Bumetanide in Autism, Potassium and Dr Ben-Ari

I started this blog when I stumbled upon a research paper, by a French Scientist called Dr Ben-Ari.  It showed that a long trusted diuretic drug, Bumetanide, could be safely used to reduced autistic behaviours.  I then looked for other drugs that might be similarly safe and effective, and started this  blog to document what I found.
 

http://epiphanyasd.blogspot.com/2013/03/for-5-years-i-have-been-learning-and.html 

http://epiphanyasd.blogspot.com/2013/03/bumetanide-how-water-pill-can-reduce.html

I then recently came back to see why potassium also seemed to play a role in autism:

http://epiphanyasd.blogspot.com/2013/08/potassium-may-play-important-role-in.html

I wrote to Dr Ben-Ari about my observation about potassium and he kindly wrote straight back.  Sadly most researchers do not repy to emails. 

yes of course K+ is important and we are often adding syrup as we cannot tolerate too reduced levels of K+ (vascular issues) 

in addition note that K+ levels also modify the actions of the transporter in which we are working

    
I was already aware from his papers, that they we giving potassium syrup to those children found to have low potassium in their blood.

Monty, aged 10 with ASD, is taking bumetanide but has normal potassium level in his blood.  I found a further improvement followed a little extra potassium.  Ben-Ari second point suggests that this improvement may also be due to the same NKCC1 transporter, that is the target of his bumetanide therapy. 

Anyway, I have some extra support to continue Monty's banana and orange juice rich diet, with an extra 1g of extra potassium on the side.





  

Nom de guerre, Mon frère - Manchopathy

Today’s post had better be a quick one.  The desk research in the background is getting complicated and I have just ordered a 900 page book on Human Physiology, so as not to spout complete nonsense.  Worse still, a couple of days ago, I received in the mail, a big brown envelope from Tokyo with a juicy report on the use of Ceredist, a TRH analog.  It is 20 pages long, and the bad news is that 18 pages are in Japanese.  The good news is that I had expected all 20 pages to be in Japanese.

To business.   You are slowly being introduced to the cast members of this blog.

The star of course is “Monty”, aged 9.

His supposedly “typical” big brother, aged 12, is going to be called “Ted”.

Head of Applied Research, part-time biker and Speech Therapist will be called Dule (“Doolay”)

Last week I decided that it was time for some good old fashioned primary research, to test a hypothesis that I had formulated.  This is what we presented to the in-house ethics committee, for approval:-

1.    Many children with autism exhibit what appears as sensory overload.  On hearing a moderately loud sound, they will cover their ears, almost as if in pain.  Bright lights, darkness, certain smells, even touch can trigger similarly strong reactions.  Entire books have been written documenting these odd behaviours, but I never read an explanation for them.

2.    In my trawl through the literature, I noted that a disorder with surprisingly similar symptoms has been documented -   Hypokalemic sensory overstimulation

This disorder manifests itself as an overwhelming feeling of sensory stimulation.  But then disappears 20 minutes after a dose of oral potassium.  A related, but much more severe, disorder that causes temporary paralysis also exists -  Hypokalemic periodic paralysis

3.    The recommended daily amount of potassium for adults is 3,500mg.  A typical banana contains 400 mg of potassium. A dissolvable tablet of Potassium Citrate contains 500mg of potassium.  So 500mg is a safe dose to experiment with.

4.    A laboratory experiment is proposed using an MP3 file of a baby crying. Dule will first establish a baseline volume (VB) at which Monty will cover his ears. Monty will be sitting in a fixed position in the lab. This test will be repeated over a few days to see if VB varies.

 

5.    Then the subject will receive 500mg of oral potassium and wait for 20 minutes. The MP3 file will be played again while he is sitting in the identical test position. Dule will crank up the volume and note the new threshold volume (VT).

 

6.    The same test will be repeated with Ted and Dule as subjects.

 

Prior to providing Dule with the oral potassium solution, Peter suggested to Dule that he would perhaps prefer if the test did not show up anything worthy of further investigation.  Since that would again drive Peter crazy, that no serious scientist had noticed this, done something about it and published their work.

Here is the raw data from the test:-

 

Volume * at which sound becomes disturbing
	7-Mar-13	8-Mar-13		11-Mar-13		11-Mar-13
						after K+
Monty	9	9		9		16
Ted				23		26
Dule				21		23
* sound level on digital display of Philips mini HiFi
room is about 20 m2, subjects were 2.5 m from HiFi unit

 

Discussion

As you see, Monty is far more sensitive to sound than both Ted and Dule.  Monty experiences a sharp increase in his capacity to cope with sound stimulation after drinking the potassium.  Ted and Dule show a small increase in capacity, that may be just down to measurement tolerance/error. (Dule was testing himself, after all)

Mon Dieu!  It looks like we have to do a serious follow on study with more subjects and some flashy equipment.  Worse still, now I have to be able to explain scientifically why this is happening !

 

The cause is related to something called VDCC (voltage dependent calcium channels) these are like little valves that open to let  Ca²⁺ ions in or out; they are misbehaving.   Recall that Bumetanide works in a similar way by triggering NKCC1 and NKCC2 (Sodium, Potassium, Chloride Cotransporters) to let in/out  Cl^- ions.  The subject of misbehaving ion channels has already been given a fancy name by scientists, its Channelopathy.  Now I was wondering how I was going to explain my use of French in this post.  It's all about the English Channel or should I say la Manche, and so we'll call it Manchopathy.

 

 

 

The Ketone D-BHB as a Medical Food for Heart, Kidney and Brain Disease (Alzheimer’s, some Autism …)

 Nestle’s research centre in Lausanne, Switzerland

I did write extensively about the potential to treat some autism using the ketone BHB (beta hydroxybutyrate). This can be achieved either by following a strict ketogenic diet or just by eating medical foods that contain/produce BHB.

Some readers are now big consumers of BHB supplements and anyone taking BHB should be interested in today’s paper, that I assume was paid for by Nestlé.

Nestlé make everything from baby milk formula to George Clooney’s Nespresso.  You may not be aware that they also have a business selling medical food; they have been looking at ketones to treat Alzheimer’s for some time.  This is quite similar to Mars developing Cocoa flavanols to improve heart and brain health.

Most ketone supplements are sold to help you lose weight or boost athletic performance.  The military also uses ketones in survival rations. 

We saw that you can increase the level of ketones in your body by supplementing: -

·        MCT oil (medium chain triglyceride oil, which usually contains about 60% caprylic C8 acid and 40% capric C10 acid).  This is a product already sold by Nestlé

·        Neat caprylic acid, C8

·        BHB salts (potassium, sodium, calcium etc)

·        BHB esters (also called ketone esters KE)

These products range from expensive to very expensive.

People requiring ketones as an alternative fuel to glucose, like those with Alzheimer’s need quite large amounts of the supplements.  In Alzheimer’s a glucose transporter at the blood brain barrier is restricting the flow of glucose in blood and so the brain is starved of “fuel”.  Mitochondria in the brain can be powered by both ketones and glucose, so if not enough glucose cannot get through, you have the option to increase the amount of ketones.

Babies fed with mother’s milk are on a high ketone diet.  You can safely combine both glucose and ketones as a fuel for your body.

The news from today’s paper has already been translated to a usable therapy. 

Metabolism of Exogenous D-Beta-Hydroxybutyrate, an Energy Substrate Avidly Consumed by the Heart and Kidney

There is growing interest in the metabolism of ketones owing to their reported benefits in neurological and more recently in cardiovascular and renal diseases. As an alternative to a very high fat ketogenic diet, ketones precursors for oral intake are being developed to achieve ketosis without the need for dietary carbohydrate restriction. Here we report that an oral D-beta-hydroxybutyrate (D-BHB) supplement is rapidly absorbed and metabolized in humans and increases blood ketones to millimolar levels. At the same dose, D-BHB is significantly more ketogenic and provides fewer calories than a racemic mixture of BHB or medium chain triglyceride. In a whole body ketone positron emission tomography pilot study, we observed that after D-BHB consumption, the ketone tracer ¹¹C-acetoacetate is rapidly metabolized, mostly by the heart and the kidneys. Beyond brain energy rescue, this opens additional opportunities for therapeutic exploration of D-BHB supplements as a “super fuel” in cardiac and chronic kidney diseases.

One of the main benefits of ketones is their ability to act as an alternative energy source to glucose or fatty acids for production of ATP by mitochondria. Caloric restriction and intermittent fasting also produce transient mild-moderate ketosis (6, 7).

While a high dose of MCT can provide a moderate increase in blood ketones (+0.5–1.0 mM), gastrointestinal intolerance and high caloric load limit their use. Second, ketone esters (KE) made of a BHB ester linked to butanediol provide one molecule of D-BHB after digestion, with the butanediol being further metabolized by the liver to D-BHB (9). KE increase blood ketones above 1 mM but are also limited at high dose by their gastric tolerability and severe bitterness (10).

Third, perhaps the most physiologic way to raise blood ketones is via the oral intake of D-BHB itself. Exogenous D-BHB is directly absorbed into the circulation, with some of it being converted to AcAc by the liver, and both ketones being distributed throughout the body. Until recently, only racemic mixtures of dextro (D) and levo (L) BHB (D+L-BHB) were available and oral human studies with them have been reported (9, 11–14). As L-BHB is not metabolized significantly into energy intermediates and is slowly excreted in the urine (9, 15), D+L-BHB would be anticipated to be less ketogenic than pure D-BHB. 

Levo, Dextro and Racemic

When certain chemicals are manufactured, they usually contain an equal mixture of the left-handed and right-handed version, this is called a racemic mixture. These versions are called enantiomers.

One enantiomer is an optical stereoisomer of another enantiomer. The two molecules are mirror images of each other, which are not superimposable - much like your left and right hand.

In the case of the chemical BHB, only the right-handed version has an effect on your body.  If you take the salt potassium BHB, half of the product has no effect other than raise your level of potassium.

Zyrtec is an antihistamine made of Cetirizine, but it is a racemic mixture.  If you want pure L-Cetirizine, you would buy Xyzal not Zyrtec.

Arbaclofen/ R-baclofen is the right-handed version of baclofen

Rezular/R-verapamil is the right-handed version of verapamil.

Back to the study:

The study compared three therapies: -

D-BHB

14.1 g of pure salts of the D enantiomer of D-BHB were used. The D-BHB supplement tested was formulated as a mixture of three salts: sodium D-beta-hydroxybutyrate, magnesium (D-beta-hydroxybutyrate and calcium (D-beta-hydroxybutyrate). Each oral serving provided 12 g D-beta-hydroxybutyric acid, 0.78 g sodium, 0.42 g magnesium, and 0.88 g calcium, citrus flavouring and sweetener (Stevia), dissolved in 150 mL of drinking water.

D+L-BHB

14.5 g of an equimolar mixture of commercial D and L beta-hydroxybutyrate salt was used (KetoCaNa, KetoSports, USA). Each serving provided a mixture of 12 g D+L-Beta-hydroxybutyric acid, 1.3 g sodium, 1.2 g calcium, orange flavoring and stevia, dissolved in 150 mL of drinking water.

MCT oil

Fifteen grams of medium chain triglyceride (MCT) (60% caprylic C8 acid and 40% capric C10 acid) emulsified in 70 mL of a 5% aqueous milk protein solution.

This chart shows the concentration of ketones in your blood plasma after taking either of the three therapies.

This chart shows the concentration of just the ketone D-BHB in your blood plasma after taking either of the three therapies.

 This chart shows the concentration of the ketone ACAc in your blood plasma after taking either of the three therapies.

  

This chart shows where the ketones are going; the chart shows the distribution of the ketone “tracer” acetoacetate (AcAc) by organ after D-BHB oral intake.  The effect is greatest on the heart and kidney, but some does reach the brain.

From the dynamic brain scan, CMR_AcAc and K_AcAc could be determined for all main regions of the brain and compared to baseline values previously determined in healthy young adults. Overall and compared to baseline, each region demonstrated an increase in CMR_AcAc and K_AcAc of ~4.7 and 2.3-fold, respectively, about 1 h after taking D-BHB. This indicated that AcAc is effectively taken by the brain and by other organs particularly the heart and the kidney.

Ketone production from an exogenous dietary source has been traditionally achieved by MCT. This requires a bolus intake to saturate the liver with MCFA, producing excess acetyl-CoA which is then transformed to AcAc and BHB, which are released into systemic circulation. The C_max achieved with MCT is usually between 300 and 600 μM, with higher values being difficult to reach due to GI side effects and liver saturation. Here we show that D-BHB, a natural and biologically active ketone isomer, raises blood ketone C_max above 1 mM without noticeable side effects. In comparison, an equivalent dose of D+L-BHB or MCT only achieved half this ketone level, with similar T_max at 1 h. Thus, compared to D+L-BHB, D-BHB significantly reduces the salt intake needed to achieve the same plasma ketone response.

Results from a previous study (9) comparing KE to D+L-BHB showed that at the same dose of D-BHB equivalent, the increase blood ketone iAUC had the same magnitude, suggesting that exogenous D-BHB and KE produce similar ketosis.

Note that KE means Ketone Ester and the study (9) is this one: -

On the Metabolism of Exogenous Ketones in Humans

Ketone esters are available, but horribly expensive and taste really bad.

Conclusion

In previous posts the numerous possible beneficial modes of action of BHB were outlined. The summary post is here: -

Ketone Therapy in Autism (Summary of Parts 1-6)

In practise some people with autism seem to benefit a lot, some moderately and some not at all.

Monty, aged 16 with ASD, fits in the “moderately benefits” category.  The combination of about 20ml of caprylic acid (C8) plus a scoop of Potassium BHB powder does produce more speech.

It is not a cheap or very convenient therapy, compared the others I use.

I would agree with Nestlé that the limiting factor with BHB salts is the “salt”.  As they comment in their paper 

“compared to D+L-BHB, D-BHB significantly reduces the salt intake needed to achieve the same plasma ketone response”

Giving someone with heart disease "sodium anything" is not a good idea. A potassium salt would be safer, but even then, your heart is the limiting factor on potassium use.  Calcium salts are unwise in people with autism, because it appears to be able to upset calcium ion signalling, which would also be a potential risk in heart disease.

As I mentioned to one parent who is a big time user of BHB salts, if you switch to D-BHB you can either produce twice the ketones of regular potassium BHB, with the existing potassium load, or reduce your dosage by half and keep the same effect and save some money.

I think potassium D-BHB is good choice.  If you are taking bumetanide you may no longer need a potassium supplement (K-BHB becomes your potassium supplement).

I think people with autism and genuine mitochondrial disease are highly likely to benefit from D-BHB.  These are people who show symptoms in their entire body, i.e. lack of exercise endurance. For these people, eating (or producing via diet) large amounts of ketones will increase the production of ATP in their brains and so improve cognitive function.  D-BHB undergoes a different process to glucose, as it “converted” to ATP by the process called OXPHOS
(Oxidative phosphorylation). Some people with autism lack the enzyme complexes needed to complete OXPHOS, these people who should try D-BHB.

BHB has other beneficial effects, some relating to inflammation that seem to explain its benefit in other types of autism.  The effects were investigated here.

In the brains of people with Alzheimer’s there is decreased expression of glucose transporter 1 (GLUT 1) at the blood brain barrier. This starves the brain of glucose, which is fuel for the brain. D-BHB is an alternative fuel for mitochondria that is not dependent on GLUT 1.  People with early onset Alzheimer's would seem the best ones for this therapy, that would include many people with Down Syndrome. 

Fenamates (Diclofenac, Ponstan etc): certainly for Alzheimer’s, maybe some Epilepsy, but Autism? I’m Impressed!

 

Some readers of this blog are interested in the potential of mefenamic acid (MFA), sold as Ponstan, to treat autism. There is a lack of evidence currently. 

On the other hand, the evidence looks pretty overwhelming in the case of this class of drug to treat Alzheimer’s, hence today’s post. If you have a case of epilepsy at home, you can follow up on that loose end I left.

I also introduce MFA as a therapy for sound sensitivity and Misophonia. It was pretty impressive in the case of Monty, aged 18 with ASD.

 

The highlights are:

 

·        Fenamate NSAIDs reduce the incidence of Alzheimer’s

·        Fenamate NSAIDs delay the progression of those already with Alzheimer’s

·        Acetaminophen/Paracetamol worsens the progression of Alzheimer’s

·        Low dose aspirin is chemoprotective, as well as reducing blood clots that cause heart attack and stroke, but offers no Alzheimer’s benefit

·        MFA/Ponstan is very effective in reducing Monty’s sound sensitivity

 

The caveats 

As is always the case, there are caveats.

It is well known that low dose aspirin can cause dangerous bleeding events in specific sub-populations.

A study of 6 million people in Denmark showed that older people taking the Fenamate Diclofenac has a slightly higher risk of heart problems than other NSAIDs. The risk is actually very low and symptoms in those affected generally appear within a month (and disappear on cessation).

 

Incidence of Alzheimer’s

 

 

 Source:  https://www.intechopen.com/chapters/43129

 

The longer you live, the chance of developing Alzheimer’s rapidly increases. 

The signs are actual visible in a CT scan decades before the symptoms are evident.

Almost two-thirds of Americans with Alzheimer's are women.

Older Black Americans are about twice as likely to have Alzheimer's or other dementias as older Whites.

Of those with I/DD (Intellectual or Developmental Disability), it is people with Down Syndrome who are at major risk of early onset Alzheimer’s.  More than 50% will develop Alzheimer's. 

 

Non drug methods to protect against Alzheimer’s and other dementia 

In this blog we have encountered numerous dietary methods associated with reduced risk of all types of dementia and Alzheimer’s specifically.

·        Dietary nitrates (beetroot, spinach etc)

·        Betanin (the pigment in beetroot)

·        Ergothioneine (from mushrooms)

·        Spermidine (from wheatgerm and mushrooms)

·        Anthocyanin pigments from superfoods (bilberry, blueberry, purple sweet potato etc)

 

Maintaining normal blood pressure, blood glucose levels and cholesterol levels are big advantages. Normal body mass and regular exercise are also important.

Fenamates are a class of NSAID pain medication that many people have at home. In the US there are 10 million prescriptions a year of Diclofenac / Voltaren.

Another common Fenamate is Mefenamic Acid (MFA), commonly sold as Ponstan.  Ponstan is only expensive in North America. 

Most people’s reaction would be “Ah, yes those are pain medications, how could they help Alzheimer’s or other neurological conditions. Aren’t they the ones with those GI side effects?” 

NSAIDS deaden pain by blocking an enzyme called cyclooxygenase-2 (COX-2). Unfortunately, they also block to some extent a very similar enzyme called  cyclooxygenase-1 (COX-1). COX-1 promotes the production of the natural mucus lining that protects the inner stomach and contributes to reduced acid secretion.  Blocking COX-1 will cause GI side effects. Most people want to take an NSAID that is selective for COX-2.

 

Low dose Aspirin – the good COX-1 effect

There is a good effect from blocking COX-1, as from low dose aspirin (LDA), because it stops blood platelets sticking together and blocking blood flow.  LDA is also substantially chemoprotective and nobody has figured out why and it likely has nothing to do with COX1 or COX2. 

“Ishikawa et al. analyzed 51 randomized controlled trials (RCTs) and the cumulative evidence strongly supports the hypothesis that daily use of aspirin results in the prevention of cardiovascular disease (CVD), as well as a reduction in cancer-associated mortality [3].”

 

Anti-inflammatories in Alzheimer’s disease—potential therapy or spurious correlate? 

Epidemiological evidence suggests non-steroidal anti-inflammatory drugs reduce the risk of Alzheimer’s disease. However, clinical trials have found no evidence of non-steroidal anti-inflammatory drug efficacy. This incongruence may be due to the wrong non-steroidal anti-inflammatory drugs being tested in robust clinical trials or the epidemiological findings being caused by confounding factors. Therefore, this study used logistic regression and the innovative approach of negative binomial generalized linear mixed modelling to investigate both prevalence and cognitive decline, respectively, in the Alzheimer’s Disease Neuroimaging dataset for each commonly used non-steroidal anti-inflammatory drug and paracetamol. Use of most non-steroidal anti-inflammatories was associated with reduced Alzheimer’s disease prevalence yet no effect on cognitive decline was observed. Paracetamol had a similar effect on prevalence to these non-steroidal anti-inflammatory drugs suggesting this association is independent of the anti-inflammatory effects and that previous results may be due to spurious associations. Interestingly, diclofenac use was significantly associated with both reduce incidence and slower cognitive decline warranting further research into the potential therapeutic effects of diclofenac in Alzheimer’s disease.

 

  

Diclofenac Use Slows Cognitive Decline in Alzheimer Disease 

CHICAGO — While most common non-steroidal anti-inflammatory drugs (NSAIDs) do not significantly affect cognitive decline in patients with Alzheimer disease or mild cognitive impairment, research presented at the 2018 Alzheimer’s Association International Conference, held July 22-26, 2018, in Chicago, Illinois suggests that diclofenac actually reduces cognitive deterioration, while paracetamol accelerates decline. 

The study investigated cognitive decline associated with NSAID use in 1619 patients from the Alzheimer’s Disease Neuroimaging Initiative dataset. The Mini-Mental State Examination and the Alzheimer disease assessment scale were used to evaluate cognitive functioning. Additional variables that potentially explain cognitive decline were identified for the cohort including gender, apolipoprotein E genotype, level of education, vascular disorders, diabetes, and medication use. 

 

Study results showed that most common NSAIDs, including aspirin, ibuprofen, naproxen, and celecoxib did not alter cognitive degeneration in patients with mild cognitive impairment or Alzheimer disease. Diclofenac was the only NSAID that demonstrated a correlation with a slower rate of cognitive decline (ADAS χ2=4.0, P =.0455, MMSE χ2=4.8, P =.029). Conversely, paracetamol was correlated with accelerated cognitive deterioration (ADAS χ2=6.6, P =.010, MMSE χ2=8.4, P =.004), as well as apolipoprotein E ε4 genotype (ADAS χ2=316.0, P <.0001, MMSE χ2=191.0, P <.0001). 

Diclofenac’s correlation with slowed cognitive deterioration provides “exciting evidence for a potential disease modifying therapeutic,” the study authors wrote. If paracetamol’s deleterious effects are confirmed to be causative, it “would have massive ramifications for the recommended use of this prolific drug.”

 

One reason why paracetamol use might harm Alzheimer’s brains is the same reason it harms autistic brains; it depletes the level of the key antioxidant glutathione (GSH).  GSH will be in big demand in a damaged brain. 

As we will see later in this post, Fenamate class NSAIDs affect numerous ion channels, specifically Kv7.1, as a result some people with heart conditions will get side effects linked to arrhythmia and should therefore discontinue use.

 

Common painkiller linked to increased risk of major heart problems: Time to acknowledge potential health risk of diclofenac and reduce its use, say researchers -- ScienceDaily

Common painkiller linked to increased risk of major heart problems

Time to acknowledge potential health risk of diclofenac and reduce its use, say researchers 

The commonly used painkiller diclofenac is associated with an increased risk of major cardiovascular events, such as heart attack and stroke, compared with no use, paracetamol use, and use of other traditional painkillers, a new study finds.

 

The risk is actual quite low and is going to appear straight away, in terms of arrhythmia. If any drug or supplement makes you feel unwell, stop taking it and tell your doctor.

 

Which Fenamate for Alzheimer’s?

To decide which Fenamate is best for Alzheimer’s and indeed which might be helpful in some autism, it helps to ponder the various modes of action unrelated to COX-1 and COX-2. 

We have the NLRP3 inflammasome, which is suggested as the mechanism in Alzheimer’s.

Here we want to block inflammatory messenger like IL-1beta. In the chart below we see that Ibuprofen is useless, Diclofenac has an effect, Mefenamic acid is better, but Meclofenamic acid is the star.

 

  

Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1) and COX-2 enzymes. The NLRP3 inflammasome is a multi-protein complex responsible for the processing of the proinflammatory cytokine interleukin-1β and is implicated in many inflammatory diseases. Here we show that several clinically approved and widely used NSAIDs of the fenamate class are effective and selective inhibitors of the NLRP3 inflammasome via inhibition of the volume-regulated anion channel in macrophages, independently of COX enzymes. Flufenamic acid and mefenamic acid are efficacious in NLRP3-dependent rodent models of inflammation in air pouch and peritoneum. We also show therapeutic effects of fenamates using a model of amyloid beta induced memory loss and a transgenic mouse model of Alzheimer’s disease. These data suggest that fenamate NSAIDs could be repurposed as NLRP3 inflammasome inhibitors and Alzheimer’s disease therapeutics.

 

Fenamates and Ion Channels

https://scholarworks.wm.edu/cgi/viewcontent.cgi?article=2671&context=aspubs

 

A very broad range of ion channels are affected by Fenamates.

Researcher Knut Wittkowski focuses on the effect on potassium channels in his theory that Fenamates can treat autism and prevent non-verbal autism if given to toddlers.

• PATENT SUMMARY - Treatment and prevention of autism and autism spectrum disorders

Fenamates actually affect numerous ion channels.

·        Chloride channels

·        Non-selective cation channels

·        Potassium channels (Kv 7.1 , KCa 4.2, K2p 2.1, K2p 4.1, K2p 10.1)

·        Opens large conductance calcium-activated K⁺ channels (BK_Ca channels) 

https://www.researchgate.net/publication/348973521_Pharmacological_inhibition_of_BKCa_channels_induces_a_specific_social_deficit_in_adult_C57BL6J_mice

“Genetic variants in large conductance voltage and calcium sensitive potassium (BKCa) channels have associations with neurodevelopmental disorders such as autism spectrum disorder, fragile X syndrome, and intellectual disability… These findings support the relationship between BKCa channel impairment and social behavior. This demonstrates a need for future studies which further examine the contribution of BKCa channels to social behavior, particularly during critical periods of development.

 

·        Sodium channels

·        Blockage of acid-sensing ion channels (ASICs), which are implicated in numerous disorders and had their own post.

https://epiphanyasd.blogspot.com/2017/08/acid-sensing-ion-channels-asics-and.html

 

Fig. 2. Ion channels targeted by flufenamic acid. Flufenamic acid produces inhibition or activation of ion channels. Colored bars near ionic channel name correspond to the estimated EC50 for flufenamic effect. References are provided within the text.

 Having noted the above graphic, which actually applies to the closely related flufenamic acid, a logical question is to ask about the effect of Flufenamic acid on seizures. 

Flufenamic acid shows promise as an epilepsy drug

I am not looking for a seizure therapy, so I leave that loose end for someone who is.

 

Conclusion

The best initial defence against dementia is good diet and exercise. Sometimes that will not be enough, because the healthier you are, the longer you will live and so the threat from dementia increases. Some people have genes that predispose them to dementia.

Since most of us struggle to follow diets like those of ultra healthy people in Okinawa, or on a Greek island, it might be worthwhile adding beneficial functional foods (neutraceuticals) to your existing diet.

I drink a small amount of beetroot juice daily, which is not such a hard step to take. In addition to benefits to your heart and brain, another benefit has just been discovered; now it improves the oral microbiome :-

 

Research suggests changes in mouth bacteria after drinking beetroot juice may promote healthy ageing 

“Our findings suggest that adding nitrate-rich foods to the diet – in this case via beetroot juice – for just ten days can substantially alter the oral microbiome (mix of bacteria) for the better.”

 

Many older people take NSAIDs to treat painful conditions like arthritis, switching to a Fenamate NSAID would not be a difficult option and would give some protection from Alzheimer’s.

People already diagnosed with Alzheimer’s currently do not have any effective therapies. Drugs like memantine exist, but are not so effective.  If I was in that position, I would want to take a low dose of Mefenamic Acid, if that was unavailable, I would settle for Diclofenac.

Diclofenac (25mg to 100mg) is prescribed in much lower doses than Mefenamic Acid (250 to 500mg tablets). We see that the effect on the NLRP3 inflammasome is actually far greater from Mefenamic Acid than Diclofenac. If the Alzheimer’s effect is via inhibiting the NLRP3 inflammasome, then you might expect that only a fraction of a standard capsule of Mefenamic would be needed.  That would then really reduce any GI side effects via the unwanted effect on COX-1 or any chance of arrhythmia. 

The ketone BHB, like fenamate NSAIDs, inhibits the NLRP3 inflammasome.  Since in Alzheimer’s the brain loses the ability to transport enough glucose across the blood brain barrier, ketones can also be used as a supplementary fuel for the brain. In one of my old posts on BHB I remember the doctor treating her husband with early onset Alzheimer’s with large doses of ketones – with some success.

 

And Autism?

Is Knut right that the potassium channel modulation from Mefenamic Acid will benefit autism, or at least a sub-set of severe autism? We do not know.

Mefenamic Acid (MFA) has so many biologic effects, I very much doubt Alzheimer’s is the only neurological condition where it could be beneficial. 

I should add that MFA undoubtedly will have negative effects in some people, this is inevitable.

Stop the noise !!

We did have a problem recently with extreme sound sensitivity. Monty, aged 18 with ASD, has had increasing sound sensitivity (Misophonia) for a year, but the only real issue was with sounds at mealtimes.  Over a recent weekend the sensitivity increased so much he could not sleep and also drank unusually large amounts of water (this also connects to K⁺). 

The next day at school he had a geography exam and he was completely dysfunctional. Monty’s assistant had prewarned the teacher and she agreed that he can sit the exam again next week.   

Fortunately, in the meantime the problem has been now been fixed (see below).

I was suggested to take to Monty to a Neurologist, but since there is no Dr Chez where we live, I did ignore that idea. In mainstream neurology sound sensitivity is just something you have got to learn to live with, perhaps with some Cognitive Behavioral Therapy (CBT) or just a pair of ear defenders, or those noise-cancelling headphones.

I did experiment years ago on the effect of an oral potassium supplement on reducing sound sensitivity, so I have long considered potassium ion channels a prime target.

Both hearing and the processing of the inputs is highly dependent on potassium channels, so I did return to MFA.  It has also been a topic in some recent email exchanges and I have long had some unopened packs of MFA at home.  The answer would be found in the kitchen cabinet and not in the neurology department

In bumetanide responders the Na-K-2Cl cotransporter (NKCC1) is over-expressed; it mediates the “coupled electroneutral movement of 1Na⁺, 1K⁺, and 2Cl^– ions across the plasma membrane of neurons”. This means that with each two chloride ions entering the neuron, come one sodium ion and one potassium ion.

 

Source: https://www.frontiersin.org/articles/10.3389/fncel.2019.00048/full

 

In summary, bumetanide responders have too much chloride in their neurons, the bubble on the left, above.

 

Knut’s theory was put to me recently as “MFA works on reducing neuron excitation by opening K+ channels, emptying the cell, which in return fills up with Cl- “.

If this is the case, MFA would do the opposite of Bumetanide.

I actually think MFA’s effect is much more complex.

The original idea of Knut was to prevent severe non-verbal autism developing in toddlers, by blocking the progression of the disease. MFA was essentially a medium-term treatment for toddlers, until the critical periods in brain development were past.  It was not a treatment for teenagers, by then the damage would have been done.

I think changing the baseline level of K+ inside neurons is going to have many effects.  Changing the baseline level of Cl- has a profound impact on cognition.

Unfortunately, everything is interrelated and so nothing is simple.

I did try MFA to eradicate the extreme sound sensitivity. I was concerned it might reduce cognition, by raising intracellular chloride and undo the bumetanide effect.

The extreme sound sensitivity did disappear following a day or two of starting 250mg a day of MFA, but that may just have been a coincidence.  The more mild sound sensitivity, that we had all learned to live with for months, also vanished; I do not see how that could be a coincidence.  Mood also became very good, perhaps a bit uncontrollably happy.

The next question is what happens to sound sensitivity when I stop giving MFA.  Time will tell, but so far the benefits have been maintained.

Sound sensitivity/Misophonia is a classic feature of autism;  TV depictions often portray a lonely looking boy wearing ear defenders. For many with Asperger’s misophonia is their main troubling issue. None of these people are taking bumetanide.  Monty has taken Bumetanide for nearly 10 years and never needed ear defenders.

You, like Prof Ben-Ari, might wonder if bumetanide use might cause a problem with potassium and hence hearing.  There is indeed a known risk of ototoxicity, which is actually a rare but possible side effect of loop-diuretic use, particularly furosemide.

Fluid in the inner ear is dependent upon a rich supply of potassium, especially in that part of the ear that translates the noises we hear into electrical impulses the brain interprets as sound.

 

Source: http://www.cochlea.eu/en/cochlea/cochlear-fluids

 

“Endolymph (in green) is limited to the scala media (= cochlear duct; 3), is very rich in potassium, secreted by the stria vascularis, and has a positive potential (+80mV) compared to perilymph.

Note that only the surface of the organ of Corti is bathed in endolymph (notably the stereocilia of the hair cells), whilst the main body of hair cells and support cells are bathed in perilymph.”

 

It is important to maintain a high level of potassium (K+) in the endolymph.

How the potassium gets there is a little bit complicated but it relies on:

·        The NKCC1 transporter

·        Potassium channel Kir4.1

·        Potassium channel KCNQ1 (Kv7.1) and in particular subunit KCNE1

 

Bumetanide blocks NKCC1 and so can potentially reduce potassium in the endolymph. Very high dose bumetanide would indeed risk ototoxicity.

We saw earlier in this post that Fenamates affect Kv7.1.

It is very poorly documented in the research, but Fenamates also affect Kir4.1.

 

The cochlea functions like a microphone. The auditory nerve then runs from the cochlea, hopefully bathed in potassium, to a station in the brainstem. From that station, neural impulses travel to the brain – specifically the temporal lobe, containing the primary auditory complex, where sound is attached meaning and we “hear”.

 

The auditory cortex is highlighted in pink and interacts with the other areas highlighted above

 

   Angular Gyrus   Supramarginal Gyrus   Broca's Area   Wernicke's Area 

 

By James.mcd.nz - self-made - reproduction of combined images Surfacegyri.JPG by Reid Offringa and Ventral-dorsal streams.svg by Selket, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=3226132

 

The peripheral auditory system links the microphone/cochlea to the brain. The Primary Auditory Neurons begin in the cochlea and terminate in the Brainstem (in the Cochlear Nuclei). In these neurons potassium channels play a key role.  These channels include K_Na1.1 and K_Na1.2, which are regulated by intracellular Na⁺ and Cl⁻, are found in a variety of neurons.

We assume that intracellular Cl⁻ is disturbed in bumetanide responsive autism.

Everything has to function to ensure normal hearing and with normal perception attached to that hearing.  Problems can arise in the cochlea (microphone) or in any of the above areas in the brain involved in transmitting or processing those signals.

 

Fenamates for some Aspie’s with Misophonia?

Misophonia has been covered in previous posts and we saw that therapies do exist in the research.  I think that there are multiple causes of sound sensitivity and likely also for those with Misophonia.

Low dose roflumilast was one interesting therapy, that works for some people but not others.  It does nothing for Monty regarding misophonia/sensory gating.

I wonder if some sound-troubled Aspies will respond to low dose MFA?

 

The top shelf

In our case, the answer to good health is usually found in the kitchen, but sometimes tucked away out of reach, up high at the back of a shelf, gathering dust, next to my stockpile of NAC.

There will be a dedicated post on sound issues in autism, which will draw everything together to include information from earlier posts.

and, not to forget, 

Danke vielmals Knut !

(Thanks to Knut!)