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Showing posts with label Histamine. Show all posts
Showing posts with label Histamine. Show all posts

Thursday, 19 April 2018

Modulation of IP3 receptors in Autism – Pancreatitis and Caffeine?



This post stems from our Greek reader Petra's original observations about the combined effects of coffee and bumetanide.

In earlier posts we learned that one likely nexus in autism is the IP3 receptor that releases calcium from a store within each cell.

It turns out that too little/too much activity from IP3 receptors is a feature of a wide range of disease, some of which you may not have heard of, including:-

·      Gillespie syndrome, a genetic condition leading to MR/ID, ataxia and notably part of the iris to be missing

·      Spinocerebellar ataxias, genetic conditions that cause loss of movement control

·      Glioblastoma, an aggressive and “untreatable” brain cancer

·      Alzheimer’s disease

·      Huntington’s disease

·      Pancreatitis, inflammation of the pancreas where your body makes its digestive enzymes and insulin 

For detail, refer to this Japanese paper:- 


Of the three types of IP3Rs, the type 1 receptor (IP3R1) is dominantly expressed in the brain and is important for brain function. Recent emerging evidence suggests that abnormal Ca2+ signals from the IP3R1 are closely associated with human brain pathology. In this review, we focus on the recent advances in our knowledge of the regulation of IP3R1 and its functional implication in human brain diseases, as revealed by IP3R mutation studies and analysis of human disease‐associated genes. 

I suspect that both hyper and hypo-active IP3 receptors will be found in different types of autism. I assume the variant I deal with in my son is more likely to be hyperactive. The research by Gargus suggested “dysregulated IP3R” in autism in 3 single gene autisms; he found depressed Ca2+ release through inositol trisphosphate receptors (IP3Rs) in patient-derived fibroblasts.


Your body contains a lot of calcium, but almost all of it is in your bones, as calcium phosphate.  Only the residual amount (about 1%) of calcium is present in solution as the ion Ca2+. Ca2+ plays an important role in many physiological functions.  An excessive elevation of Ca2+ inside cells will kill them. Cells must maintain the intracellular Ca2+ concentration at the low level of ~10−7 mol/L, against the much higher extracellular Ca2+ concentration (~10−3 mol/L).

Cells must be able to rapidly and dynamically change the intracellular Ca2+ concentration in response to extracellular stimuli to regulate physiological functions such as cell proliferation, fertilization, immune response, and brain functioning.
To dynamically change the intracellular Ca2+ level, cells use two sources of Ca2+:
·      Ca2+ influx from outside (the extracellular space)
·      Ca2+ release from inside (the intracellular Ca2+ store, the endoplasmic reticulum – ER)
Many Ca2+ handling molecules (Ca2+ ion channels, Ca2+ pumps, Ca2+ sequester proteins) work to maintain the correct balance. The IP3 receptor is a key protein in the regulation of the intracellular Ca2+ dynamics, because it  controls the release of intracelluar Ca2+.
If IP3R is left open, Ca2+ levels inside cells become too high; if it is left shut Ca2+ becomes too low.
No medical therapy currently exists to inhibit/block IP3 receptors, but today’s post considers one potential therapy – caffeine. 

Caffeine
Caffeine is a drug, although it is not regulated as one.  At high doses caffeine is toxic, but at non-toxic doses caffeine does have some potent medical effects and it does protect against certain diseases.
It protects against pancreatitis, for example.
It would be very hard to drink yourself to death with coffee. Just like eating numerous bananas does not cause death by having too much potassium in your blood. Supplements have more risks than food. 

Pancreatitis IP3R and Caffeine 


Significance of this study
What is already known on this subject?
·       Acute pancreatitis is a major health problem without specific drug therapy.
·       Coffee consumption reduces the incidence of acute alcoholic pancreatitis.
·       Caffeine blocks physiological intracellular Ca2+ oscillations by inhibition of inositol 1,4,5-trisphosphate receptor-(IP3R)-mediated signalling.
·       Sustained cytosolic Ca2+ overload from abnormal Ca2+ signalling is implicated as a critical trigger in the pathogenesis of acute pancreatitis.
What are the new findings?
·       Caffeine and its dimethylxanthine metabolites inhibit IP3R-mediated, sustained cytosolic Ca2+ elevations, loss of mitochondrial membrane potential and necrotic cell death pathway activation in pancreatic acinar cells.
·       Neither specific phosphodiesterase inhibitors nor cyclic adenosine monophosphate and cyclic guanosine monophosphate inhibit sustained Ca2+ elevations in pancreatic acinar cells.
·       Serum levels of xanthines after 25 mg/kg caffeine administration are sufficient to inhibit IP3R-mediated Ca2+ overload in experimental acute pancreatitis.
·       Caffeine but not theophylline or paraxanthine administered at 25 mg/kg significantly ameliorated pancreatic injury in experimental acute pancreatitis through IP3R-mediated signalling inhibition.
How might it impact on clinical practice in the foreseeable future?
·       These findings support an approach of inhibition of Ca2+ overload and of its consequences as novel potential therapy for acute pancreatitis.
·       Methylxanthine-based structures are suitable starting points for drug discovery and development to treat acute pancreatitis. 

The Pancreas and Autism
The biomarker proposed by Joan Fallon/Curemark for her autism treatment (CM-AT) is low fecal chymotrypsin level. Chymotrypsin is a digestive enzyme produced in the pancreas and it can be used as a test for early cystic fibrosis. In adults low chymotrypsin indicates a pancreatic disease like pancreatitis.
Many people with autism have GI problems, but there are several distinct sub-groups. Some people have inflammatory bowel disease (IBD) potentially leading to ulcerative colitis, but most do not. Some people with autism have GI dysfunctions that remain undiagnosed, for some it is as if they do not digest food the same way as other people.
If IP3R hyperactivity is a feature of some autism and IP3R hyperactivity is inherent in pancreatitis, is it a surprise that some people with autism do not seem to digest their food properly? Or is it just a coincidence?

Brain Cancer
We did come across glioblastoma in a previous post that looked at off-label therapies for some cancers. In that post we came across an academic from San Diego, who decided to read the research and try and reverse his incurable aggressive brain cancer. This involved driving across the border to Mexico to freely acquire the prescription drugs he used to treat himself.  Two decades later he is still very much alive. 


According to the study below, a hot cup of strong Greek coffee might be a good choice to maintain Professor Williams in good health.


IP3Rs are known to be difficult to study especially due to the lack of suitable inhibitors and subtype specific blockers. We found that caffeine paradoxically inhibited IP3R-mediated Ca2+ responses in a subtype 3 specific manner (Figure 5). Using caffeine as a tool to inhibit IP3R3-mediate Ca2+ release, we have demonstrated that inhibiting IP3R3 effectively reduced the migration, invasion, and survival of glioblastoma cells (Figure 2). The gene silencing of IP3R3 by shRNA also effectively reduced the caffeine sensitivity of Ca2+ signaling and invasiveness in the Matrigel invasion assay (Figure 5). Our results are the first to demonstrate the involvement of IP3R3 in glioblastoma Ca2+ signaling and invasion. Furthermore, we suggest that IP3R3 can be specifically targeted for therapeutic intervention in glioblastoma patients with minimal influence on normal glial as well as neuronal functions.
Whether caffeine can directly affect the gating of IP3R3 channels or not is still unknown. However, according to previous studies demonstrating that caffeine can compete with ATP binding to IP3Rs (21) at millimolar concentrations (20), caffeine could selectively bind to IP3R3 and affect the gating of IP3R3. Further work is required to investigate the direct role of caffeine on IP3R3 gating in comparison to other subtypes of IP3R.
In summary our study provides IP3R3 as a novel therapeutic target for glioblastoma treatment. Our study also provides new insights into the detailed molecular mechanism of caffeine action on migration and invasion of glioblastoma. The apparent beneficial effect of caffeine suggested by our study should trigger future investigations of the therapeutic potential for caffeine to treat this deadly disease that otherwise has no cure. 

Conclusion
Caffeine is the most obvious modulator of IP3R in your kitchen or at the local pharmacy.
cAMP plays a complex role in IP3R, PKA is involved so PDE4 should be. Parathyroid hormone (PTH) is also important. PTH is secreted to tell your bones to release Ca2+ into the bloodstream, but it has multiple roles. PTH causes the release of IP3 and DAG and hence release of calcium from the store within cells (the ER). PTH release is stimulated when Ca2+ is low but also by other things, such as notably by histamine. PTH also is reported to increase the sensitivity of IP3R receptors, so too much PTH would clearly be a bad idea.
Primary Hyperparathyroidism (PHPT) is characterized by hypercalcaemia and elevation of parathyroid hormone.  Children with PHPT may present with non-specific complaints such as behavioural change and deteriorating school performance.  As we know, behavioural change in the form of aggression sometimes occurs in autism, ADHD and various other mood disorders. It may also present as a psychiatric manifestation of an endocrine disorder such as Primary Hyperparathyroidism (PHPT).
It is not surprising that histamine can cause aggression in the same way that Primary Hyperparathyroidism does. Aggression in all psychiatric disorders very likely has a biological cause, you just have to look for it. 

How about checking kids with aggression/SIB for PHPT, or just high levels of calcium (hypercalcaemia). Or perhaps:-
Going Loco? Think histamine, calcium and hyper-parathyroidism, before taking antipsychotics.

Back to caffeine.
In people with hyperactive IP3 receptors, such as those who damaged their pancreas by drinking too much alcohol, caffeine looks a smart therapy. The same would apply to people with autism and hyperactive IP3 receptors. So for those people, drink coffee, preferably Greek coffee (or Turkish coffee, which is the same thing). Some Latin American countries also make potent coffee drinks. Your cup of instant coffee, or chain store coffee is not going to do much.
There are numerous interesting substances in less processed coffee, not just caffeine. The key is to process it as little as possible, as we saw cocoa. In instant coffee only the caffeine is going to have much effect.
Chlorogenic acid, an OAT3 inhibitor, that should enhance bumetanide, is there in coffee.
Coffee contains small amounts of Caffeic acid. What we would really like is Caffeic Acid Phenethyl Ester (CAPE), which is a substance found in some bee propolis. CAPE acts as a PAK1 inhibitor, among other potentially beneficial effects.
Catechin, epicatechin, and surprisingly vanillin are present in coffee.
Roasting coffee makes big changes to its chemical composition and of course to its taste. Green coffee bean extract, used as a supplement for weight loss, is a rich source of chlorogenic acid.
Perhaps someone should do a study on adults with autism using 2 cups of Greek coffee a day.  Alternatively you could just use caffeine pills, with or without coffee bean extract for those interesting flavanols.





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.







Tuesday, 16 January 2018

How much Histidine? Dermatitis and FLG mutations


Today’s post is not about autism, it is about allergy and atopic dermatitis in particular.
Many people are affected by atopic dermatitis (AD), also known as eczema; it is particularly common in those with autism. Children who develop asthma have often first developed atopic dermatitis (AD).
Atopic Dermatitis is another of those auto-immune conditions and the sooner you stabilize such conditions the better the prognosis.




Skin therapies from a company
spun-off from Manchester University


Histidine
A while back on this blog I was looking at the various amino acids and came across the observation that histidine, a precursor of histamine, appears to be a mast cell stabilizer. Mast cells are the ones that release histamine and IL-6 into your blood. Histamine then does on the trigger yet more IL-6 to be produced.  IL-6 is a particularly troublesome pro-inflammatory cytokine.
At first sight giving a precursor of histamine to people who want less histamine seems a crazy thing to do, but plenty of people report their allergies improving after taking histidine. As we have discovered, feedback loops are very important in human biology and these can be used sometimes to trick the body into doing what you want it to do. Having a higher level of histidine in your blood might make histamine production easier but it might also be telling the body not to bother, or just to delay mast cells from degranulating.  Whatever the mechanism, it does seem to work for many people. 

How Much Histidine?
Most histidine pills are 0.5g and it appears people use about 1g to minimize their allergy. 1g is the dose Monty, aged 14 with ASD, has been using during the pollen allergy season.
My sister recently highlighted a new "high tech" OTC product for skin conditions, Curapella/Pellamex, its main ingredient is histidine and it is a lot of histidine, 4g.




The company that produces the supplement have teamed up with the Universities of Edinburgh and Manchester to make a clinical trial, which is featured below.
They are considering the interaction between histidine and filaggrine (produced by the FLG gene). 

Mutations in the FLG gene are associated with atopic dermatitis and indeed with asthma, hay fever, food allergies, and, rather bizarrely, skin sensitivity to nickel.
In effect it is suggested that histidine makes filaggrine work better and thus atopic dermatitis and some other skin conditions will improve.  



Atopic dermatitis (AD), also known as eczema, is one of the most common chronic skin conditions worldwide, affecting up to 16% of children and 10% of adults. It is incurable and has significant psychosocial and economic impacts on the affected individuals. AD etiology has been linked to deficiencies in the skin barrier protein, filaggrin. In mammalian skin, l-histidine is rapidly incorporated into filaggrin. Subsequent filaggrin proteolysis releases l-histidine as an important natural moisturizing factor (NMF). In vitro studies were conducted to investigate the influence of l-histidine on filaggrin processing and barrier function in human skin-equivalent models. Our further aim was to examine the effects of daily oral l-histidine supplementation on disease severity in adult AD patients. We conducted a randomized, double-blind, placebo-controlled, crossover, nutritional supplementation pilot study to explore the effects of oral l-histidine in adult AD patients (n=24). In vitro studies demonstrated that l-histidine significantly increased both filaggrin formation and skin barrier function (P<0 .01="" respectively="" span="" style="background: yellow; margin: 0px;">Data from the clinical study indicated that once daily oral l-histidine significantly reduced (P<0 .003="" 34="" 39="" 4="" ad="" after="" and="" assessment="" by="" disease="" eczema="" measure="" of="" oriented="" patient="" physician="" scoringad="" self-assessment="" severity="" span="" the="" tool="" treatment="" using="" weeks="">. No improvement was noted with the placebo (P>0.32). The clinical effect of oral l-histidine in AD was similar to that of mid-potency topical corticosteroids and combined with its safety profile suggests that it may be a safe, nonsteroidal approach suitable for long-term use in skin conditions that are associated with filaggrin deficits such as AD. 
In this paper, we suggest that a simpler, nutritional supplementation of l-histidine may have a beneficial potential in AD.

l-histidine is a proteinogenic amino acid that is not synthesized by mammals. In human infants, it is considered “essential” due to low levels of histidine-synthesizing gut microflora and minimal carnosinase activity, which helps in releasing free l-histidine from carnosine.24 Our interest in the use of l-histidine in AD was stimulated by several observations. Firstly, in both infants and adults, a histidine-deficient diet results in an eczematous rash.25 In rodents, 3H-histidine is rapidly (1–2 hours) incorporated into profilaggrin within keratohyalin granules after intraperitoneal or intradermal injection14,26 and within 1–7 days is released as a free NMF amino acid in the upper stratum corneum.14 Furthermore, reduced stratum corneum levels of free NMF amino acids, including histidine and its acidifying metabolite urocanic acid (UCA), are associated with AD disease severity and FLG genotype.27,28

Given this evidence for the dependence of filaggrin processing and NMF formation on suitable levels of l-histidine, we hypothesized that l-histidine would both enhance filaggrin processing in an in vitro, organotypic, human skin model and have beneficial effects as a nutritional supplement in subjects with atopic dermatitis. 

After a 2-week wash-out period in which subjects were asked not to use any medicinal product for their AD, the same measures were repeated and patients were provided with identical sachets containing either 4 g l-histidine (Group A) or 4 g placebo (erythritol); Group B) which was taken once a day, dissolved in a morning fruit drink.  





Conclusion

It looks like 4g of histidine has the same potency as mild topical steroid creams, when treating atopic dermatitis.
The big problem with topical steroids is that you can only use them for a week or two. It you use them for longer, you end up with a bigger problem than the one you were trying to treat.
The 4g a day of histidine is put forward as a safe long term therapy.
Is the mode of action related to mast cells or filaggrin (FLG)? Or perhaps both?
If 1g of histidine does improve your allergies, perhaps you should feel free to try a little more.
You can buy histidine as a bulk powder. Pellamex is quite expensive, particularly if more than one family member is affected, as you would expect to find in a genetic condition.  




Wednesday, 4 January 2017

Histidine for Allergy, but as an effective MTOR inhibitor?



Today’s post is likely to be of interest to those dealing with allergy and mast cell activation, but it may have broader implications for those with excess brain mTOR activity.
In the jargon, we are told that:
enhanced mammalian target of rapamycin (mTOR) signaling in the brain has been implicated in the pathogenesis of autism spectrum disorder”.
I have discussed mTOR and mTOR inhibitors previously on this blog.



Amino acids, not just for body builders?


mTOR plays a key role in aging and many human diseases ranging from cancer, diabetes and obesity to autism and Alzheimer’s.

The greatest interest in mTOR seems to be in cancer care.  Many cancer genes and pathways are also involved in autism, so we can benefit from the cancer research.  Another autism gene that is also a cancer gene is PTEN.  PTEN is a tumor suppressor and in the most common male cancer, prostate cancer (PCa), what happens is that PTEN gets turned off and so the cancer continues to grow.  If you upregulate PTEN you slow the cancer growth and if you upregulated this gene in those people at risk of Pca perhaps they would never develop this cancer in the first place?  PTEN is upregulated by statin-type drugs and people already on this type of drug have better PCa prognoses.   The beneficial of effect of statins on PCa is known, but the mechanism being PTEN upregulation does not seem to have been noticed. No surprise there.

Inhibiting mTOR using cancer drugs is very expensive.

Other substances affecting mTOR include amino acids, growth factors, insulin, and oxidative stress.

The amino acid Leucine is an mTOR activator, we don’t need that.  We actually want the opposite effect and, at least in mice, we can get it from some of the other amino acids. 


          Highlights 

·        Amino acids, his, lys and thr, inhibited mTOR pathway in antigen-activated mast cells



·        Amino acids, his, lys and thr inhibited degranulation and cytokine production of mast cells



·        Amino acid diet reversed mTOR activity in the brain and behavioral deficits in allergic and BTBR mice.



Neuroprotective and anti-inflammatory diet reduced behavioral deficits only in allergic mice.

              Abstract

Enhanced mammalian target of rapamycin (mTOR) signaling in the brain has been implicated in the pathogenesis of autism spectrum disorder (ASD). Inhibition of the mTOR pathway improves behavior and neuropathology in mouse models of ASD containing mTOR-associated single gene mutations. The current study demonstrated that the amino acids histidine, lysine, threonine inhibited mTOR signaling and IgE-mediated mast cell activation, while the amino acids leucine, isoleucine, valine had no effect on mTOR signaling in BMMCs. Based on these results, we designed an mTOR-targeting amino acid diet (Active 1 diet) and assessed the effects of dietary interventions with the amino acid diet or a multi-nutrient supplementation diet (Active 2 diet) on autistic-like behavior and mTOR signaling in food allergic mice and in inbred BTBR T + Itpr3tf/J mice. Cow’s milk allergic (CMA) or BTBR male mice were fed a Control, Active 1, or Active 2 diet for 7 consecutive weeks. CMA mice showed reduced social interaction and increased self-grooming behavior. Both diets reversed behavioral impairments and inhibited the mTOR activity in the prefrontal cortex and amygdala of CMA mice. In BTBR mice, only Active 1 diet reduced repetitive self-grooming behavior and attenuated the mTOR activity in the prefrontal and somatosensory cortices. The current results suggest that activated mTOR signaling pathway in the brain may be a convergent pathway in the pathogenesis of ASD bridging genetic background and environmental triggers (food allergy) and that mTOR over-activation could serve as a potential therapeutic target for the treatment of ASD.

  

So in mice a combination of the three amino acids Histidine, Lysine and Threonine reduced brain mTOR activity and improved autism.

I did look at all three of these amino acids and their other effects and I choose Histidine. 
Histidine can be produced in adult humans in very small amounts, but in young children they need to obtain some from other sources, usually dietary.

Histidine is the precursor of histamine.  Histamine has both good and bad effects.

Histidine decarboxylase (HDC) is the enzyme that catalyzes the reaction that produces histamine from histidine with the help of vitamin B6 as follows:



You can treat allergy by inhibiting HDC.

Tritoqualine, is an inhibitor of the enzyme histidine decarboxylase and therefore an atypical antihistamine,

You might think that having extra histidine would result in extra histamine, but this appears not to be the case.  There is a paradoxical reaction where increasing histadine actually seems to reduce the release of histamine from the mast cells that store it.  This may indeed be a case of feedback loops working in our favour.

So it seems that histidine may give two different benefits, it reduces IgE-mediated mast cell activation and it reduces mTOR signalling in the brain.

If the effect on mTOR is sufficient we would then benefit from an increase in autophagy, the cellular garbage disposal service that does not work well in autism.  We might eventually see a benefit from increased synaptic pruning which might be seen in improved cognition.  



Recap on mTOR and Synaptic Pruning

This has been covered in earlier posts.

In autism loss of mTOR-dependent macro-autophagy causes synaptic pruning deficits; this results in too many dendritic spines.









A dendritic spine (or spine) is a small membranous protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body. The dendrites of a single neuron can contain hundreds to thousands of spines. In addition to spines providing an anatomical substrate for memory storage and synaptic transmission, they may also serve to increase the number of possible contacts between neurons.

A feature of autism is usually too many, but can be too few, dendritic spines.  In an earlier post we saw how the shape of individual spines affects their function.  The shape is constantly changing and can be influenced by external therapy. Wnt signaling affects dendritic spine morphology and so using this pathway you could fine-tune dendritic spine shape.  We did look at PAK1 inhibitors in connection with this.

Synaptic pruning is an ongoing process well into adolescence.

So it may be possible to improve synapse density and structure well after the onset of autism.

It should be noted that using Rapalogs, the usual mTOR inhibiting drugs, would have a negative effect in the minority of autism that feature hypo-active growth signalling.  That would be people born with small heads and small bodies.  So a child affected by the zika virus, might very likely exhibit autism and ID, but likely has too few dendritic spines and would then need more mTOR, rather than less.

Rapalog drugs like Everolimus are very expensive, but as in this recent paper do show effect in some autism. 



The mTOR pathway is a central regulator of mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain, and is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers.

mTOR Complex 1 (mTORC1) is composed of MTOR, regulatory-associated protein of MTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the non-core components PRAS40 and DEPTOR. This complex functions as a nutrient/energy/redox sensor and controls protein synthesis. The activity of mTORC1 is regulated by rapamycin, insulin, growth factors, phosphatidic acid, certain amino acids and their derivatives (e.g., L-leucine and β-hydroxy β-methylbutyric acid), mechanical stimuli, and oxidative stress

Rapamycin inhibits mTORC1, and this appears to provide most of the beneficial effects of the drug (including life-span extension in animal studies). Rapamycin has a more complex effect on mTORC2.



How do amino acids affect mTOR?

This is not fully understood by anyone, but here is a relevant paper, for those interested.




Mammalian target of rapamycin (mTOR) controls cell growth and metabolism in response to nutrients, energy, and growth factors. Recent findings have placed the lysosome at the core of mTOR complex 1 (mTORC1) regulation by amino acids. Two parallel pathways, Rag GTPase-Ragulator and Vps34-phospholipase D1 (PLD1), regulate mTOR activation on the lysosome. This review describes the recent advances in understanding amino acid-induced mTOR signaling with a particular focus on the role of mTOR in insulin resistance.

We then discuss how mTORC1 activation by amino acids controls insulin signaling, a key aspect of body metabolism, and how deregulation of mTOR signaling can promote metabolic disease. 

Concluding remarks


Recent findings of new mediators and their regulatory mechanisms have broadened our understanding of amino acid-induced mTOR signaling. In addition to the role of the TSC1-TSC2-Rheb hub in transducing upstream signals from growth factors, stressors and energy to mTOR, the lysosomal regulation of mTOR functions as a platform to connect nutrient signals to the Rheb axis. Furthermore, two parallel pathways of amino acid signaling explain the diverse regulation of mTOR signaling. It is yet to be determined which regulators sense amino acids directly and whether the two pathways require separate amino acid sensing mechanisms. The identification of a direct amino acid sensor will shed light on these uncertainties.

A more integrated understanding of mTOR regulation in amino acid signaling will open the door for new therapeutic approaches for metabolic diseases, especially type 2 diabetes. Already, metformin, an antidiabetic drug, inhibits mTOR in an AMP-activated kinase (AMPK)-independent and Rag-dependent manner,64 providing further support for the idea that the regulation of amino acid sensing could be a therapeutic target for diabetes.



How typical is the level of amino acids in autism?



As regards essential amino acid levels, autistic children had significant lower plasma levels of leucine, isoleucine, phenylalanine, methionine and cystine than controls (P < 0.05),while there was no statistical difference in the level of tryptophan, valine, threonine, arginine, lysine and histidine (P > 0.05). In non-essential amino acid levels, phosphoserine was significantly raised in autistic children than in controls (P < 0.05). Autistic children had lower level of hydroxyproline, serine and tyrosine than controls (P < 0.05). On the other hand there was no significant difference in levels of taurin, asparagine, alanine, citrulline, GABA, glycine, glutamic acid, and ornithine (P > 0.05).

There was no significant difference between cases and controls as regards the levels of urea, ammonia, total proteins, albumin and globulins (alpha 1, alpha 2, beta and gamma) (P > 0.05).



  

Conclusion 

For the more common hyperactive pro growth signaling pathway types of autism, histidine should be a good amino acid, whereas for the hypoactive type, that might feature microcephaly, leucine should be a good choice.

Histidine is already used by some people to treat allergy.

Histidine does have numerous other functions and one relates to zinc, so it is suggested that people who supplement histidine add a little zinc. For this reason German histidine supplements thoughtfully all seem to include zinc.

Histidine also has some direct antioxidant effects and has an effect on Superoxide dismutase (SOD).

It is not clear how much histidine would be needed in humans to achieve the mTOR inhibiting effect found in mice.

The RDA for younger teenagers is histidine  850 mg and leucine 2450 mg.  What the therapeutic dose to affect mTOR in humans remains to be seen.

Histidine is also claimed to help ulcers, which is plausible.

For allergy some people are taking 1,500mg of histidine a day.