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Thursday 23 May 2019

Take Away Points from Thinking Autism 2019 Conference in London


This is not a summary of the recent conference I attended in London, it is just the impressions I left with, which will be very different to those of the delegates and the other speakers.

Hopefully I do not upset too many people.

Here is information on the conference and PDF versions of the two presentations I gave.






https://drive.google.com/file/d/1ZaK0C6wiTz8SrqFVwNbe6B8bGpSbYpNv/view?usp=sharing ht






This is the only autism event I have ever attended, other than a discussion over lunch at a university reunion where someone organised a meeting for those from our year with an interest in autism. Other than that, I have really only ever met a handful of autism parents face to face.

I did meet our reader Petra in Thessaloniki a few years ago.  As expected, Petra is a very nice person in reality and not just in the comments on this blog

This weekend I met face to face with Agnieszka, Natasa who comments frequently and helps run the Think Autism charity in the UK, as well as many others who comment less frequently. I met my first MAPS-type doctor, Richard Frye and had a chat over lunch. It was a bit one-sided because I know a lot about him and his research and he knows nothing about me and my online collection of research.

I did meet some of the UK doctors who have a child with autism and an interest in doing something about it.  I genuinely wish them all the best in reforming the system.

Yes, I do actually exist

One teacher from North London said that she had been wondering if I really exist. Now she knows I do.

Why does everyone seem to know you?

There is a magazine for autism parents in the UK and the lady who runs it came up to me to give me her card and asked why she had never heard of me, but so many others had.  The world has changed and blogs have advantages over print media - people like the comments and the hyperlinks.

Yes, an Alternative Reality for Autism

I was told a few years ago that I appear to live in a different world to most other people, at least when it comes to autism.  I suppose that is true and I do only very rarely encounter that other world.  This conference was one of those rare events.

In my world anything is possible, until proven otherwise. I prefer to keep it that way.

Many people do have a choice and over the decades you will get to see the consequences of those choices; for better or worse.

Since not all parents are science wizards, there should be some support from both public health and educational services to ensure every child has a basic level of provision.  That basic level is not very high anywhere in the world.

If you want more you have to go and find it.

How much effort do you really want to make? What short term discomfort are you willing to take to ensure a brighter future?

I am surprised how much variation there is.  Some parents will do just about anything, while some others do nothing.

Personally, I am a proactive person. When something is broken, I try to fix it. If the “expert” gives me lame excuses, I do not accept them; I look for different solutions and maybe a different “expert”. 

Clearly, I am far from typical.  Thank god.

I do not lie in bed at night wondering what will happen to my son when I am dead.  I do not get depressed about the curtailed life expectancy in severe autism; rather I think it is up to me to make a difference while I am still very much alive.  The future is very much determined by past actions.

Other people are very welcome to visit this alternative reality where an open-minded science-based approach is encouraged.  An open mind is actually more important than a clever mind.

I did mention to Dr Frye about Potassium Bromide (KBr) for autism/epilepsy and his first reaction was “child protective services!”, someone else once mentioned “that is for pets!”.  Actually, Potassium Bromide (KBr) was the original human drug for epilepsy and to this day is successfully used in Germany for treatment resistant pediatric epilepsy. It saves lives.  Untreated epilepsy will kill you. About 30% of epilepsy does not respond well enough to mainstream therapies. Numerous modern studies regarding KBr have been published.  You just have to keep an open mind.  The Germans, Japanese, Chinese may know something Americans do not.

I did get indirect feedback that an autism parent showed the German/Austrian KBr research to a leading US neurologist, I think it was Dr Chez, and his comment was that he wished he could prescribe it to patients. For the moment in the US it is dogs with epilepsy rather than children with Dravet’s Syndrome and others that benefit.

Italy has some nice doctors

I have noted before on my blog that within Europe, Italy seems very different. We had a presentation from a Gastroenterologist from Turin who has been studying the bowels of kids with autism for 15 years and regarded it as a perfectly normal thing to do. No UK Gastroenterologist would do this. We had a chat about Milan, which I am now becoming more familiar with due to my elder son studying there. The top Italian researcher Dr Fasano, whose research I have covered in this blog, has moved to the US.  (one less clever doctor in Italy).

Israel has some nice doctors

We took Monty to Israel earlier this year, but it was to see the historical sites rather than to see the doctors.  There were a couple of speakers from Israel talking about cannabis in autism. They were really interesting and “well-adjusted”, they know their area of research is a bit controversial, but they find a way forward. I did cover in a recent post that you can use PEA instead of cannabis and they are aware of this, but cannabis is their research drug. They say that PEA has fewer side effects.

In their medical practise they actively treat autism, which no medical doctor does in the UK.  

Poland has some nice doctors

We already knew that Agnieszka is busy helping people in Gdansk and much further afield.  She is busy helping the UK charity Thinking Autism.   A husband and wife research team came from Lublin to talk about the ketogenic diet with a very thorough science-based presentation. They suggest a PET scan might identify responders. I think this is actually just one very specific sub-type, because it relates “simply” to altered glucose uptake to the brain being the underlying biological problem.

America has the most Autism Doctors, by far, at least one of whom is also a nice guy

There are so many horror stories of American DAN-type doctors charging huge fees for consultations and testing, you might imagine them all to be evil. I have never consulted a DAN/MAPS doctor, but Dr Frye definitely is a good guy and very willing to share his knowledge with others.

I did actually put him on my Dean’s list a while back, with some encouragement from our reader Roger.

The United Kingdom has no “Autism Doctors”

Many of the parents I met were English and very many of them had all been seeing the same doctor, who was then banned from seeing patients with autism. In the United Kingdom autism is untreatable.

If you want treatment, call it something else like auto-immune encephalopathy.

I am so glad I do not live in the UK

Many parents in the UK really struggle to achieve anything meaningful in regard to treating autism. I am glad to live in a different reality where the main limiting factor is the science itself, not the absurd things the UK parents have to deal with.

Bumetanide Clinical Trial Success

We had the absurd situation recently when it seemed that in the second largest country in the EU, almost no hospitals wanted to participate in the Bumetanide Phase 3 European trial for autism.

Fortunately, one of the parents at the conference is a Psychiatrist working in London. He has an interest in autism, because his child has it and he is already involved in the Balvotam trial for autism. Hopefully his hospital will become another centre for the trial starting this summer, that would be a big success.

Come on Agnieszka, see more Patients

Lots of people ask me for my email address and you may have noticed I always encourage them to contact me in public on this blog. I do this for several reasons including.

I am not a doctor and I am not giving medical advice. The comments are just a public discussion tagged on to a blog written by a parent whose albeit lengthy scientific education was not in biology.

Some comments and the ensuing discussion are really interesting for other people and it would be a shame for it to be hidden away.

I do think people in Europe should be able to access safe, evidence-based, off-label therapies, of the kind that Dr Frye is openly prescribing at the Phoenix Children’s Hospital. This is not really permitted in the United Kingdom, although there is a tiny bit of “wriggle room” if you have money, perseverance and some knowledge yourself.

I did ask Agnieszka if she is going to get into the same kind of trouble in Poland that any doctor would in the UK, if she openly held an autism clinic. Apparently not. Is her husband going to like it? I suppose we will find out.

How many people would actually come to Poland for a one-stop diagnostic work-up, where you could choose from a menu of MRI, whole exome screening, sleep EEG, 24 hour EEG, full blood work up testing all the things Dr Frye would test in Phoenix, once you could actually get an appointment to see him. As our reader Roger has told us, it is not so easy to get an appointment to see Dr Frye.  I suggested having Dr Frye also review the data and that if it was clear that there were GI problems there could be a referral to our new friend in Turin who has been treating the guts of kids with ASD for 15 years. You could then proceed to actually trial the off-label drugs that were indicated. 

None of this is cheap, but it is much cheaper than doing the diagnostics in the US, or the UK if you could actually access it.

Then I was thinking why leave it at evidence-based therapies for autism. Why not treat other poorly managed neurological diseases like Multiple Sclerosis (MS), there are so many things that can be done and actually much cheaper than in the US.

Then I came down to earth and realized that actually very few parents, at least ones from the UK, would take out their wallet and pay for all these tests, even though it would be a fraction of the cost that they would pay in US.

In the United Kingdom people expect their healthcare to be free from cradle to the grave. If it is free, although you do pay via your taxes, you are not the customer. The patient is the consumer, but he/she has little say in the therapy. If you need eye glasses, you might spend a day trying on frames in different shops to see what suits you, but if you need an operation you will have little say in the type of operation, you will get what the guidelines says is the cost effective therapy. If you have prostate cancer, you will not get proton beam therapy, that was developed years ago to minimize the side effects by focusing the radiation onto only the affected tissue rather than zapping all the surrounding tissue and giving you possible severe side effects.    

Who would invest a few thousand pounds/dollars to diagnose their child’s autism as accurately as possible? And then start treatment.

It would be nice to think there would be a long line. I think there would initially be a line for prescriptions for bumetanide. The real idea though is to make a thorough investigation to rule out treatable ID, single gene autisms, metabolic dysfunctions etc, not to be a prescription signing service.

So, as I said to Agnieszka, don’t plan to give up your day job any time soon.  Have treating autism as a side-line, make a list of therapies that you think are evidence based. It would not include things like the Nemechek protocol, I think it would include things like Bumetanide, Dr Frye’s Leucovorin, Propranolol and the many existing drugs already tested in clinical trials.  For Nemechek you can buy his book, no doctor is needed.

Where are all the younger parents?

Given that I have one son already moved out of the country to go to University, I was expecting to be feeling old surrounded by all those young parents working out what to do with their very young children recently diagnosed with autism.  There were some parents in their 30s, but most were much older.

It was nice that at least one Grandpa was there, looking for ideas for his adult Grandson. I did actually make a point of pointing him towards the science relating to his issues.

The Microbiome comes from the Mother

This may be obvious, should not be forgotten and sounds quite catchy.

It does not matter so much what is in Dad’s microbiome. It does matter what is in his epigenome and of course his regular genes matter.

Mum/Mom provides here half of the child’s regular DNA, her epigenome, all of the mitochondrial DNA and all of the microbiome that filters through to the child during pregnancy and during delivery (assuming there was no C-section).


Conclusion  

Having spent a couple of days mainly with British parents dealing with autism, I came home and told everyone how glad I am that I do not live there.  It would drive me crazy!

They can wait for years to get a diagnosis

No doctor is supposed to treat autism, even comorbidities may go untreated, because that might imply you are treating autism.   But many people still think they have a world class healthcare system (in some areas this really is true).

US style free early intervention for very young children does not exist. 

They have a very backward-looking Autism Charity (NAS) that is dominant and supposedly represents them.

Provision of special schools is highly variable and often parents take legal action to get better provision.  This means the less able parents that do not know how to play the system have even less resources allocated to their kids. 

They have about 2,000 young people with autism locked up for years in small, poorly supervised, private mental institutions. Just today another horror story has been released about the abuse that can occur.



The end result is some pretty browbeaten parents.

I was once asked if I would speak in the US and I asked what they would like me to speak about, it was very much TREAT AUTISM NOW !!!  Those are my kind of people.  More dynamic, pushier and demanding more – it is the only way to be.

The Israeli clinicians at the conference told us the only way they managed to move therapies, including cannabis, forward and actually treat autism was pressure on the government from parents. I guess Israelis know how to push. Now UK parents fly to Tel Aviv to treat their child with autism, some others fly to California and I met one nice lady who takes her daughter to Italy.





Tuesday 14 May 2019

Making best use of existing NKCC1/2 Blockers in Autism






Azosemide C12H11ClN6O2S2  


Today’s post may be of interest to those already using bumetanide for autism and for those considering doing so.  It does go into the details, because they really do matter and does assume some prior knowledge from earlier posts.

There has been a very thorough new paper published by a group at Johns Hopkins:-
It does cover all the usual issues and raises some points that have not been covered yet in this blog.  One point is treating autism prenatally. This issue was studied twice in rats, and the recent study was sent to me by Dr Ben Ari.  Short term treatment during pregnancy produced a permanent benefit.

Maternal bumetanide treatment prevents the overgrowth in the VPA condition

            
Brief maternal administration of bumetanide before birth restores low neuronal intracellular chloride concentration ([Cl]i) levels, produces an excitatory-to-inhibitory shift in the action of γ-aminobutyric acid (GABA), and attenuates the severity of electrical and behavioral features of ASD (9, 10), suggesting that [Cl]i levels during birth might play an important role in the pathogenesis of ASD (7). Here, the same bumetanide treatment significantly reduced the hippocampal and neocortical volumes of P0 VPA pups, abolishing the volume increase observed during birth in the VPA condition [hippocampus: P0 VPA versus P0 VPA + BUM (P = 0.0116); neocortex: P0 VPA versus P0 VPA + BUM (P = 0.0242); KWD] (Fig. 3B). Maternal bumetanide treatment also shifted the distribution of cerebral volumes from lognormal back to normal in the population of VPA brains, restoring smaller cerebral structure volumes (Fig. 3C). It also decreased the CA3 volume to CTL level after birth, suggesting that the increased growth observed in this region could be mediated by the excitatory actions of GABA (Fig. 3D). Therefore, maternal bumetanide administration prevents the enhanced growth observed in VPA animals during birth.

One issue with Bumetanide is that it affects both:-

·        NKCC2 in your kidneys, causing diuresis
·        NKCC1 in your brain and elsewhere, which is divided into two slightly different forms NKCC1a and NKCC1b

NKCC1 is also expressed in your inner ear where it is necessary for establishing the potassium-rich endolymph that bathes part of the cochlea, an organ necessary for hearing. 

If you block NKCC1 too much you will affect hearing.

Blocking NKCC1 in children and adults is seen as safe but the paper does query what the effect on hearing might be if given prenatally as the ear is developing.

Treating Down Syndrome Prenatally

While treating autism prenatally might seem a bit unlikely, treating Down Syndrome (DS) prenatally certainly is not.  Very often DS is accurately diagnosed before birth creating a valuable treatment window.  In most countries the vast majority of DS prenatal diagnoses lead to termination, but only a small percentage of pregnancies are tested for DS. In some countries such as Ireland a significant number of DS pregnancies are not terminated, these could be treated to reduce the deficits that will otherwise inevitably follow.



The research does suggest that DS is another brain disorder that responds to bumetanide.


Back to autism and NKCC1

This should remind us that a defect in NKCC1 expression will not only cause elevated levels of chloride with in neurons, but will also affect the levels of sodium and potassium with neurons.

There are many ion channel dysfunctions (channelopathies) implicated in autism and elevated levels of sodium and potassium will affect numerous ion channels.  The paper does suggest that the benefit of bumetanide may go beyond modifying the effect of GABA, which is the beneficial mode of action put forward by Dr Ben Ari.
We have seen how hypokalemic sensory overload looks very similar to what often occurs in autism and that autistic sensory overload is reduced by taking an oral potassium supplement.

The paper also reminds us that loop diuretics like bumetanide and furosemide not only reduce inflow of chloride into neurons, but may also reduce the outflow. This is particularly known of furosemide, but also occurs with bumetanide at higher doses.
The chart below shows that the higher the concentration of bumetanide the strong its effect becomes on blocking NKCC1.


But at higher doses there will also be a counter effect of closing the NKCC2 transporter that allows chloride to leave neurons.
At some point a higher dose of bumetanide may have a detrimental effect on trying to lower chloride within neurons.

Since Dr Ben Ari’s objective is to lower chloride levels in neurons  it is important how freely these ions both enter and exit.  The net effect is what matters. (Loop diuretics block NKCC1 that lets chloride enter neurons but also block the KCC2 transporter via which they exit)

Is Bumetanide the optimal existing drug to lower chloride within neurons?  Everyone agrees that it is not, because only a tiny amount crosses into the brain. The paper gives details of the prodrugs like BUM5 that have been looked at previously in this blog; these are modified versions of bumetanide that can better slip across the blood brain barrier and then react in the brain to produce bumetanide itself.  It also highlights the recent research that suggests that Bumetanide may not be the most potent approved drug, it is quite conceivable that another old drug called Azosemide is superior.

The blood brain barrier is the problem, as is often the case.  Bumetanide has a low pH (it is acidic) which hinders its diffusion across the barrier.  Only about 1% passes through.

There is scepticism among researchers that enough bumetanide can cross into the brain to actually do any good.  This is reflected in the review paper.

The paper reminds us of the research showing how you can boost the level of bumetanide in the brain by adding Probenecid, an OAT3 inhibitor.  During World War 2 antibiotics were in short supply and so smaller doses were used, but their effect was boosted by adding Probenecid. By blocking OAT3, certain types of drug like penicillin and bumetanide are excreted at a slower rate and so the net level in blood increases.

The effect of adding Probenecid, or another less potent OAT3 inhibitors, is really no different to just increasing the dose of bumetanide.

The problem with increasing the dose of bumetanide is that via its effect on NKCC2 you cause even more diuresis, until eventually a plateau is reached.

Eventually, drugs selective for NKCC1a and/or NKCC1b will appear.

In the meantime, the prodrug BUM5 looks good. It crosses the BBB much better than bumetanide, but it still affects NKCC2 and so will cause diuresis.  But BUM5 should be better than Bumetanide + Probenecid, or a higher dose of Bumetanide.  BUM5 remains a custom-made research drug, never used in humans.

I must say that what again stands out to me is the old German drug, Azosemide.

In a study previously highlighted in this blog, we saw that Azosemide is 4 times more potent than Bumetanide at blocking NKCC1a and NKCC1b.

Azosemide is more potent than bumetanide and various other loop diuretics to inhibit the sodium-potassium-chloride-cotransporter human variants hNKCC1A and hNKCC1B

Azosemide is used in Japan, where recent research shows it is actually more effective than other diuretics

Azosemide, a Long-acting Loop Diuretic, is Superior to Furosemide in Prevention of Cardiovascular Death in Heart Failure Patients Without Beta-blockade 

As is often the case, Japanese medicine has taken a different course to Western medicine.

Years of safety information has already been accumulated on Azosemide.  It is not an untried research drug. It was brought to market in 1981 in Germany. It is available as Diart in Japan made by Sanwa Kagaku Kenkyusho and as a cheaper generic version by Choseido Pharmaceutical. In South Korea Azosemide is marketed as Uretin.


In any other sector other than medicine, somebody would have thought to check by now if Azosemide is better than Bumetanide.  It is not a matter of patents, Ben-Ari has patented all of the possible drugs, including Azosemide and of course Bumetanide.

So now we move on to Azosemide.



When researchers came to check the potency of the above drugs the results came as a surprise.  It turns out that the old German drug Azosemide is 4 times as potent as bumetanide.






The big question is how does it cross the blood brain barrier.


“The low brain concentrations of bumetanide obtained after systemic administration are thought to result from its high ionization (>99%) at physiological pH and its high plasma protein binding (>95%), which restrict brain entry by passive diffusion, as well as active efflux transport at the blood-brain barrier(BBB). The poor brain penetration of bumetanide is a likely explanation for its controversial efficacy in the treatment of brain diseases

“… azosemide was more potent than any other diuretic, including bumetanide, to inhibit the two NKCC1 variants. The latter finding is particularly interesting because, in contrast to bumetanide, which is a relatively strong acid (pKa = 3.6), azosemide is not acidic (pKa = 7.38), which should favor its tissue distribution by passive diffusion. Lipophilicity (logP) of the two drugs is in the same range (2.38 for azosemide vs. 2.7 for bumetanide). Furthermore, azosemide has a longer duration of action than bumetanide, which results in superior clinical efficacy26 and may be an important advantage for treatment of brain diseases with abnormal cellular chloride homeostasis.”


Dosage equivalents of loop Diuretics


Bumetanide has very high oral bioavailablity, meaning almost all of what you swallow as a pill makes it into your bloodstream.

Furosemide and Azosemide have much lower bioavailability and so higher doses are needed to give the same effect.

Both Furosemide and Bumetanide are short acting, while Azosemide is long acting.

For a drug that needs to cross the blood brain barrier small differences might translate into profoundly different effects.

The limiting factor in all these drugs is their effect on NKCC2 that causes diuresis.

1mg of bumetanide is equivalent to 40mg of furosemide.
2mg of bumetanide is equivalent to 80mg of furosemide.

The standard dose for Azosemide in Japan, where people are smaller than in the West, is 30 mg or 60mg. 

Research suggests that the same concentration of Azosemide is 4x more potent than Bumetanide at blocking NKCC1 transporters, other factors that matter include:-

·        How much of the oral tablet ends up in the bloodstream.
·        How long does it stay in the blood stream
·        How much of the drug actually crosses the blood brain barrier
·        How does the drug bind to the NKCC1 transporters in neurons
·        How rapidly is the drug excreted from the brain
·        What effect is there on the KCC2 transporter that controls the exit of chloride ions from neurons.

All of this comes down to which is more effective in adults with autism 2mg of bumetanide or 60mg of Azosemide.

The side effects, which are mainly diuresis and loss of electrolytes will be similar, but Azosemide is a longer acting drug and so there will be differences. In fact Azosemide is claimed to be less troublesome than Bumetanide in lower potassium levels in your blood.

Conclusion  

The open question is whether generic Azosemide is “better” than generic Bumetanide for treating brain disorders in humans.

I did recently ask Dr Ben-Ari if he is aware of any data on this subject. There is none.

Many millions of dollars/euros are being spent getting Bumetanide approved for autism, so it would be a pity if Azosemide turns out to be better. (Dr Ben Ari’s company Neurochlore wants to develop a new molecule that will cross the blood brain barrier, block NKCC1 and not NKCC2 and so will not cause diuresis).

The hunch of the researchers from Hanover, Germany seems to be that the old German drug Azosemide will be better than Bumetanide.

I wonder if doctors at Johns Hopkins / Kennedy Krieger have started to prescribe bumetanide off-label to their patients with autism.  Their paper shows that they have a very comprehensive knowledge of the subject.


===========

I suggest readers consult the full version of the Johns Hopkins review paper on Bumetanide, it is peppered with links to all the relevant papers.

Bumetanide (BTN or BUM) is a FDA-approved potent loop diuretic (LD) that acts by antagonizing sodium-potassium-chloride (Na-K-Cl) cotransporters, NKCC1 (SLc12a2) and NKCC2. While NKCC1 is expressed both in the CNS and in systemic organs, NKCC2 is kidney-specific. The off-label use of BTN to modulate neuronal transmembrane Clgradients by blocking NKCC1 in the CNS has now been tested as an anti-seizure agent and as an intervention for neurological disorders in pre-clinical studies with varying results. BTN safety and efficacy for its off-label use has also been tested in several clinical trials for neonates, children, adolescents, and adults. It failed to meet efficacy criteria for hypoxic-ischemic encephalopathy (HIE) neonatal seizures. In contrast, positive outcomes in temporal lobe epilepsy (TLE), autism, and schizophrenia trials have been attributed to BTN in studies evaluating its off-label use. NKCC1 is an electroneutral neuronal Climporter and the dominance of NKCC1 function has been proposed as the common pathology for HIE seizures, TLE, autism, and schizophrenia. Therefore, the use of BTN to antagonize neuronal NKCC1 with the goal to lower internal Cl levels and promote GABAergic mediated hyperpolarization has been proposed. In this review, we summarize the data and results for pre-clinical and clinical studies that have tested off-label BTN interventions and report variable outcomes. We also compare the data underlying the developmental expression profile of NKCC1 and KCC2, highlight the limitations of BTN’s brain-availability and consider its actions on non-neuronal cells.

Btn Pro-Drugs and Analogs

To improve BTN accessibility to the brain, pro-drugs with lipophilic and uncharged esters, alcohol and amide analogs have been created. These pro-drugs convert to BTN after gaining access into the brain. There was a significantly higher concentration of ester prodrug, BUM5 (N,N – dimethylaminoethyl ester), in mouse brains compared to the parent BTN (10 mg/kg, IV of BTN and equimolar dose of 13 mg/kg, IV of BUM5) (Töllner et al., 2014). BUM5 stopped seizures in adult animal models where BTN failed to work (Töllner et al., 2014Erker et al., 2016). BUM5 was also less diuretic and showed better brain access when compared to the other prodrugs, BUM1 (ester prodrug), BUM7 (alcohol prodrug) and BUM10 (amide prodrug). BUM5 was reported to be more effective than BTN in altering seizure thresholds in epileptic animals post-SE and post-kindling (Töllner et al., 2014). Furthermore, BUM5 (13 mg/kg, IV) was more efficacious than BTN (10 mg/kg, IV) in promoting the anti-seizure effects of PB, in a maximal electroshock seizure model (Erker et al., 2016). Compared to BUM5 which was an efficacious adjunct to PB in the above mentioned study, BTN was not efficacious when administered as an adjunct (Erker et al., 2016). In addition to seizure thresholds, further studies need to be conducted to assess effects of BUM5 on seizure burdens, ictal events, duration and latencies.
Recently, a benzylamine derivative, bumepamine, has been investigated in pre-clinical models. Since benzylamine derivatives lack the carboxylic group of BTN, it results in lower diuretic activity (Nielsen and Feit, 1978). This prompted Brandt et al. (2018) to explore the proposed lower diuretic activity, higher lipophilicity and lower ionization rate of bumepamine at physiological pH. Since it is known that rodents metabolize BTN quicker than humans, the study used higher doses of 10 mg/kg of bumepamine similar to their previous BTN studies (Olsen, 1977Brandt et al., 2010Töllner et al., 2014). Bumepamine, while only being nominally metabolized to BTN, was more effective than BTN to support anticonvulsant effects of PB in rodent models of epilepsy. This GABAergic response, however, was not due to antagonistic actions on NKCC1; suggesting bumepamine may have an off-target effect, which remains unknown. However, the anticonvulsive effects of bumepamine, in spite of its lack of action on NKCC1, are to be noted. Additionally, in another study by the same group, it was shown that azosemide was 4-times more potent an inhibitor of NKCC1 than BTN, opening additional avenues for better BBB penetration and NKCC1-antagonizing compounds for potential neurological drug discovery (Hampel et al., 2018).

Conclusion


The beneficial effects of BTN reported in cases of autism, schizophrenia and TLE, given its poor-brain bioavailability are intriguing. The mechanisms underlying the effects of BTN, as a neuromodulator for developmental and neuropsychiatric disorders could be multifactorial due to prominent NKCC1 function at neuronal and non-neuronal sites within the CNS. Investigation of the possible off-target and systemic effects of BTN may help further this understanding with the advent of a new generation of brain-accessible BTN analogs.




Monday 6 May 2019

Mushrooms and Cognitive Function - Something healthy in the English Breakfast!




Breakfast overlooking the river Thames


















The more typical English Breakfast


If you happen to stay at a very nice hotel in London, the best meal to have is breakfast and after that comes tea.  The other meals are unlikely to feature much memorable English food.

Whether it is the five-star Savoy, overlooking the river Thames, or the Travelodge by the station, mushrooms will be on the menu. 

The movers and shakers actually get up early and have their power meetings over breakfast at the Savoy. This is not so expensive and a good way to experience British cuisine, served in a much more spacious environment than most restaurants.  Scotland contributes its porridge and black pudding, kippers might be on offer, but there will be mushrooms, a regular part of even the humblest hotel’s English breakfast.


Eating mushrooms more than twice a week could prevent memory and language problems occurring in the over-60s, research from Singapore suggests.
A unique antioxidant present in mushrooms could have a protective effect on the brain, the study found.
The more mushrooms people ate, the better they performed in tests of thinking and processing. The researchers point to the fact that mushrooms are one of the richest dietary sources of ergothioneine - an antioxidant and anti-inflammatory which humans are unable to make on their own.
Mushrooms also contain other important nutrients and minerals such as vitamin D, selenium and spermidine, which protect neurons from damage. 



We examined the cross-sectional association between mushroom intake and mild cognitive impairment (MCI) using data from 663 participants aged 60 and above from the Diet and Healthy Aging (DaHA) study in Singapore. Compared with participants who consumed mushrooms less than once per week, participants who consumed mushrooms >2 portions per week had reduced odds of having MCI (odds ratio = 0.43, 95% CI 0.23–0.78, p = 0.006) and this association was independent of age, gender, education, cigarette smoking, alcohol consumption, hypertension, diabetes, heart disease, stroke, physical activities, and social activities. Our cross-sectional data support the potential role of mushrooms and their bioactive compounds in delaying neurodegeneration.




Fig. 1. Functional dependence of mild cognitive impairment on mushroom consumption (treated as continuous variable): the solid curve is estimated via the smoothing spline approach. Adjusted for age, gender, education, cigarette smoking, alcohol consumption, hypertension, diabetes, heart diseases, stroke, physical activities, social activities.

Using data from the Diet and Healthy Aging Study in Singapore, we found that mushroom consumption was associated with reduced odds of having MCI. The reduction was significant for participants who consumed greater than 2 portions of mushrooms per week

The observed correlation between mushrooms and reduced odds of MCI in our study sample is biologically plausible. Certain components in mushrooms, such as hericenones, erinacines, scabronines and dictyophorines may promote the synthesis of nerve growth factors. Bioactive compounds in mushrooms may also protect brain from neurodegeneration by inhibiting production of amyloid- and phosphorylated tau, and acetylcholinesterase. Mushrooms are also one of the richest dietary sources of ergothioneine (ET). ET, a thione-derivative of histidine is an unique putative antioxidant and cytoprotective compound. While humans are unable to synthesize ET, it can be readily absorbed from diet (main source is mushrooms) and actively accumulated in the body and the brain via a specific transporter, OCTN1. Our recent study in elderly Singaporeans revealed that plasma levels of ET in participants with MCI were significantly lower than age-matched healthy individuals, leading us to believe that a deficiency in ET may be a risk factor for neurodegeneration, and increase ET intake through mushroom consumption might possibly promote cognitive health.

In summary, using community-based data in Singapore, we found that mushroom consumption was associated with reduced odds of MCI. Based on current evidence, we propose that mushroom consumption could be a potential preventive measure to slow cognitive decline and neurodegeneration in aging.


Conclusions

Studying all possible forms of cognitive impairment is interesting if you want to understand autism. 

Mushroom would appear to have a similar scale of potential benefit in MCI (mild cognitive impairment) to cocoa flavanols, which have been commercialized as a therapy by Mars. 

We did see previously how one specific type of mushroom (Lion’s Mane) has a particular effect of raising levels of NGF (nerve growth factor).  Oyster mushrooms produce Lovastatin.

Mushroom contain spermidine and so will improve autophagy, the intracellular garbage collection service that is impaired in many neurological conditions.

Eat mushrooms.