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.

Inhibitory activity of loratadine and descarboxyethoxyloratadine on histamine-induced activation of 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.

Human Mast Cells(HMC-1 5C6) Enhance Interleukin-6 Production by Quiescent and Lipopolysaccharide-Stimulated Human Coronary Artery Endothelial Cells

"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.

Cetirizinea histamine H1 receptor antagonist improves viral myocarditis

"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.

Links

Blog with 1000s of parent comments, some are very insightful

  

Theoharides on mast cells

On this blog:-

http://epiphanyasd.blogspot.com/2014/02/is-subtype-of-autism-allergy-of-brain.html

http://epiphanyasd.blogspot.com/2014/03/palmitoylethanolamide-pea-vs-flavonoids.html

http://epiphanyasd.blogspot.com/2013/07/histamine-allergies-and-reducing.html

http://epiphanyasd.blogspot.com/2013/11/seasonal-autistic-mastocytosis.html

Dr Chez’s Trial of Lenalidomide, a TNF- α and IL-6 Inhibitor in Autism

 

An interesting trial of a TNF- α and IL-6 inhibitor in autism has been brought to my attention.  It was by Michael Chez, the neurologist from Sacramento, who has made several appearances on this blog.

By coincidence, a copy of his book arrived this week.  The book is called “Autism and its Medical Management”, Chez is one of the few mainstream doctors who does try and treat autism.  The book is rational, readable and in no way radical, so you could show it to your family doctor without upsetting him/her.  Chez does particularly focus on distinguishing regressive from non-regressive autism, as do I. His view is that it is regressive autism, even if it was regression from slightly abnormal.  The important part is that some learned skills, like language, were lost sometime after 12 months of age.  He believes that regressive autism has a different basis to non-regressive autism; he has his own ideas about this, but he admits there is no concrete proof.

The book is a few years old and Chez has published much work in the intervening few years.    

The paper I was referred to is:-

Safety and Observations in a Pilot Study of Lenalidomide for Treatment in Autism

Lenalidomide, an analogue of thalidomide, has the potential to invoke significant changes in TNF-α and other immunomodulatory cytokines.  If thalidomide sounds familiar, it is the drug from the 1950s, that turned out to be very unsafe for use in pregnant women and around the world 10,000 babies were born with malformation of the limbs.

Lenalidomide has been used to successfully treat both inflammatory disorders and cancers in the past 10 years. There are multiple mechanisms of action.  It is extremely expensive, according to NICE:-

“Lenalidomide 25 mg capsules cost £4368 per 21 capsules (excluding VAT; ‘British national formulary’ [BNF] edition 55). Dosage is continued or modified based upon clinical and laboratory findings. For example, if lenalidomide is continued for ten 28-day cycles without dose reduction, the cost would be £43,680.”

 

Dr Chez does not mention the cost of Lenalidomide, but he uses a tiny dose of 2.5 mg; This would cost £20, or $30, a day.  This might also explain the small number (7) of participants in the trial.

 

“2.2. Drug and Dosing. Lenalidomide 2.5mgs was given daily

for 12 weeks. This low dose was selected to minimize the risk

of adverse effects. In addition, because this was a pilot study,

the goal was to test the lowest dose that could potentially lead to improvements.”

 

The drug did reduce TNF-α levels and there were some behavioral improvements, but nothing dramatic.  Perhaps a higher dosage would have had a greater effect?

 

There were only seven participants and the data on the seven is not complete; also the dose of Lenalidomide was very low.  I think it is really only fair to conclude that the trial is interesting but that a much cheaper drug would need to be found and tested on a much larger number of participants.

“Despite the limitations, to our knowledge, this open-label study represents the first attempt to treat autism by specifically targeting elevated innate inflammatory cytokine levels. Safety monitoring and pharmacokinetic data were successfully completed during this pilot study and exploratory observations of clinical and cytokine changes suggest a trend towards improvement. Correlating treatment outcomes with cytokine level changes may be a target in future autism spectrum treatment, especially in those with known maternal or postnatal immunological risk factors. Larger blinded and placebo-controlled studies assessing cytokine measurement and cytokine-targeted treatment in autism patients with TNF-α or other inflammatory cytokine elevation are warranted.”

To his credit, unlike the researchers in Athens who trialed Neuroprotek in a recent post, Chez went about his pilot study in a scientific manner and collected both the biological and the behavioral data.  In other words, he measured the before and after levels of the inflammatory cytokines and the before and after behavioral rating scales.  Well done Dr Chez.

 

 

Let’s be Serious about the Data - Flavonoids, Cytokines & Autism

You may be wondering why, with so many research papers written about autism, so little progress has been made.  It is a very complex task, but nobody is coordinating it.

How do you find a Boeing 777 missing somewhere in Asia?  Another daunting challenge, but with the right people and resources it can be done.  With the wrong people, it will prove to be impossible.

Ashwood et al have documented the level of various inflammatory markers in autism.  Very helpfully, they created three groups: typical children, children with non-regressive autism, and children with regressive autism.

Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome

Table 2, on the third page, tells us what we need to know.  Certain cytokine levels are markedly elevated in regressive autism, including IL-6 and TNF-alpha.  Furthermore, the difference between the two types of autism is dramatic; rather implying the existence of two distinct conditions.

 

So now, I move on to what could have been an amazingly helpful study, had they spent 1% more time on it and collected some blood samples and split the kids into regressive and non-regressive groups.

Last year in Athens, a study was done using Theoharides’ mix of luteolin and quercetin flavonoids to look at the effect of mast cell stabilization on behaviour in autism.  From recent posts, you will recall that these flavonoids reduce the level of inflammatory cytokines, histamine and nerve growth factor, by stabilizing so called mast cells.  In effect, the study was looking at the impact of inhibiting certain cytokines on behaviour in autism.

An Open-Label Pilot Study of a Formulation Containing the Anti-Inflammatory Flavonoid Luteolin and Its Effects on Behavior in Children With Autism Spectrum Disorders

This sounds great and just what I wanted to find.  Get 40 kids with ASD measure their level of these cytokines/histamine and assess their behaviour.  Give them the cytokine inhibitor/mast cell stabilizer for six months, measure the levels in their blood and assess the behaviour again.

Sadly, they did not bother to take the before and after blood samples and send them downstairs to the hospital’s laboratory.

So we have a paper that took years of planning that tells us that the flavonoids do seem to help; but we do not know exactly why and we cannot correlate improvement in behaviour with change in cytokine levels.

What a pity.  

  

IL-6 Disrupts the GH→IGF-1 Axis in Autism

 

Regular readers of this blog will see that there is an underlying logic behind recent posts.  We know levels of the cytokine IL-6 are raised in autism and we know that high levels of IL-6 in mice produces a baby with autism and we know this can be reversed by giving IL-6 antibodies to the mother, prior to birth.
We also know from numerous previous posts that growth hormone (GH) and the growth factor IGF-1 are implicated in autism.  Both GH and IGF-1 are used in clinical trials for autism.

Today’s post draws all this together.  It turns out that IL-6 disrupts the GH-IGF-1 axis.  The hormone GH is supposed to control the release of IGF-1; so a little more GH should produce a little more IGF-1.  The problem is that the cytokine IL-6 disrupts this relationship.  In the presence of elevated amounts of IL-6, which is characteristic of autism, and regressive autism in particular, GH does not produce the expected increase in IGF-1; IGF-1 levels are actually reduced.

This is very important.

A great deal of money is being spent researching and developing IGF-1 based therapies for autism and Retts syndrome.  Perhaps a much better strategy would be to clear the disruption from the GH-IGF-1 axis, so that IGF-1 levels could be restored naturally.  This means reducing IL-6 levels and IL-6 mediated disruption. We already know how to do this, from previous posts.

Now for some supporting evidence:-

In the following study, IL-6 was given to healthy volunteers and the over the next 8 hours their levels of GH and IGF-1 were measured.

The study confirmed earlier observations that IL-6 infusion leads to increased circulating GH. Despite the increase in GH levels, the study demonstrated an IL-6 infusion-associated reduction in IGF-I. 

Effect of rhIL-6 infusion on GH→IGF-I axis mediators in humans

 

Coming back to mice being given IL-6 to produce autistic pups, Autism Speaks funded a very thorough post-doctoral study at Caltech that focused on understanding this very issue (in mice at least).  The study aimed to find out how IL-6 ends up causing autism.  The conclusion is very interesting and again comes back to endocrine changes and the disrupted GH-IGF-1 axis.

I rest my case. 

Activation of the maternal immune system induces endocrine changes in the placenta via IL-6

"Activation of the maternal immune system in rodent models sets in motion a cascade of molecular pathways that ultimately result in autism- and schizophrenia-related behaviors in offspring. The finding that interleukin-6 (IL-6) is a crucial mediator of these effects led us to examine the mechanism by which this cytokine influences fetal development in vivo. Here we focus on the placenta as the site of direct interaction between mother and fetus and as a principal modulator of fetal development. We find that maternal immune activation (MIA) with a viral mimic, synthetic double-stranded RNA (poly(I:C)), increases IL-6 mRNA as well as maternally-derived IL-6 protein in the placenta. Placentas from MIA mothers exhibit increases in CD69+ decidual macrophages, granulocytes and uterine NK cells, indicating elevated early immune activation. Maternally-derived IL-6 mediates activation of the JAK/STAT3 pathway specifically in the  pongiotrophoblast layer of the placenta, which results in expression of acute phase genes. Importantly, this parallels an IL-6-dependent disruption of the growth hormone-insulin-like growth factor (GHIGF) axis that is characterized by decreased GH, IGFI and IGFBP3 levels. In addition, we observe an IL-6-dependent induction in pro-lactin-like protein-K (PLP-K) expression as well as MIA-related alterations in other placental endocrine factors. Together, these IL-6-mediated effects of MIA on the placenta represent an indirect mechanism by which MIA can alter fetal development. 

Furthermore, we find an IL-6-dependent dysregulation of the GH-IGF axis in MIA placentas, characterized by decreased levels of GH and IGFI mRNA, with corresponding decreases in placental IGFI and IGFBP3 protein. The actions of GH are achieved through the stimulation of IGFI production in target tissues. In addition, GH regulates the activity of IGFI by altering the production of either facilitatory or inhibitory binding proteins, including the IGFI stabilizing protein, IGFBP3. This suggests that the decreased GH levels seen in MIA placentas leads to the observed downstream suppression of IGFBP3 and IGFI production. It is believed that IGFs in the maternal circulation do not enter the placenta, and therefore IGFs in the placenta are derived from the placental compartment itself We demonstrate that the changes in IGFI and IGFBP3 expression are mediated by IL-6. However, it is unclear whether decreases in placental GH and subsequent effects on IGF production are downstream of IL-6-specific STAT3 activation. IL-6 does modulate IGFI and IGFBPs in several tissues, including placenta and cord blood. Pro-inflammatory cytokines, including IL-6, decrease circulating and tissue concentrations of GH and IGFI. We observe that IL-6- mediated STAT3 activation is associated with the expected IL-6- mediated increase in SOCS3 expression, along with other acute phase genes. Factors like SOCS play an important role in the down-regulation of GH and GH signaling. Importantly, it is reported that IL-6 inhibits hepatic GH signaling through up-regulation of SOCS3. As such, it is possible that, in MIA placentas, maternal IL-6-induced STAT3 activation and downstream sequelae lead to suppression of placental GH levels, disruption of IGFI production and further consequences on maternal physiology, placental function and fetal development. Altered placental physiology and release of deleterious mediators to the fetus are important risk factors for the pathogenesis of neurodevelopmental disorders. Placental IGFI in particular regulates trophoblast function , nutrient partitioning and placental efficiency. Moreover, altered IGFI levels are associated with intrauterine growth restriction (IUGR) and abnormal development. Animal models of IUGR and intrauterine infection, where the immune insult is confined to the uteroplacental compartment, highlight the key role of placental inflammation in perinatal brain damage, involving altered cortical astrocyte development, white-matter damage, microglial activation, cell death and reduced effectiveness of the fetal blood–brain barrier. In addition, adult pathophysiology is subject to feto-placental ‘‘programming’’, wherein molecular changes that occur prenatally reflect permanent changes that persist throughout postnatal life. Interestingly, placental responses to maternal insults can potentiate sexually dimorphic effects on fetal development. Obstetric complications are linked to schizophrenia risk and to the treatment responses of schizophrenic individuals. Notably, a greater occurrence of placental trophoblast inclusions was observed in placental tissue from children who develop autism spectrum disorder (ASD) compared to non-ASD controls. Chorioamnionitis and other obstetric complications are significantly associated with socialization and communication deficitis in autistic infants. The characterization of placental pathophysiology and obstetric outcome in ASD and schizophrenic individuals will be useful for the identification of molecular mechanisms that underlie these disorders and for potential biomarkers for early risk diagnosis. In addition to the observed effects of IL-6 on placental physiology and its downstream effects on fetal brain development and postnatal growth, direct effects of IL-6 on the fetal brain are also likely. Maternal IL-6 can potentially cross the placenta and enter the fetus after MIA. Furthermore, IL-6 mRNA and protein are elevated and STAT3 is phosphorylated in the fetal brain itself following MIA, raising the obvious possibility that IL-6 acts directly on the developing brain to influence astrogliosis, neurogenesis, microglial activation and/or synaptic pruning. However, recall that the identification of IL-6 as a critical mediator of MIA is based on maternal co-injection of poly(I:C) and anti-IL-6 blocking antibody, in addition to experiments inducing MIA in IL-6 KO animals. As such, in considering which pool(s) of IL-6 (e.g. maternal, placental, fetal brain, fetal periphery) is the ‘‘critical mediator’’, it will be important to understand the potential interaction between maternal IL-6 and fetal brain IL-6 expression. While we believe that the endocrine changes triggered by maternal-IL-6 signaling in the placenta reported here are important for fetal growth, it will be crucial to assess the potential impact of these placental changes on offspring behavior and neuropathology. We are currently exploring the effects of MIA in targeted IL-6Ra KOs in order to tie tissue- and cell-specific IL-6 activity to the manifestation of schizophrenia- and autism-related endophenotypes."