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Showing posts with label H3. Show all posts
Showing posts with label H3. Show all posts

Tuesday, 2 February 2016

Central histamine (dys)function, antidepressants, appetite, autism and behavior

One day last week Monty, aged 12 with ASD, was watching an old Tom and Jerry DVD.  These DVDs, along with the other action-packed ones, once got hidden away because they drove Monty wild; now they do not.

This is what I was doing while Tom was chasing                                                                         Jerry.

I received another interesting comment from a reader who found a small dose of an antidepressant had a very positive effect on his 9 year old daughter:-


“My daughter (9, ASD) recently started on a very small dose of Remeron, in an effort to increase weight and as a bonus, hopefully improve sleep. It has done both. It also had an immediate unexpected but delightful side effect of improved social skills, more fluent speech and increased amount of conversation. The first day she tried it she made friends with random children in the park, and they had a discussion about how they would design their dream playground. (DD said she would invent and upside down slide, where you start at the bottom and slide up.) It has been amazing for her (so far.)  ”


In most families it is the parents who take the antidepressants.

I recalled that one class of antidepressant was actually developed from an old antihistamine drug, tricyclic antidepressants.

Remeron, otherwise known as Mirtazapine, is indeed a tricyclic antidepressant.


Not only is Remeron, in effect, a first generation antihistamine, i.e. one that was not designed to stay outside the blood brain barrier, but it is a rather potent one.

Within the brain Remeron/Mirtazapine:-

HR occupancy (HRO) of mirtazapine reached 80-90 % in the cerebral neocortex


Histamine H receptor occupancy by the new-generation antidepressants fluvoxamine and mirtazapine: a positron emission tomography study in healthy volunteers.

This means that 80-90% of the type 1 histamine receptors in that part of the brain are blocked from action.



Histamine Receptors and the Blood Brain Barrier

There were several earlier posts in this blog regarding histamine.

There are four known types of histamine receptors H1, H2, H3 and H4.

In one way or the other, all four are likely relevant to autism.  Drugs are not yet available for H4.  H3 therapies are likely to improve cognitive function in some. H4 appears to play a role in the overexpression of mast cells in allergic tissues.  So those with severe mast cell issues should watch the H4 drug pipeline.

Histamine H4 Receptor Mediates Chemotaxis and Calcium Mobilization of Mast Cells



An important point to remember is that while histamine does not cross the Blood Brain Barrier (BBB), H1 antihistamines do cross, including the ones designed not to cross.

All antihistamines cross blood-brain barrier



Within the brain, histamine functions as a neurotransmitter, but it is not the same histamine as that released by mast cells in your nose, when you have hay fever.  Histamine is also produced inside the brain.

H3 receptors in the brain modulate the release of histamine.  Histamine release in the brain triggers secondary release of excitatory neurotransmitters such as glutamate and acetylcholine via stimulation of H1 receptors in the cerebral cortex. Consequently, unlike the H1 antagonist antihistamines which are sedating, H3 antagonists have stimulant and nootropic effects, and are being researched as potential drugs for the treatment of neurodegenerative conditions such as Alzheimer's disease and also for ADHD.

H1 agonists should increase appetite and H3 agonists should reduce appetite.  So one day do not be surprised to read about wonder H3 slimming pills.

Outside the brain (CNS) all four types of receptor are found and have specific functions.

H1 receptors modulate circadian rhythm (sleep) as well as all those allergy and asthma symptoms.

H2 receptors modulate sinus rhythm (in your heart), stimulate  gastric acid secretion, inhibit antibody synthesis, T-cell proliferation and cytokine production.

So histamine dysfunction would contribute to many conditions that are known to be comorbid with autism:-

·        Obesity and also low appetite (both extremes)
·        Poor sleep
·        GERD/GORD/reflux
·        Cognitive impairment
·        Allergy
·        Mood disorders

As usual things are complicated, because the histamine receptors are slightly different in each part of the brain so your histamine antagonist/blocker “sticks” better on some than on others.  So one H1 antihistamine will be more sedating, or more appetite-increasing than another one.



H1 antihistamines in Autism

Most attention in this blog has been directed to the effect of H1 antihistamines outside the brain/CNS.  To a greater or lesser extent, all H1 antihistamines are also mast cell stabilizers.  They reduce the release of histamine itself, as well as blocking H1 receptors (and so relieving allergy symptoms).

Blocking the release of histamine outside the BBB stops the release of inflammatory cytokines like IL-6, which can, directly or indirectly, cross the blood brain barrier.

However many people report that common H1 antihistamines seem to improve autistic behavior, irrespective of any allergy being present. My assumption is that this may be the case with nine year old girl, certainly worth investigating.

Either there is a mild allergy that has gone unnoticed, or this must be the effect of blocking H1 receptors within the brain/CNS.


H3 antihistamines in Autism

I think it quite likely that some people with autism and schizophrenia would experience cognitive improvement from H3 antagonists.

It is perhaps odd that nobody has investigated the cognitive effects of Betahistine.

Betahistine has a very strong affinity as an antagonist for histamine  H3 receptors and a weak affinity as an agonist for histamine H1 receptors.

The disadvantage is that betahistine increases histamine levels outside the BBB, so not good for someone with asthma.


There is data on the effect of Betahistine on weight gain in schizophrenia:-


Reducing antipsychotic-induced weight gain in schizophrenia: a double-blind placebo-controlled study of reboxetine-betahistine combination.

It was safe, well tolerated and did reduce weight gain.  I would have liked to know the effect on cognitive function.





Conclusion

There may be too much histamine being released, or its degradation might be impaired (DAO, SAMe, & HMT are all implicated in autism/schizophrenia), or there may be over/under expression of histamine receptors in certain places.

For example in schizophrenia,  metabolites of histamine are increased in the cerebrospinal fluid of people, while the efficiency of H1 receptor binding sites is decreased.

The role of the central histaminergic system on schizophrenia.



It would not be surprising if people with autism and histamine/mast cell related issues outside the brain, also have central (in the brain) histamine dysfunctions.

There are only 24,000 genes found in humans (there are 700+ autism genes).  As a result these genes have to be reused many times all over the body.  Any dysfunction may be reappear in surprising parts of the body.  Add to this the way the body is controlled by feedback loops and you can see a how very many things are inter-related.

This also explains why very clever ideas can work in vitro (in the lab) but completely fail when applied to humans. "Stumbled upon", which must really annoy some clever scientists, is a very valid discovery method and can still earn you top marks.

This also means that many potential therapies can have unintended side effects. Like the H3 antagonist Betahistine, which can cause gastric acid problems and itching.  Betahistine acting in the brain might be good for cognition, but might not be without drawbacks elsewhere in the body.


Coming back to Tom and Jerry and where this post started

As usual Jerry got the better of Tom.

Since continued used of Remeron might lead to obesity, it would be interesting to see if the autism benefits were maintained by using a more conventional H1 antihistamine.  The older ones should better cross the BBB, but will be more sedative.

The people currently using conventional H1 antihistamines to treat their n=1 case of autism, might want to compare the effect of the very small dose of Remeron.

The people using second generation conventional H1 antihistamines (Zyrtec, Claritin etc) to treat their n=1 case of autism might want to compare the effect of the old fashioned versions that, like Remeron, have high much higher HR occupancy in the brain.



For those still hungry (too much histamine) for more:-



Histamine H3 receptor antagonists/inverse agonists on cognitive and motor processes: relevance to Alzheimer's disease, ADHD, schizophrenia, and drug abuse


The role of hypothalamic H1receptor antagonism in antipsychotic-induced weight gain.

  

Therapeutic potential of histamine H3 receptor agonist for thetreatment of obesity and diabetes mellitus






Monday, 24 March 2014

Summertime Raging in Autism – H1 Anti-histamine Effect on Histamine Levels and IL-6



Last summer, I wrote a lot about autism getting much worse in that time of the year and how I found that common “24 hour” anti-histamine drugs seemed to have a magical effect; but one that lasted only 2-3 hours. There were only visible signs of a mild allergy, which could indeed easily be overlooked.

I did later receive a message from a reader who noticed his child’s ASD behaviours were greatly improved by Zrtec and his doctor agreed to prescribe this H1 antihistamine all year round.

Recently, I stumbled upon a blog, rich with many comments of parents of kids with severer types of autism.  Here I noted some parents referring to “summertime raging”, and I thought to myself, I know what they mean.  Fortunately, I found out how to make it go away.


Ant-histamine drugs

The two most common antihistamine drugs are Claritin (Loratadine), its active derivative Aerius (Desloratadine) and Zrtec (Ceterizine) and its active derivative Xyzal (levocetirizine).

The main action of an antihistamine is not actually to reduce the amount of histamine in your blood, rather it is to block the effect of histamine on the H1 receptors.

An H2 antihistamine blocks H2 receptors that are mainly in your intestines, and is used to reduce the amount of acid in the stomach.

This led me on a quest for substances that actually stop the increase in histamine, rather than just blocking some effects.  The only thing that does this is something that can stop so-called mast cells from degranulating and spilling their load of histamine, serotonin, nerve growth factor and cytokines, including IL-6, into the blood; from where, all except serotonin, are free to travel to the brain, across the blood brain barrier (BBB).  Serotonin cannot cross the BBB.

According to the mast cell specialist Theoharides, conventional drugs are not genuine mast cell stabilizers.  There are some partial ones, like Ketotifen, Cromalin, Rupatadine and Azelastine, but Theoharides thinks naturally occurring flavonoids like Luteolin and Quercetin work best.

Last summer in this blog I looked at newly discovered histamine receptors types H3 and H4 which are known to be present in the brain.


So how is it that Claritin and Zrtec can reduce autistic behaviours ?

I did note that both the above drugs did reduce summertime raging and also the Theoharides' research that showed they probably should not, since they are not mast cell stabilizers. 

Since my blog reader also found Zrtec helpful, so much so he gives it to his kid year round and it now seems summertime raging is not an unusual phenomenon in autism, I did some more checking.

In spite of what Theoharides tells us, it turns out that both Claritin and Zrtec do indeed reduce the amount of histamine in the blood.

Also, it turns out that not only is the pro-inflammatory cytokine IL-6 released from mast cells but it is also released from another type of cell, called the endothelial cell.

The endothelium is the thin layer of cells that lines the interior surface of blood vessels and lymphatic vessels, forming an interface between circulating blood or lymph in the lumen and the rest of the vessel wall. The cells that form the endothelium are called endothelial cells. Endothelial cells in direct contact with blood are called vascular endothelial cells, whereas those in direct contact with lymph are known as lymphatic endothelial cells.

And what prompts endothelial cells to release IL-6? Histamine does.

Indeed we have studies showing how Claritin (loratadine) and  Zrtec (Ceterizine) reduce histamine and IL-6; it is the IL-6 from the endothelial cells.


"CONCLUSION:

These results demonstrate that both L and DCL are active to reduce the histamine-induced activation of EC. Interestingly, DCL seems to be effective at lesser concentrations especially to inhibit cytokine secretion."

The above study would suggest that Aerius (DCL) should be more effective than Claritin (L) its predecessor.



"Histamine is a major constituent of the mast cell. The effect of histamine on endothelial cells is primarily mediated through H1R

Collectively, our results suggest that mast cell-derived histamine and proteases play an important role in vascular inflammation and calcification in addition to their well-recognized participation in allergic diseases."

This study, and others like it, show how mast cell degranulation contributes to heart disease.  This would suggest that mast cell stabilizers have a much wider role in human health than is realized.  Another example of how a red apple a day (with the skin) may indeed help keep the doctor away and a glass of red wine will do the same.  Both are rich sources of the mast stabilizer Quercetin.  The alcohol increases the bio-availability.


"Conclusion

These results suggest that cetirizine exerts its beneficial effects on viral myocarditis by suppressing expression of pro-inflammatory cytokines, genes related to cardiac remodeling in the hearts of mice."


So how do Claritin and Zrtec reduce summertime/year round raging in autism?  Well it could be histamine or it could be IL-6, we cannot know for sure.  The science tells us that the brain has many H3 and H4 receptors, so they are possibly to be implicated.  Or, it may just be IL-6;  histamine’s involvement could be just provoking the endothelial cells to release more IL-6.


Conclusion

Claritin/Zrtec/Xyzal are relatively cheap, in theory they are long lasting drugs.  In Monty, aged 10 with ASD, they all work for summertime time raging, but not for long.  Adults should take one per 24 hours.  Monty would need one every 3 hours.

The, supposedly better, mast cell stabilizers like Ketotifen and Rupatadine take a few days before they have any effect at all.  Azelastin is available as a nasal spray and is supposed to be effective quickly as an allergy treatment.

My preferred mast cell stabilizing, IL-6 inhibiting, strategy is to combine PEA (palmitoylethanolamide) which is already naturally in your body, with the flavonoid quercetin, which is found in the skin of red apples and red grapes.  In theory, according to the research, this is both a potent combination and should be free of harmful side effects.

Very frequent doses of Claritin/Zrtec/Xyzal are not going to be good.


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