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Monday, 5 March 2018

Autism and Non-Antibiotic Properties of Common Beta-lactam Antibiotics


If you are looking for personalized medicine, you or your doctor need to be a good detective. Not to mention you need some clues.
If you are treating a condition like autism and certain things cause a marked change in the severity of the condition, these are pretty good places to start.
In the case of our reader in Delhi, it is Beta-lactam antibiotics (penicillin, amoxicillin etc), that consistently seem to improve her son’s autism. Improvement during treatment with antibiotics is reported quite often in autism, but with all kinds of different antibiotic.  Nothing is simple.
For non-medical readers, there are several categories of antibiotics; common types including:-
·        Beta-lactams (e.g. Penicillins)

·        Macrolides (e.g. Erythromycin, Azithromycin)

·        Fluoroquinolones (e.g. Ciprofloxacin) 

·        Tetracyclines (e.g. Minocycline) 

Macrolides have already had a dedicated post about their immunomodulatory effects, which did also cover some history about Poland from Monty's homework.

Macrolide Antibiotics for Some Autism? Or better still, Azithromycin analogue CSY0073, or just Nystatin?



Beta Lactam Antibiotics
In earlier posts we came across something called glutamate transporter GLT1 (also known as EAAT2).
Glutamate is the major excitatory neurotransmitter, and is inactivated by uptake via GLT-1 (EAAT2) and GLAST (EAAT1) transporters.
Many people given the observational diagnosis of autism appear to have an underlying imbalance between excitatory and inhibitory neurotransmitters (E/I imbalance). By correcting the specific type of E/I imbalance, even profound symptoms of autism including MR/ID and epilepsy can be moderated. If you have autism and/or epilepsy tuning your E/I imbalance is likely the most important step you can take.
Some drugs increase the expression of GLT-1 and so reduce the amount of glutamate. Macrolide antibiotics are one of these drugs.
So if a person has too much glutamate and this causes/contributes to their E/I imbalance then improved behaviour while taking penicillin antibiotics, who have a simple explanation.
Since you would not want to take penicillin forever you would then look for a non antibiotic drug that also increases the uptake of Glutamate. Once such drug, Riluzole, does exist and has already been trialed on children with OCD. 
But beta-lactams have other effects, so it is not certain that GLT-1 accounts for the beneficial effect sometimes found in autism. Fortunately some researchers have assembled most previous research into a single review paper. This paper does not mention autism and does miss some things out.


There are seven categories:-
·        Antibiotic

·        Epileptogenic

·        Neuroprotective

·        Analgesic

·        Immunomodulatory

·        Anxiolytic

·        Antineoplastic



Antibiotic Effect
We all know something about bacteria. If you have a bacterial infection like an ear infection your doctor might prescribe you an antibiotic.

As well as inflaming your ear, the bacteria may well affect gene expression. We saw in a previous post that bacteria and viruses change the expression of many genes, but the study of this is in its infancy. In autism we know that many genes are miss-expressed, but this varies from person to person. So a bacteria or virus has the potential to make autism worse (e.g. PANS and PANDAS), but also better. Bacteria are not always bad.
A person whose autism responds to an antibiotic might have bacteria that are worsening his autism. This is simplest of explanation of all.

The question then is where is the bacteria? If it is an intestinal bacterium this could be proven by using an antibiotic that only works there, like Vancomycin.

Epileptogenic effects
In this review they concluded the effects relate to GABA and here we are talking about negative effects. 

penicillin is a potent epileptogenic agent = it is capable of causing an epileptic attack

“This could mean that penicillin is a competitive GABA specific antagonist, which would further explain its epileptogenic properties.”

The paper omits to point out that in some people beta-lactams protect from epileptic seizures. The effect on Glutamate is likely at least sometimes what stops seizures.


The really clever thing in the above case report is that appears that the effect on glutamate may be by an epigenetic mechanism (via GLT1), since the effect is long lasting. Read later in this post about the epigenetic effects of beta-lactams.

Neuroprotective properties
“These results suggest that the neuroprotective effect induced by beta-lactam antibiotics is due to their capacity to stimulate GLT1 expression and thus regulate the concentration of glutamate in the synaptic cleft. GLT1 is a glutamate transporter inducing its reuptake by astrocytes preventing excessive glutamate concentration in the synaptic cleft
It was subsequently shown that the neuroprotective effect of BLMs was due not only to glutamate down regulation, but also to a diminished glutamate-induced intracellular Ca2+ concentration and an increased uptake of glutamate
Another probable mechanism of neuroprotection induced by BLMs is down-regulation of oxidative stress and modulation of apoptotic pathways shown in rat spinal cord when CFX was administered for 7 days prior to induction of constrictive neuropathy. This effect was apparently mediated by both a reduction in proapoptotic proteins Bax, and an increment in the antiapoptotic protein Bcl2.
CFX (Ceftiaxone) may induce neuroprotection by other mechanisms besides GLT1 overexpression. Yamada and Jinno [51] reported that the antibiotic reversed axotomy-induced up regulation of GFAP, a neuronal damage marker, and increased neuronal survival; apparently not only through glutamatergic regulation, but also by direct reduction of glial hypereactivity. Supplementary to this is the finding of an attenuation of microglial activation induced IL-1 expression in an ischemic injury model when CFX was administered as a pre-treatment [52]. This result may indicate a direct action on glial cells since partial reduction of astrocytes and microglia was observed.”

Analgesic (pain killing) Properties
“Interestingly, despite the widespread clinical use of BLMs (beta-lactams), some of their known non-antibiotic effects have been either disregarded or misinterpreted as resulting from bacterial microbiome regulation. For example, Caperton, Heim-Duthoy [54] hypothesized that chronic inflammatory arthritis could have a bacterial component and that therefore the clinical course of a patient could be affected by administration of CFX (Ceftriaxone).
Both the anti-inflammatory and neuromodulating effects exerted by BLMs either peripherally or centrally may be related to their analgesic properties in some pathologies that are difficult to treat such as the complex regional pain syndrome [65] or to the analgesic effect of a single preoperative dose of CFX in a clinical protocol [66].

Immunomodulatory Properties 
Not many people seem to have read this paper. They did not flesh out immunomodulation, so I draw on a different paper. People who write about immunomodulation usually say that beta-lactams do not have this effect, but that appears to be incorrect. 

Recent work has suggested that beta-lactam antibiotics might directly affect eukaryotic cellular functions. Here, we studied the effects of commonly used beta-lactam antibiotics on rodent and human T cells in vitro and in vivo on T-cell–mediated experimental autoimmune diseases. We now report that experimental autoimmune encephalomyelitis and adjuvant arthritis were significantly more severe in rats treated with cefuroxime and other beta-lactams. T cells appeared to mediate the effect: an anti-myelin basic protein T-cell line treated with cefuroxime or penicillin was more encephalitogenic in adoptive transfer experiments. The beta-lactam ampicillin, in contrast to cefuroxime and penicillin, did not enhance encephalomyelitis, but did inhibit the autoimmune diabetes developing spontaneously in non-obese diabetic mice. Gene expression analysis of human peripheral blood T cells showed that numerous genes associated with T helper 2 (Th2) and T regulatory (Treg) differentiation were down-regulated in T cells stimulated in the presence of cefuroxime; these genes were up-regulated in the presence of ampicillin. The T-cell protein that covalently bound beta-lactam antibiotics was found to be albumin. Human and rodent T cells expressed albumin mRNA and protein, and penicillin-modified albumin was taken up by rat T cells, leading to enhanced encephalitogenicity. Thus, beta-lactam antibiotics in wide clinical use have marked effects on T-cell behavior; beta-lactam antibiotics can function as immunomodulators, apparently through covalent binding to albumin.

 Anxiolytic effects (reduce anxiety)
“CA (Clavulanic acid) has proven effective as an anxiolytic drug, since it was reported that this drug diminished anxiety-like conduct in both rodent and primate models”

Antineoplastic effects (preventing tumors)
“CFX (Ceftriaxone) elicit antitumor activity both in vitro and in vivo models”

Addiction
Addiction did not appear in the chart above, but it gets a mention in the text 
“When tested in an opiate dependence model, both CFX [72] and CA [73] inhibited both physical dependence and withdrawal symptoms. This could mean that the effect shown by CFX is not due to its particular molecular structure, but can be reproduced by other BLMs (several BLMs effects shown on Fig. 3)

Other effects
“CA (Clavulanic acid) has been shown to increase dopamine release”

Epigenetic Effects
These were not mentioned in the paper, but I do think epigenetics is a fundamental part of many diseases, including much autism.
The paper really explains why short term use of beta-lactams can stop a person with epilepsy having seizures for a long time.

Off-Target drug effects resulting in altered gene expression events with epigenetic and"Quasi-Epigenetic" origins.


This review synthesizes examples of pharmacological agents who have off-target effects of an epigenetic nature. We expand upon the paradigm of epigenetics to include "quasi-epigenetic" mechanisms. Quasi-epigenetics includes mechanisms of drugs acting upstream of epigenetic machinery or may themselves impact transcription factor regulation on a more global scale. We explore these avenues with four examples of conventional pharmaceuticals and their unintended, but not necessarily adverse, biological effects. The quasi-epigenetic drugs identified in this review include the use of beta-lactam antibiotics to alter glutamate receptor activity and the action of cyclosporine on multiple transcription factors. In addition, we report on more canonical epigenome changes associated with pharmacological agents such as lithium impacting autophagy of aberrant proteins, and opioid drugs whose chronic use increases the expression of genes associated with addictive phenotypes. By expanding our appreciation of transcriptomic regulation and the effects these drugs have on the epigenome, it is possible to enhance therapeutic applications by exploiting off-target effects and even repurposing established pharmaceuticals. That is, exploration of "pharmacoepigenetic" mechanisms can expand the breadth of the useful activity of a drug beyond the traditional drug targets such as receptors and enzymes.








DAO inhibition
As our reader Agnieszka pointed out in the comments section, one commonly prescribed beta-lactam antibiotic called Augmentin contains a second antibiotic, Clavulanic acid, to boost its effectiveness; by chance is also a very potent DAO inhibitor. Diamine oxidase (DAO), also known as histaminase, is an enzyme in your body that is used to inactivate histamine. Histamine is found in food that you eat as well as being produced in your body and released by your mast cells during an allergic reaction.

DAO neutralizes the histamine in food so it does not enter your bloodstream.
So this particular antibiotic should be avoided by those people who are histamine intolerant and so do not produce enough DAO. This is about 1% of the general population, but might be more common in those with autism although there is no data on this subject.

Some people believe that ADHD is associated with a reduced level of DAO.
Indeed there is a patent to treat ADHD with a combination of DAO and caffeine.



[0087] DAO can also be mixed with caffeine, strengthening the role of prevention and treatment of attention deficit hyperactivity disorder. Thus, also disclosed herein compositions comprising DAO and caffeine. 
[0088] Caffeine, a xanthine alkaloid group having stimulating properties for the treatment of attention deficit hyperactivity disorder. 
[0089] DAO content of the present invention per unit dose 0 · l-50mg, preferably 2-20mg. 
[0090] The present invention is caffeine content per unit dose 1-lOOmg, preferably 5-50mg. 
[0091] for the prevention and treatment of attention deficit hyperactivity disorder DAO or compositions comprising DAO may be before a meal or postprandial meal administration.
[0092] The use of DAO of the invention or compositions comprising DAO directly affect blood histamine levels, thus affecting the symptoms of attention deficit cumulative histamine levels induced hyperactivity disorder.

You can actually buy DAO supplements and of course caffeine.
Perhaps people consuming DAO inhibitors long term, such as NAC and Verapamil, and have chronic allergies or mast cell disorders might benefit from extra DAO. 




Most DAO is actually in your digestive tract, where the dietary histamine is.

You can measure DAO levels in your blood.

We can conclude that determination of DAO activity in serum is a useful diagnostic tool, together with detailed history to differentiate between food allergy and histamine intolerance.
We found that DAO activity was significantly lower in patients than in healthy control subjects.

Conclusion
I think there is plenty of food for thought here for parents of children whose autism and/or epilepsy improves when taking a beta-lactam antibiotic.  Hopefully some people will figure out which effect is the beneficial one and find something else to replicate it.

There is a lot previously written in this blog about upregulating GLT1, other than by a beta-lactam. My favoured option was Riluzole, but Bromocriptine will also do this, among its other actions. Riluzole is a drug for ALS, that has been trialed in children with OCD, without side effects.    

People technically without histamine intolerance (normal levels of DAO) who incidentally take large amounts of DAO inhibitors, may end up exacerbating an existing mast cell related problem. One potential solution for that small group might be taking an OTC DAO supplement.







64 comments:

  1. Hi Peter and Tyler, I can get bromocriptine, could be another way to treat his OCD. But it stimulates D1 dopaminergic receptors while antagonizes D2. Do you think that it could work in this way or even so is better stay away? Valentina

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    1. Valentina, I wanted to tell you another thing I forgot to mention in my last reply to you - since my son has been on this medicine regimen, suddenly he has become very interested in art and has been painting so much. His handwriting has also improved. He is so happy and at peace. He has finally gained some weight too. He was always rail thin.. With the artwork - it is a very different side of him- as if he is a more thoughtful and deliberate kid. Whereas before his thrill seeking athletic endeavors ruled the day - so it is nice to see his interest in art now. Like you mentioned in the other comment - if the medicine is helping so much it will be hard to think about stopping. But this is doctor’s orders for now. We will see how things go.

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    2. I am guessing bromocriptine was suggested to you by a doctor as a remedy to side-effects from antagonism of the tuberoinfundibular dopamine pathway which leads to hyperprolactinemia which is a very undesirable side-effect in an almost teenage boy. Risperidone of course achieves these undersirable side effects so one might imagine a doctor adding in Bromocriptine as an adjunct therapy to address some of the downsides of Risperidone.

      Bromocriptine is a strong D2 receptor agonist and as such will eventually lead to withdrawal symptoms, so anything in that category should not be given to anyone who is not near the end of their natural lives (such as very old people with Parkinsons). That is just my moral opinion on the matter. Doctors in the USA at least, have very short-term considerations for their patients as long-term problems are some other doctor's problem to make money off of (I think Uruguay has a much different health care system than the USA, but here doctors number one priority is making their clients happy so they keep coming back for visits, as opposed to making them healthy which is a much more complex issue not financially connected to patient satisfaction).

      Bromocriptine as I understand it has been used to help treat Parkinson's disease in the past where excess activity in the indirect pathway leads to excessive thalamic inhibition, so I am not sure what the motivation here is though I will admit I know very little about Bromocriptine aside from what you have probably already read yourself.

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    3. Valentina, Sarcosine looks a very much safer thing to try. It does have evidence to support its use in OCD. Very clearly not everyone with OCD responds to it.

      Sarcosine is OTC and another of these products that is very cheap in the US, but harder to find elsewhere.

      Based on the trials 1g would seem a good place to start. Some use 2g but it is documented that for some people this is too much.

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    4. Peter, I was already lookig at sarcosine and I can have it by April. Answearing Tyler too,what I want to look for now is go by the glutamate side that, with his high dopamine are generating the symptoms that look like the OCD. I already had a bad experience with memantine and don´t want to throw everything away.Regarding dopamine, it doesn´t exist a medication that selectively agonizes d1 and antagonizes d2,I read it about bromocriptine and I got impressed, but it is not correct, I have the source.So apart from bcaas all I had tried is for the worse, may be aspartic acid is a good choice! Regarding bumetanide, it is excellent for him, when he is quiet is when you really can see the change. My sister goes to Spain in April, do you know where could she find bumetanide without prescription? It seems that is not easy,a friend of my mother in law was looking for it, she lives in Alicante but they don´t sell it.May be in a bigger city and depending on the pharmacy?
      Valentina

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    5. Valentina, in Spain bumetanide is sold under the brand name FORDIURAN (Leo Pharma). Pharmacies get deliveries every day, so even if they do not have it in the store, they will order it for the next day.

      In Spain they will give this type of drug without prescription. If your sister says it is not available back home and so she wants a 1 year supply, I think they will be happy to help. Just tell her not to mention autism, just say it is for an older relative.

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    6. Thankyou Peter, the friend of my mother in law must have screwed up! I will instruct my sister, sure she will manage to ge it.She lives in Bariloche Argentina,I could go this winter season with my son,to bring it back and do some skiing!Your son is adorable. Valentina

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    7. Valentina, there are indirect ways of regulating dopamine via opioid receptors and cannabinoid receptors and quite a bit else, though I would look at supprrssing mu-opioid receptors or else boosting kappa opioid receptors first just don't overdo it. Aspartic acid seemed to work for my son but the more traditional approach has been naltrexone which you may be able to get by prescription easier in your country than in the USA where we have very stupid drug laws.

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    8. Tyler, what could I use as a cannabinoid receptor type 2 agonist?
      Valentina

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    9. Valentina, ask your sister in Argentina to look in the local pharmacy for BUTINAT, this is Sanofi "Bumetanida".

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    10. Peter, my sister will look into her local pharmacy, I don´t think that it is available. It would be almost a miracle.I looked into Sanofi´s web in Argentina and the name Butinat is crossed out, as if missing.Valentina

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    11. Well, CB2 is primarily expressed in the gut and helps modulate the immune system. I don't know of any SAFE and SELECTIVE drugs for CB2 agonism, however, since CB2 receptors are upstream in the pathway affecting immune regulation, you can employ TRPV channel agonism downsteam instead via the use of capsaicin (chili powder).

      http://www.pnas.org/content/pnas/114/19/5005.full.pdf

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    12. Thankyou Tyler,another powerful reason to continue using cayenne, at least for my son.I make my own capsules but the empty capsules had ran out and didn´t continue. I will use it again daily from now. Valentina

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  2. It would have been nice if that "figure 4" above had a row on drugs/active ingredients that actually raises DAO. Vitamin C perhaps?

    /Ling

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    1. Ling, there is lipid/fat induced secretion of DAO in your intestines. This apparently involves H4 histamine receptors. It does depend which type of fat you have eaten

      Lymphatic diamine oxidase secretion stimulated by fat absorption is linked with histamine release.
      https://www.ncbi.nlm.nih.gov/pubmed/23413254

      For entirely different reasons, some people currently treat their histamine intolerance by consuming large amounts (half a cup a day) of olive oil (unheated, so not used in cooking).

      Olive oil has so many other benefits, it is certainly work a try for people worried about DAO and mast cells

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  3. Ling, B6 does as well. I assume my son has (or had) DAO problems - after about 4 months on Verapamil he broke out in hives after eating a corn tortilla. His hives reactions in the past only came after intense stress that trigger emotional reaction, never from food.

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  4. Hi Peter, is it possible, fever after several days use of NAC is caused by its DAO inhibitor properties?

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    1. Abdul, all kinds of unusual things are possible, but quite likely this was just a coincidence. I would wait a few weeks and then try again and see what happens.

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  5. Hi everyone,

    Check out this interesting article, and the relevant paper:

    https://medicalxpress.com/news/2018-03-gene-responsible-neurodevelopmental-disorders-autism.html

    http://www.nature.com/articles/s41380-018-0025-5

    Definitely worth a read, and the researchers are from McMaster University very close to where I am.

    AJ

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  6. Hello Peter,

    Thank you so much for this post.. I have a question. Would it be wise to use an antibiotic itself for getting the desired effects....what would be the safe frequency if any, can we use a lower dose than the one used for treating infections. I know it is not really a perfect solution but then who is insane enough to look for one.

    DAO might help with histamine induced hyperactivity disorders? I am certain my son has histamine issues...histamine intolerance I am not sure. Will the sodium potassium bicarb combination, touted as a natural antihistamine help there as well? I should try this out. Too many questions. But I know one thing...if I ever see things getting out of hand, I am going for the antibiotic therapy, infection or not. And I will try my best to get diagnostic tests done to rule out or in possible maladies.

    I dont care whats right or wrong, but I will try to understand
    Let the devil ( or whoever) take away our sorrows, for tonight Ill learn and attend.



    My regards

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    1. Kritika, the problem with antibiotics is the more they are used the less well they will work, so called antibiotic resistance.

      It did occur to me that using an old antibiotic, that no longer works well due to antiobiotic resistance, might not be such a bad idea, if it is the non-antibiotic effects that you are after.

      It would be interesting to know what % of people with autism who improve on beta-lactams improve on Riluzole. Maybe one day somebody will research this. Then you would have more idea of what to do.

      It might even be just a tiny dose of Riluzole to give the same GLT-1 as a beta lactam. Beta lactams do help in ALS (the approved use of Riluzole). It just a question of relative potency.

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    2. Peter,

      In fact I would love to trial riluzole. I did enquire from our local chemists but they did not seem to have it. Getting a prescription will not be easy at all. Well..I will try harder to get it without one and run a trial.



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  7. Tanya, is amazing what you told me about your son.Achieving stability is what we all want after trying and trying,be it with our detective work as said Peter or as in your case, what is proven, or call it the traditional way, is giving your son that stability. You were in a difficult situation.It is not an easy desition,all things considered.In my son´s case, he started with tardive diskynesias and I decided to stop the traditional way.It was my desition because the neurologist wanted to double the dose.But I don´t know what would have done if he was in good mood, with hand writing improvements and without side effects. It is great that the art side has aweakened in him,it can go far if you support it, this kids are like pandora´s box. In the case of my son, music is what he loves, he listen to all kind of music and knows the biographies of many of the great musicians of the 80s and 90s to F.Sinatra and E.Presley.Sings very well, he has an excellent ear. Valentina

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    1. Valentina, your son sounds like one cool kid! My son loves music too..
      Yes it is nice the traditional way is helping him so much without the negative side effects. He is on low doses though. And maybe the omega oils help in some way to off set side effects? I did read giving high doses of omegas when using lithium reduces any negative effect. I also read adding vit E helps too. I think what is helping him the most is the lithium. I am amazed by it. I read about using low dose aspirin with it - did you ever try it when your son was taking valproate ?
      https://www.ncbi.nlm.nih.gov/m/pubmed/24786695/?i=3&from=/19939659/related

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    2. I hope to transition to lithium orotate when it is time to wean.

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    3. Tanya, I gave him sodium valproate with lithium orotate for a few years.The match worked really very well,with a sinergestic effect.If I could add lithium orotate to bumetanide, I wouldn´t hesitate. It is the kind of supplement that I´m missing and can´t find nothing similar. Valentina

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    4. Lithium Orotate upregulates tyrosine hydroxylase which will increase dopamine synthesis. Just something to consider with regards to dosage.

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    5. Tyler, I am still trying to figure all of this out - as best I can - it is complicated and from what I’ve read it is still not fully understood exactly how lithium works for bipolar. I have read many people with bipolar I successfully use lithium to manage things.. Are you aware of this?

      “New hypothesis
      The findings suggest that lithium treatment silences activity in neurons that rely on BPNT1, which Meisel and Kim found intriguing because many human brain cells also depend on this protein. In humans, PAP, which BPNT1 degrades, is usually found in neurons that secrete dopamine, epinephrine, or norepinephrine, which are all neurotransmitters that stimulate brain activity.
      “We think that it’s perfectly reasonable to add BPNT1 onto the list of hypotheses for how lithium is affecting the brain,” Meisel says. “Silencing dopaminergic neurons I would think would make you less manic because of how dopamine affects the brain.”
      http://news.mit.edu/2016/new-clue-how-lithium-works-brain-bipolar-0707

      Valentina, oh I didn’t know your son was on lithium carbonate with valproate! My nephew with bipolar was never on lithium. He is 25 now and off medication and doing well (knock on wood).
      I think I am going to try the low dose enteric Coates aspirin and maybe boost his omega3 more - maybe add more DHA and see what happens. I am trying to get a plan together for May, when he comes off the medication.
      And, naturally, Peter had a post on low dose aspirin and the arachidonic cascade! He’s a dynamo https://epiphanyasd.blogspot.com/2016/10/regulation-of-arachidonic-acid-aa.html?m=1

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    6. Tyler, I think lithium boosting the expression of tyrosine hydroxylase was a study for those with Parkinson’s - so lithium acts more like a modulator. It can boost if dopamine levels are too low as with Parkinson’s - but doesn’t act in a one directional way only.

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    7. Tanya, I think that just with the Omega 3,you can regulate or reduce the AA.The best would be to increase the dose.
      My son didn´t take lithium carbonate,only orotate. Valentina

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    8. Oh that’s right Valentina! Thank you . Would be overkill to add low dose aspirin. I will just increase the omegas. he also eats plenty of olive oil. He even craves it on his blueberries! And he is a very healthy eater - naturally wants the Mediterranean diet foods - so that is helping him too. I did read that chicken and eggs are very high in AA and I have noticed with eggs especially he doesn’t do well but I thought that could be a histamine issue. Maybe it was too much AA all along?

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    9. Tanya, this recent study might be of interest:-

      Treatment of bipolar depression with minocycline and/or aspirin: an adaptive, 2×2 double-blind, randomized, placebo-controlled, phase IIA clinical trial
      https://www.nature.com/articles/s41398-017-0073-7

      I would be interested to know if anyone has tried low dose aspirin in autism and in particular in autism with aspects of bipolar.

      It would be nice to know the relative benefit/potency of things like olive oil and low dose aspirin. Clearly food is preferable, but how much olive oil = 75 mg aspirin ?

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    10. Thanks so much Peter - very intriguing! And good to know checking iL6 levels is an indicator as to whether he would respond. I will ask his doctor about this as a future treatment plan and to check iL6 with his next blood test.
      I would love to hear from others too. I do know that the mast cell doc, Dr Afrin, has a place for low dose aspirin therapy in his treatment plan.

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    11. I have trouble understanding the back and forth here. Apparently there is discussion on lithium orothate and bumetanide. Is there reason not to take the two together? We are looking to add nutritional lithium doses (mcg doses), and bumetanide works really nicely for us.

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  8. Hi Ling,

    Hope all is well with you.

    Ling, I was going through some papers and saw this one which you may find of interest:

    http://www.nature.com/articles/s41598-018-22148-5

    They found that phospholipid concentrates of Krill Oil and Buttermilk upregulated the expression of several genes including SATB2.

    "Three genes – Capn7, Tshz3 and Satb2 – coding for proteins involved in neurological processes were confirmed to have increased expression in the BMFC + KOC supplemented group compared to control."

    Interestingly enough, there were also a lot of miRNA levels in the hippocampus as well as a reduction of ceramide levels.

    I don't know if this is helpful, but I thought I would share given your interest in SATB2. I hope it is helpful Ling!

    AJ

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    1. Thank you very, very much AJ!
      I will definitely check this up, especially since I haven't seen it before and there really isn't that much written on SATB2.
      Sharing is caring!
      :)

      /Ling

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    2. Hi Ling,

      It's my pleasure :) We're all in this together.

      As soon as I saw SATB2 in the paper, my first thought was to share it with you just in case there was a helpful nugget of info there.

      I'm now waiting for my genetic test results, will be another 4 weeks. I don't know if it will turn up anything, but if it does, I will become an expert on that gene(s) like I'm sure you're an expert on SATB2
      now.

      With all the improvements being made daily in CRISPR and related gene-editing tech, who knows how long it will be until we can get access to a gene-editing treatment to help treat our kids.

      Check out this article I recently read about how far China has gone in using CRISPR in real patients:

      https://gizmodo.com/china-has-already-gene-edited-86-people-with-crispr-1822297524

      It's not for ASD yet, but at the speed they are going forward with CRISPR trials in China, I wonder how long it will be until they trial, and succeed, with gene editing in the CNS. Once it is shown that gene-editing can be done successfully in the CNS, things should get very interesting.

      Have a great day Ling and I'll keep an eye out for any SATB2 papers I can find!

      AJ


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    3. I don't know yet if your finding can be translated from aged rats to human toddlers, but AJ, you truly found a gem.
      I really couldn't have asked for more than a paper showing how food-grade compounds can up the expression of the very (insufficient) gene causing my daughters condition.

      Thank you, again.

      ------
      As a side-note, this was the first paper I've ever seen on a milk product being beneficial for (some) autisms. The Tshz3 gene is also an autism gene.

      Reading up on buttermilk, MFGM (milk fat globule membrane), sphingolipids and more, I must say I get both impressed and intrigued.
      Having properties like anti-cancer, anti-cholesterol, anti-virus, anti-hypertension, modulator of PKC, procognitive, pro dopaminergic and glutamatergic transmission, pro-myelin I think it deserves at least some attention.
      Oddly enough, this is not a highly sought-after nootropic to buy expensively. Rather a byproduct from dairy industry that doesn't even exist as a consumer product in some countries. And yet, it (MFGM) is added to infant formulas for its immune- and cognition boosting properties.

      This is strange!

      /Ling

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    4. Ling, it looks like Denmark/Sweden is the centre for MFGM research and production.

      https://www.arlafoodsingredients.com/our-ingredients/pediatric-ingredients/phodpholipids-mfgm/

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    5. Hi Ling,

      My pleasure, I really hope this will help!

      I'll be so happy if this turns out to make a difference for your daughter.

      And Peter found a great source in Arla Foods. I wonder if they would be willing to send you the relevant items as an individual ... otherwise, if they don't sell to individuals directly, you could always start a (very) small baby food company, and have them ship small orders of product to your small business to allow you to test market the product ;)

      Again, I'm really happy this may be helpful.

      All the best Ling,

      AJ

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    6. Who knew I would be hunting the local milkman for autism treatments? Autism world is absurd! :-))

      /Ling

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    7. LOL Ling, our adventures as ASD parents reminds me of the Seinfeld episode where George is waiting for the baldness cure from China ... I've got shipments coming in from literally all over the world and my mailman and FedEx guy must be suspicious about what I'm up to.

      Oh, the things we do for our kids :-)

      AJ

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    8. Ling, since they already give MFGM to babies and it seems to have numerous health benefits (lowers cholesterol etc) giving/making traditional buttermilk looks like a very smart thing to do.

      I also thought that since the Karolinska Institute are already teamed up with Arla and they also do good autism research, they might well be interested to hear from you. Your daughter has a very specific, well-defined condition, that really should spark an interest from their side. They can measure if SATB2 expression really is increased when a person with SATB2 takes MFGM.

      Delete
    9. Looking more closely into these two compounds, I can see that Krill Oil has a certain amount of Astaxanthin in it.
      This is a betacarotene/antioxidant and a red pigment in salmons and crustaceans that also happens to be a p38 MAPK inhibitor.
      Now, from another paper (on cancer, so maybe it can't be translated to normal conditions) we learn that:
      "Inhibition of p38 leads to increased Akt activation and upregulation of SATB2 expression"
      http://journals.sagepub.com/doi/full/10.1177/1010428317706212

      Astaxanthin looks like one compound that is researched for its memory/cognition boosting properties:
      https://www.ncbi.nlm.nih.gov/pubmed/26643409
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352583/
      https://www.sciencedirect.com/science/article/abs/pii/S036192301730014X

      Also, there is phosphatidylcholine, phosphatidylserine and sphingomyelin in Krill Oil + MFGM, and these are all known as choline contributors which often are found in memory stacks.

      /Ling

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    10. Hi Ling,

      Hope all is well!

      Ling, I've had my daughter on Astaxanthin for many months due to it's ability to inhibit NKCC1:

      https://www.ncbi.nlm.nih.gov/pubmed/28490320

      As I couldn't get Bumetanide, I looked for a natural way to inhibit NKCC1, and the best way I could find was Astaxanthin.

      Also Ling, if inhibiting p38 results in upregulation of SATB2, would Panax Ginseng help?

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745843/

      I've also got my daughter on this supplement, no negatives, but I don't know what her genetic issue(s) is yet. As soon as I do, which is hopefully a couple of weeks away, I'll be able to do some serious research on it.

      I started Panax Ginseng about a year ago due to the following paper (and a few others):

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737717/

      I can't say specifically if this is why she continues to improve, but again, I've had no issues with this, so if you're looking to target p38, maybe this is an option?

      I hope this helps Ling!

      AJ

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    11. Hi AJ, and thank you for those interesting links!
      I hope your waiting for DNA results is over soon.

      A quick question: How do you supplement the astaxanthin? The Krill oil arrived here yesterday and let’s say that the taste of the opened capsules wasn’t approved of anyone in the household... Maybe a dry powder would be easier to administrate along the better tasting fish oil we use occasionally.

      /Ling

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    12. The Astaxanthin trail might have been a mistake (or not) because I have found other sources where p38 inhibition actually downregulates SATB2, but there also are differences in which tissue we are talking about and whether it was measured in vitro or in vivo.
      Since there also are discussions on DHA eventually blocking properties of EPA I think it is best separate some of the Krill Oil compounds (phospholipids/astaxanthin/EPA/DHA).
      Phospholipids will be my next main focus, but they work synergistically with the DHA/EPA so maybe I’ll add in vegEPA later.

      /Ling

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    13. I must say that the koreans are very much for panax ginseng for kids:
      http://globalkgc.com/shop/3/krg-kids-tonic-step1-age34/

      /Ling

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    14. And for the MFGM trail:
      According to Arla in Denmark, there is a baby formula called BabySemp 1 that contains 5 g Lacprodan MFGM-10 per 100 g. I think that this equals around 325 mg phospholipids, according to some patent I found.

      /Ling

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    15. This easy-to-read presentation by people at Arla (the danish milk company) mentions a lot of research results regarding MFGM:
      https://mejeritekniskselskab.dk/sites/default/files/dms/Dokumenter/esben_skipper_og_anne_staudt_maelk_til_hjernen.pdf
      The focus is of course on infants, but they also mention research on elderly and the effect on BBB permeability:
      "In the MFF project brain milk we have shown that endogenous milk peptides are able to reduce ERK
      phosphorylation and to increase the integrity
      of the blood-brain barrier"

      /Ling

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    16. And for anyone interested, here is the phospholipid content of Lacprodan MFGM-10 as per a reply from Arla:
      ----------------------------
      Sphingomyelin 1.6%
      Phospatidylethanolamine 1.9%
      Phosphatidylcholine 1.8%
      Phosphatidylinositol 0.8%
      Phosphatidylserine 0.5%
      ----------------------------

      So, I am doing a trial with the above + some extra citicolin (phosphatidylcholine) + some extra phosphatidylserine (+ EPA for synergy). This should definitely raise choline and perhaps also acetylcholine and SATB2 expression.

      Now, digging deeper into research, I see that there might be a problem in m daughter with low choline acetyltransferase, the enzyme responsible for the synthesis of the neurotransmitter acetylcholine from choline. If this is the case, my current intervention might not work at all, or very poorly. I guess the next step then would be to look at acetylcholinesterase inhibitors, that inhibit breakdown of acetylcholine.
      I think you wrote about this in 2013 or so, Peter, mentioning Donepezil and Galantamine. Also, Huperzine A looks quite popular. My main concern is the safety profiles and long-term effectiveness. Only Donepezil has been used in kids as young as 2 years, and only for 12 weeks.

      Anyone who'd like to share some experience or insights?

      /Ling

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    17. We trialled phosphatidylserine for a while, and my daughter had her first ever nightmare. Woke up screaming in the middle of the night and frantically signed "hat!" "hat!" As I finally got her the hat she went to sleep very promptly.

      Nightmares and vivid dreams are a common side effect both of choline precursors but also of acetylcholinesterase inhibitors like Donezepil.
      So I guess the phosphatidylserine/citicolin I supplemented eventually got converted to some extra (too much?) acetylcholine which also would mean that there was no problem with the conversion from choline.
      I did not se any spectacular results besides the nightmare-thing, so I am heading forward with other trials for a while. I'll keep the baby formula though for a while until my EPA runs out, because I think it is a great way to enhance uptake + it's got some nice nutrients.

      Also, I found this article (phytoceramides are down the sphingolipid pathway):
      "Administration of Phytoceramide Enhances Memory and Upregulates the Expression of pCREB and BDNF in Hippocampus of Mice"
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3830122/

      /Ling

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    18. I just found a new article on PubMed from the authors of that first krill oil+buttermilk paper. This time they have put rats through different psychological tests:

      "Buttermilk and Krill Oil Phospholipids Improve Hippocampal Insulin Resistance and Synaptic Signaling in Aged Rats."
      https://www.ncbi.nlm.nih.gov/pubmed/29397560

      I hope there are someting interesting in it, but haven't had the time to read it all yet.

      /Ling

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    19. I just found out that Astaxanthin (found in krill oil) can convert to retinol in retinol-deficient rodents.
      https://www.ncbi.nlm.nih.gov/pubmed/20962897

      So, Astaxanthin possibly targets retinoic acid signalling pathways, at least in some parts of the body. Probably in the skin and eyes judging by its use as a supplement, but maybe also in the brain as there is some research on it for cognitive effects. If the latter holds true it would be interesting to see if it has any impact on language skills or not, since the FOXP2 "language" gene is very much connected to the retinoic acid pathways.

      /Ling

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    20. Ling one more possible link that I have found between autism/asd (myself included) that links metabolism with brain function and social stuff aswell.

      This seems to be mediated by the following pathway

      adiponectin ->leptin/ghrelin->neuropeptide y/pomc neurons in arcuate->kisspeptin/oxytocin regulation (through modulation of 5ht2c, 5ht1b and neuropeptide y1 receptor).

      vitamin d3, taurine, inositol and astaxanthin all powerfully modulate adiponectin/leptin.

      Dehydration for example (and wouldnt be surprised if bumetanide also affects neuropeptide and 5ht2c to some extend)

      I really do hope sigma-1 manipulation is my personal way out, all my research Ive done shows that im on the right path:

      Modulation of [3H]Dopamine Release from Rat Nucleus Accumbens by Neuropeptide Y May Involve a Sigma 1-like Receptor
      http://jpet.aspetjournals.org/content/284/2/553

      Kisspeptin: a new peptidergic system regulating oxytocin neurons and their reproductive plasticity in the hypothalamo‐neurohypophysial system
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5285614/

      Something for Peter:

      Kisspeptin increases gamma-aminobutyric acidergic and glutamatergic transmission directly to gonadotropin-releasing hormone neurons in an estradiol-dependent manner
      https://www.ncbi.nlm.nih.gov/pubmed/19880809

      Estrogen Modulation of Neuropeptide Y Receptor Signaling in Magnocellular Oxytocin Neurons of the Hypothalamus
      https://www.fasebj.org/doi/abs/10.1096/fasebj.24.1_supplement.627.7

      "Overall, the results of these studies indicate that estrogen increases the expression of NPY Y1 receptors in the hypothalamus which is correlated with increased oxytocin secretion. The in vitro studies demonstrate that stimulation of ERβ increases the expression of NPY Y1 receptor immunoreactivity."

      Influence of dehydration on the expression of neuropeptide Y Y1 receptors in hypothalamic magnocellular neurons.
      https://www.ncbi.nlm.nih.gov/pubmed/16728491

      "These data demonstrate that NPY Y1R gene and protein expression are increased in the SON of salt-loaded and water-deprived animals and provide a mechanism whereby NPY can support VP/OT release during prolonged challenges to fluid homeostasis."

      Fluvoxamine Attenuated Endoplasmic Reticulum Stress-Induced Leptin Resistance
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355886/

      "Treatment with tunicamycin, an ER stress-inducing reagent, caused cell death which was significantly inhibited by fluvoxamine. Leptin activates JAK2–STAT3 signaling. ER stress caused an impairment of leptin-induced STAT3 phosphorylation which was reversed by fluvoxamine. Fluvoxamine would be a novel leptin-sensitizing drug, which targets ER stress."

      ----->> "Knocking down sigma-1 receptor attenuated leptin’s signal" <<------

      So sigma-1 receptors can regulate leptin signalling and downstream express normal levels of NPY in the brain.

      This could also explain the link between insufficient adiponectin (often in autism), out of whack leptin/ghrelin balance (often in autism), leptin resistance (often in autism and obesity).

      Delete
  9. Have you seen Roche's new drug balovaptan? Thoughts on that?

    ReplyDelete
    Replies
    1. There are some earlier comments on this subject.

      Balovaptan is a an antagonist of one vasopressin receptor. This is odd because vasopressin itself (ie an AGONIST) has been found beneficial in some autism. Maybe balovaptan will work, hopefully it does.

      Oxytocin is very similar to vasopressin, and oxytocin trials do not show a major impact. Oxytocin release via gut bacteria is a nice idea and does work, but it is just a small benefit.

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  10. Hi,

    My son was diagnosed at 3 and we strongly feel that he got it after HFMD at 2 years age. We recently visited Dr. T to check for PANS/PANDAS. He was given a steroid burst for 5 days and there was good improvement observed with no negatives. Then he was put on antibiotics (Augmentin in the morning and Azithromycin in the night) for 10 days. We observed some positives (increased verbal, increased imagination and much more connected - started playing with his sister) and negatives (aggressive, kicking, biting, non-compliant when asked to do things he did not want to). Do you think the negatives are because of DAO inhibition?

    ReplyDelete
    Replies
    1. That is possible, but if it was the case a blood test for DAO would show that your son has histamine intolerance. So this is a good test to do.

      I think it might have been better to first use Augmentin and then afterwards use Azithromycin. Then you would know what drug produced which effects.

      Steroids do seem to benefit many people with autism, but you can only use them for a few days without side effects.

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    2. Thanks Peter. It looks like there is no DAO deficiency test in US.

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    3. The test must exist in the US, you have tests for things nobody else tests.

      Maybe ask by its full name.

      Serum diamine oxidase (DAO) activity as a diagnostic test for histamine intolerance

      Delete
  11. I forgot to add that he also developed a new tic of closing and opening fingers in front of his eyes. The tic has not gone away even after more than 6 weeks.

    ReplyDelete
    Replies
    1. Once a tic or stim develops it is always hard to get rid of.

      Delete
    2. Most of the negatives went away or became milder. Thought the tic also would go away.

      Delete

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