1.1 to Cav1.4.

We also so that in autism the change in expression of NKCC1 and KCC2 as the brain matures failed to occur and so in effect they remain immature and therefore malfunction.

So it is plausible that sodium channels may also malfunction in a similar way. 
  



Hypokalemic periodic paralysis (hypoPP) is an autosomal dominant neuromuscular disorder characterized by episodes of flaccid skeletal muscle paralysis accompanied by reduced serum potassium levels. It is caused by mutations in one of two sarcolemmal ion channel genes, CACNA1S and SCN4A1-3 that lead to dysfunction of the dihydropyridine receptor or the alpha sub-unit of the skeletal muscle voltage gated sodium channel Nav1.4. Seventy to eighty percent of cases are caused by mutations of CACNA1S and ten percent by mutations of SCN4A4. 

There are no consensus guidelines for the treatment of hypoPP. Current pharmacological agents commonly used include potassium supplements, potassium sparing diuretics and carbonic anhydrase inhibitors (acetazolamide and dichlorphenamide). Dichlorphenamide is the only therapy for hypoPP to have undergone a randomized double blind placebo controlled cross over trial. This trial showed a significant efficacy of dichlorphenamide in reducing attack frequency but the inclusion criteria were based on clinical diagnosis of hypoPP and not genetic confirmation.

  


Cav1.1 also known as the calcium channel, voltage-dependent, L type, alpha 1S subunit, (CACNA1S), is a protein which in humans is encoded by the CACNA1S gene




Nav1.4

Sodium channel protein type 4 subunit alpha is a protein that in humans is encoded by the SCN4A gene.

The Nav1.4 voltage-gated sodium channel is encoded by the SCN4A gene. Mutations in the gene are associated with hypokalemic periodic paralysis, hyperkalemic periodic paralysis, paramyotonia congenita, and potassium-aggravated myotonia.



Ranolazine

Ranolazine is an antianginal and anti-ischemic drug that is used in patients with chronic angina. Ranzoline blocks Na+ currents of Nav1.4. Both muscle and neuronal Na+ channels are as sensitive to ranolazine block as their cardiac counterparts. At its therapeutic plasma concentrations, ranolazine interacts predominantly with the open but not resting or inactivated Na+ channels. Ranolazine block of open Na+ channels is via the conserved local anesthetic receptor albeit with a relatively slow on-rate.


Muscle channelopathies:does the predicted channel gating pore offer new treatment insights for hypokalaemic periodic paralysis?


Beneficial effects of bumetanide in a CaV1.1-R528H mouse model of hypokalaemic periodic paralysis
Transient attacks of weakness in hypokalaemic periodic paralysis are caused by reduced fibre excitability from paradoxical depolarization of the resting potential in low potassium. Mutations of calcium channel and sodium channel genes have been identified as the underlying molecular defects that cause instability of the resting potential. Despite these scientific advances, therapeutic options remain limited. In a mouse model of hypokalaemic periodic paralysis from a sodium channel mutation (NaV1.4-R669H), we recently showed that inhibition of chloride influx with bumetanide reduced the susceptibility to attacks of weakness, in vitro. The R528H mutation in the calcium channel gene (CACNA1S encoding CaV1.1) is the most common cause of hypokalaemic periodic paralysis. We developed a CaV1.1-R528H knock-in mouse model of hypokalaemic periodic paralysis and show herein that bumetanide protects against both muscle weakness from low K+ challenge in vitro and loss of muscle excitability in vivo from a glucose plus insulin infusion. This work demonstrates the critical role of the chloride gradient in modulating the susceptibility to ictal weakness and establishes bumetanide as a potential therapy for hypokalaemic periodic paralysis arising from either NaV1.4 or CaV1.1 mutations.







Mode of action

The research does state that nobody knows why Diamox is effective in many cases of hypoPP.

My reading of the research has already taken me in a different direction.  While researching the GABAA receptor that is dysfunctional in some autism, it occurred to me that in addition to targeting the NKCC1 receptor with bumetanide, another way of lowering chloride levels within the cells might well exist.

I suggested in an earlier post that Diamox could be used to target the AE3 exchanger.


What Diamox (acetazolamide) does is lower the pH of the blood in the following way.


Acetazolamide is a carbonic anhydrase inhibitor, hence causing the accumulation of carbonic acid Carbonic anhydrase is an enzyme found in red blood cells that catalyses the following reaction:




hence lowering blood pH, by means of the following reaction that carbonic acid undergoes


In doing so there will be an effect on both AE3 and NDAE, below.  This will change the intracellular concentration of Cl-, and hence give a similar result to bumetanide.

This would also explain the phenomenon cited below that pH affects the excitability of the brain.

Over excitability of the brain is the cause of some of the effects seen as autism and clearly Over excitability of the brain will be the cause of some people’s seizures/epilepsy.

Not surprisingly, then one of the uses of Diamox is to avoid seizures.





  




Anion exchanger 3 (AE3) in autism

Anion exchange protein 3 is a membrane transport protein that in humans is encoded by the SLC4A3 gene. It exchanges chloride for bicarbonate ions.  It increases chloride concentration within the cell.  AE3 is an anion exchanger that is primarily expressed in the brain and heart

Its activity is sensitive to pH. AE3 mutations have been linked to seizures


Bicarbonate (HCO3-) transport mechanisms are the principal regulators of pH in animal cells. Such transport also plays a vital role in acid-base movements in the stomach, pancreas, intestine, kidney, reproductive organs and the central nervous system.


Abstract

Chloride influx through GABA-gated Cl channels, the principal mechanism for inhibiting neural activity in the brain, requires a Cl gradient established in part by K+–Cl cotransporters (KCCs). We screened for Caenorhabditis elegans mutants defective for inhibitory neurotransmission and identified mutations in ABTS-1, a Na+-driven Cl–HCO3 exchanger that extrudes chloride from cells, like KCC-2, but also alkalinizes them. While animals lacking ABTS-1 or the K+–Cl cotransporter KCC-2 display only mild behavioural defects, animals lacking both Cl extruders are paralyzed. This is apparently due to severe disruption of the cellular Cl gradient such that Cl flow through GABA-gated channels is reversed and excites rather than inhibits cells. Neuronal expression of both transporters is upregulated during synapse development, and ABTS-1 expression further increases in KCC-2 mutants, suggesting regulation of these transporters is coordinated to control the cellular Cl gradient. Our results show that Na+-driven Cl–HCO3 exchangers function with KCCs in generating the cellular chloride gradient and suggest a mechanism for the close tie between pH and excitability in the brain.



Abstract

During early development, γ-aminobutyric acid (GABA) depolarizes and excites neurons, contrary to its typical function in the mature nervous system. As a result, developing networks are hyperexcitable and experience a spontaneous network activity that is important for several aspects of development. GABA is depolarizing because chloride is accumulated beyond its passive distribution in these developing cells. Identifying all of the transporters that accumulate chloride in immature neurons has been elusive and it is unknown whether chloride levels are different at synaptic and extrasynaptic locations. We have therefore assessed intracellular chloride levels specifically at synaptic locations in embryonic motoneurons by measuring the GABAergic reversal potential (EGABA) for GABAA miniature postsynaptic currents. When whole cell patch solutions contained 17–52 mM chloride, we found that synaptic EGABA was around −30 mV. Because of the low HCO3 permeability of the GABAA receptor, this value of EGABA corresponds to approximately 50 mM intracellular chloride. It is likely that synaptic chloride is maintained at levels higher than the patch solution by chloride accumulators. We show that the Na+-K+-2Cl cotransporter, NKCC1, is clearly involved in the accumulation of chloride in motoneurons because blocking this transporter hyperpolarized EGABA and reduced nerve potentials evoked by local application of a GABAA agonist. However, chloride accumulation following NKCC1 block was still clearly present. We find physiological evidence of chloride accumulation that is dependent on HCO3 and sensitive to an anion exchanger blocker. These results suggest that the anion exchanger, AE3, is also likely to contribute to chloride accumulation in embryonic motoneurons.
 



Conclusion

So the science does confirm that “chloride accumulation following NKCC1 block was still clearly present”.  This means that bumetanide is likely only a partial solution.

We also see that “anion exchanger, AE3, is also likely to contribute to chloride accumulation in embryonic motoneurons” and “that chloride accumulation that is dependent on HCO3”.

This is a subject of some research, but it is still early days.

  
I suggest that Diamox, via its effect on HCO3, may affect anion exchanger AE3 and further reduce chloride accumulation within cells.  This may have a further cumulative effect on GABA.

As we saw earlier, bumetanide does indeed shift GABA from excitatory to inhibitory in people who neurons remain in an immature state (like those of a typical two week old baby).  To my surprise, the use of micro-dose Clonazepam, as proposed by Professor Catterall, but in addition to Bumetanide, has a further effect on GABA’s excitatory/inhibitory imbalance.

Taken together this would highlight the possible further benefit of Diamox.

Normal blood pH is tightly regulated between 7.35 and 7.45.  I do wonder if perhaps in some people with autism, the pH of their blood is slightly elevated (alkaline), this would contribute to excitability of the brain.

Since Diamox increases the oxygen carrying capacity of the blood, I further wonder if this additional oxygen may also be beneficial in some cases.  Since some people are adamant that hypobaric oxygen therapy has beneficial (although not sustained) effects in autism, surely a better treatment would be Diamox?

Since the body is controlled via so-called feedback loops, perhaps in a small subset of people with autism who respond to extra O2, they actually have blood pH that is higher than 7.45.  In which case measuring blood pH would be a biomarker of who would respond to hypobaric oxygen therapy.  Not surprisingly then, trials of hypobaric oxygen therapy in autism fail, because most of the trial subjects do not have elevated blood pH.
  
So there are many reasons that Diamox should be trialed in autism.  I did find one (DAN) doctor currently using it, but they do not really explain why.

Biomedical Treatment of the Young Adult with ASD