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Saturday, 14 January 2017

Tideglusib, Repairing  Dental Cavities, Wnt signaling, GSK-3 and Autism


Kings College in London seem to be more effective in dentistry than autism; they have just published research showing how they effectively regrew a tooth to repair a cavity.  That is rather clever.

Perhaps soon to be a thing of the past?


Using biodegradable collagen sponges to deliver the treatment, the team applied low doses of small molecule glycogen synthase kinase (GSK-3) inhibitors to the tooth. They found that the sponge degraded over time and that new dentine replaced it, leading to a complete, natural repair.




The full paper is here:- 




All very well, but what has this got to do with Autism?

As regular readers will be aware, autism turns out to be multigenic (it involves lots of different genes) and no single gene seems to account for more than one or two percent of cases.  A small number of any of hundreds of possible genes can be disturbed and then affect so-called signaling pathways  that control our bodies.  These pathways have evolved over millions of years and can seem quite unnecessarily complex.  The pathways overlap with each other and at certain critical points it seems like different genetic dysfunctions can lead to the same dysfunctional point, or nexus.  
We previously saw one such nexus, IPR3, suggested by Gargus:-




 but another one may be the Synaptic Wnt/GSK3β signaling hub. 


We came across Wnt signaling in earlier posts.  Among other things, it relates to those RASopathies that often lead to cognitive dysfunction; but RAS dysfunction can also lead to common cancers, so called RAS-dependent cancers.

Wnt signaling is also involved in hair growth and hair greying, as one of our more adventurous readers experienced.  So using a PAK1 inhibitor to modulate the Wnt pathway may make your hair go grey.

BCL-2 is another autism gene that affects hair growth/loss.

It has been suggested by some of the very clever researchers (Chauhan and Chauhan) that the BDNF-Akt-Bcl2 anti-apoptotic signaling pathway is compromised in the brain of autistic subjects.

So while the gene Bcl-2 might be the dysfunction in one per cent of people, in more cases it is the pathway along which Bcl-2 lies, that is the problem.

There is also so called cross-talk between pathways connecting Bcl-2 to RAS.

Then you will see that some drugs affect both Bcl-2 and RAS.  So on the one hand things get much more complicated than just 20,000 different genes, but on the other hand the really good interventions will likely solve multiple dysfunctions. This is why we have talk about a nexus, or hub, where different dysfunctions lead to common points.

It makes sense to focus on identifying the limited number of these hubs, rather than getting lost in thousands of possibly dysfunctional genes. 


GSK-3 (Glycogen synthase kinase 3)

This area is very complex and really only a few people, mainly cancer researchers, and at least one dentist, understand it.

In essence, among other effects, GSK-3 inhibitors activate Wnt signaling. 

Glycogen synthase kinase 3 is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, Glycogen synthase ]GSK-3 has since been identified as a kinase for over forty different proteins in a variety of different pathways.  In mammals GSK-3 is encoded by two known genes, GSK-3 alpha (GSK3A) and GSK-3 beta (GSK3B). GSK-3 has recently been the subject of much research because it has been implicated in a number of diseases, including Type II diabetes (Diabetes mellitus type 2), Alzheimer's Disease, inflammation, cancer, and bipolar disorder. 


Glycogen synthase kinase-3 (GSK3) may be the busiest kinase in most cells, with over 100 known substrates to deal with. How does GSK3 maintain control to selectively phosphorylate each substrate, and why was it evolutionarily favorable for GSK3 to assume such a large responsibility? GSK3 must be particularly adaptable for incorporating new substrates into its repertoire, and we discuss the distinct properties of GSK3 that may contribute to its capacity to fulfill its roles in multiple signaling pathways. The mechanisms regulating GSK3 (predominantly post-translational modifications, substrate priming, cellular trafficking, protein complexes) have been reviewed previously, so here we focus on newly identified complexities in these mechanisms, how each of these regulatory mechanism contributes to the ability of GSK3 to select which substrates to phosphorylate, and how these mechanisms may have contributed to its adaptability as new substrates evolved. The current understanding of the mechanisms regulating GSK3 is reviewed, as are emerging topics in the actions of GSK3, particularly its interactions with receptors and receptor-coupled signal transduction events, and differential actions and regulation of the two GSK3 isoforms, GSK3α and GSK3β. Another remarkable characteristic of GSK3 is its involvement in many prevalent disorders, including psychiatric and neurological diseases, inflammatory diseases, cancer, and others. We address the feasibility of targeting GSK3 therapeutically, and provide an update of its involvement in the etiology and treatment of several disorders.



GSK-3 and Autism

The good news is that the Alzheimer’s researchers have already developed a GSK-3 inhibitor, the current favourite is called Tideglusib.  This is also the one the clever dentists at King’s College used.

Researchers in Santiago, Chile, have proposed the role of GSK-3 in the onset and development of ASDs through direct modulation of Wnt/β-catenin signaling.





 Figure 1: Wnt/β-catenin signaling in ASDs. Wnt binding to FZD-LRP5/6 complex receptor at the membrane recruits the destruction complex and inhibits GSK3β activity thus stabilizing β-catenin in the cytoplasm and nucleus. Activation of the Wnt/β-catenin pathway facilitates synaptic plasticity through the activation of voltage gated ion channels that allows activation of CAMK and CREB mediated transcription. Mutations in TSC associated with ASD prevent β-catenin degradation which results in a gain of function of the Wnt pathway. In the presynaptic terminal cadherin mediated cell adhesion between synapses is weakened by phosphorylation of β-catenin and synaptic vesicle clustering is enhanced through DVL1. Clustering is also dependent on NLGN/NRXN cell adhesion complexes. Both lithium (LiCl) and VPA activate Wnt/β-catenin signaling through inhibition of GSK3β activity. Conversely, in the absence of a Wnt ligand, activated GSK3β targets β-catenin for proteosome-mediated degradation. Mutations associated with DISC1 fail to inhibit GSK3β and thus activate Wnt/β-catenin pathway. In the presynaptic side Wnt signaling buffering of synaptic vesicles is inhibited and adherens junctions mediated by cadherins are strengthened.

This becomes more interesting because a clinical trial has already been put in motion to trial Tideglusib in autism.  I am not sure if the Canadian researchers are just trying an Alzheimer’s drug on the off-chance it might help autism, or whether they are really up to speed with their Wnt signaling pathway.  I suspect the former, but it does not really matter.



This might be of interest to our reader Alli in Switzerland.


Conclusion 

It pays to read the science reports that appear to have nothing to do with autism.










18 comments:

  1. Hi Peter and community,

    First of all, great article and thanks for sharing the relevant paper (i.e. GSK3 Beta as an autism hub) Peter!

    After reading your post, I was really interested in finding out what can inhibit GSK3 Beta and I found the following (have to look under Fixes and Advanced Fixes)

    https://www.selfdecode.com/gene/gsk3b

    The good news is that many of the inhibitors are easily accessible, and well-known substances.

    I actually started using Apigenin (noted to be a potent inhibitor of GSK3 Beta) thanks to Tyler's recommendation for an IDO inhibitor (to block Quinolinic Acid), so Apigenin looks like a good option as it is noted to be a potent inhibitor of GSK3 Beta.

    On a slightly related note, I would appreciate the insights of the knowledgable members of the community (Peter, Tyler, Agnieszka, etc.) on the following:

    I was looking for another IDO inhibitor to pair with Apigenin (as Quinolinic Acid is no nasty I wanted to hit it on multiple fronts) and I found something potentially interesting that I wanted to share, and it started with the following:

    https://www.ncbi.nlm.nih.gov/pubmed/28077028

    So according to this Ferulic Acid is an IDO inhibitor, which is great. But where I would really appreciate expert insights is in the following:

    https://www.ncbi.nlm.nih.gov/pubmed/28083818
    https://www.ncbi.nlm.nih.gov/pubmed/27940143
    https://www.ncbi.nlm.nih.gov/pubmed/24707860

    Based on the above papers, Ferulic Acid:
    - Increases expression of HO-1
    - Significantly up-regulates BDNF, PSD95 and synapsin I (The increase in Synapsin I may not be ideal for all people with ASD)
    - Preventing brain damage caused by exacerbation of glutamatergic toxicity in nervous system disorders

    Based on the above, Ferulic Acid looks to be an interesting option to try for ASD, but I don't know if this has been tried before, or if there is some info that would make this a poor option.

    I'd really appreciate any insights the community may have on why Ferulic Acid would or would not be a good option to try.

    Thanks very much in advance!

    AJ

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    1. I must stress that it is important to understand why the brain upregulates the kynurenine pathway relative to the serotonin pathway during inflammatory challenges (like sickness) and that involves the body's response to trying to upregulate NAD+ which if completely depleted will cause cells to die. This is why IDO, kynurenine, and quinolinate (or quinolinic acid) are not necessarily bad things or "nasty", but give quinolinic acid's properties, excess and chronic amounts of it help contribute to a cycle of problems in the brain. Addressing quinolinic acid excess is a band-aid to other problems and is why if you feel you need to lower its levels, I think you really need Nicotanimide Riboside as an adjunct to any strong attempt at reducing the natural levels of kynurenine in the body, because what is arguably even worse than quinolinic acid in the brain is for neurons and all of the cells that support them to have their NAD+/NADH ratio get too low. Apigenin, btw also raises NAD+ levels (how I can't remember, just that I know it does).

      Last but not least, do not overdo apigenin. I accidentally took three myself over the course of a day and felt very strange (kind of like a headache) as I almost always test personally what I would ever give to my children first (the exception being low doses of common vitamins or something like that). It could of been a coincidence, but apigenin has a very long half-life (like 24 hours) and I learned my lesson then.

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    2. Hi Tyler,

      As always, I genuinely appreciate your valuable insights!

      As I am using Apigenin as an IDO inhibitor, I will get some Nicotinamide Riboside as you've suggested.

      As ASD kids have higher levels of Quinolinic Acid than NT kids, and that it can be neurotoxic, in trying to ensure that if it is a factor for my daughter, that I'm addressing it.

      Also appreciate your advice in being cautious with Apigenin dosage.

      Have a great day Tyler!

      AJ

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  2. Hey everyone,

    As I go further down this rabbit hole, Astaxanthin appears to be another interesting option and any opinions on this would also be appreciated - some very interesting findings below:

    1. It appears to decrease expression of NKCC1! I'm going to do everything I can to access Bumetanide, but this may be a good adjunct to Bumetabide, and might be a good alternative / interim step in the meantime.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007682/

    2. In Traumatic Brain Injury, Astaxanthin "also restored the levels of brain-derived neurotropic factor (BDNF), growth-associated protein-43 (GAP-43), synapsin, and synaptophysin (SYP) in the cerebral cortex, which indicates the promotion of neuronal survival and plasticity."

    https://www.ncbi.nlm.nih.gov/pubmed/28048972

    3. "Further neurochemical assays suggested that LPS-induced overexpression of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) in the hippocampus and the prefrontal cortex (PFC) can also be reversed by trans-astaxanthin treatment. Moreover, trans-astaxanthin at 80mg/kg was demonstrated to effectively antagonize iNOS, nNOS and COX-2 expression, both at mRNA and protein levels, nitric oxide (NO) levels, via regulating NF-κB in the hippocampus and PFC."

    https://www.ncbi.nlm.nih.gov/pubmed/27559013

    4. "Our results showed that ATX significantly attenuated glutamate-induced cell viability loss and lactate dehydrogenase (LDH) release, decreased the expression of caspase-3/8/9 activity and cleaved PARP, and suppressed the intracellular accumulation of ROS in HT22 cells after exposure to glutamate. ATX also increased the mitochondrial expression of AIF, Cyto-c as well as Bax while decreased Bcl-2. Moreover, ATX also induced the HO-1 expression in a dose and time-dependent manner, increased the antioxidant-responsive element (ARE) activity and nuclear Nrf2 expression. Furthermore, treatment with ATX restored the p-Akt and p-GSK-3β (Ser9) as well as HO-1 expression reduced by glutamate. This protective effect was partially blocked by the inhibitors lithium chloride treatment in HT22, indicating the involvement of Akt/GSK-3β inactivation during the neuroprotective effect of ATX. Our results provide the first evidence that ATX can protect glutamate-induced cytotoxicity in HT22 via attenuating caspase activation and mitochondrial dysfunction and modulating the Akt/GSK-3β signaling, indicating ATX may be useful for the treatment of neurodegenerative disorders such as AD."

    https://www.ncbi.nlm.nih.gov/pubmed/26197224

    5. I) "Unlike other common antioxidants, AST can cross blood brain barriers (BBBs), inducing neuroprotective effects."

    II) "Rats fed a PA-contaminated diet showed high levels of glutamate (GLU), aspartate (ASP), and gamma amino butyric acid (GABA), with observed necrosis or absence of Purkinjie neurons, typical of PA-induced neurotoxicity. Dopamine (DA), serotonin (5-HT), and norepinephrine (NE) levels were abnormal, Nitric Oxide (NO) and Malondialdehyde (MDA) levels were significantly increased, and total antioxidant capacity (TAC) level in serum and brain homogenates was significantly decreased in PA-treated rats. DHA and AST treatments effectively counteracted the toxic effects of PA and normalized most biochemical parameters in rats. DHA and AST can be useful food additives to prevent and reverse PA food-induced toxicity."

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5128751/

    Thanks everyone in advance for your insights - I'm really considering adding Ferulic acid and Astaxanthin to my daughter's treatment so any insights would be much appreciated.

    AJ

    P.S. Peter, I checked out the Tideglusib trial you noted, and I could throw a rock and hit a trial site ... but unfortunately they are only looking for kids between 12 - 17 :-( . I will say that the trial is being managed by some of our best institutions so they may have actually planned this understanding the biology (versus throwing a neurology drug at the problem).

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    1. Hi AJ.
      I was aware of some of the benefits of Astaxanthin but had no idea about effects on NKCC1.
      Thank you for bringing this up.

      Jane.

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    2. Hi Jane,

      I'm happy to help!

      Anything I find in my research that may be helpful to all, I will certainly share. I just ordered some Astaxanthin so will let everyone know how if there is an impact.

      We're all in this together.

      Have a great day Jane!

      AJ

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  3. Peter covered Astaxanthin a while ago:

    https://epiphanyasd.blogspot.com/2015/12/treatable-id-and-some-autism.html?showComment=1450907855459#c3131046760834430786

    To save yourself some time since there is truly a massive amount of information now on Peter's blog and in the comments, try doing this in Google:

    INSERT_SEARCH_WORDS_OR_PHRASE "site:epiphanyasd.blogspot.com"

    So for me to find this post of Peter's (because I remember the topic a while back for whatever reason) I put this in the search bar:

    Astaxanthin "site:epiphanyasd.blogspot.com"

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    1. Thanks Tyler! I used the search function and couldn't find it, and also looked at the key words on the side and couldn't find it, but your method brought it up.

      AJ

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  4. Tyler, I would like your views on ethanol exposure and the autistic brain/gut.
    I know that ethanol cannot be used as treatment but I also know that it makes my son neurotypical.
    I thought I should try and find out more about the underlying mechanism in case there are some other interventions simulating the effect of ethanol.

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    1. Well, first of all ethanol does a lot of things and most of them are very negative and ethanol if you think of it as a drug, well then it should be considered a very dirty drug that is non-selective in what it does.

      Also, in addition to caffeine, I think it happens to be about the most studied substance in the medical literature which suggests that while it does not have the kind of acute negative health effects of say ricin, and does not build up in your tissues like lead, it literally shaves off lifespan every time you ingest it, especially in significant quantities. Just like cigarettes, ethanol is carcinogenic and mutagenic and damages mitochondria as well.

      And I suspect a small minority of autism cases are actually undiagnosed Fetal Alcohol Syndrome. Here is a recent study on the worldwide toll of FAS:

      https://www.sciencedaily.com/releases/2017/01/170113155419.htm

      Now, I don't know much about your son exactly, but it sounds like he is a high-functioning autistic (my oldest son has ID), so you obviously want him to be more social so he can be happy, get a girlfriend, get married, etc. like everyone else. I think alcohol is a terrible, if albeit desperate way of medicating your son's anxiety.

      Alcohol does many things, but the primary method of it "loosening" people up is that it acts in multiple ways as a GABA agonist as well as a positive allosteric modulator of GABA receptors in that they don't cause the ion pores to open directly, but rather they extend the duration that ion pores are allowed to be opened.

      It is funny (actually sad) that Picamilon was an OK GABA agonist that could get into the brain (just like alcohol), but that it was banned due to the will of one corrupt United States Senator acting on behest of the pharmaceutical industry that is her second largest campaign contributor, yet alcohol (and now marijuana) is legal and do so much more damage to society.

      Now as far as alternatives, well there is a long-list. I think Peter has probably written about more much about GABA receptors on his blog now than many scientists who study GABA receptors. I would also give intranasal oxytocin a shot (I assume you are already doing Biogaia) as oxytocin helps normalize the amygdala which can have strong effects on general excitability on the brain and levels of anxiety (oxytocin does a lot of things and may do nothing, but it is one of the more promising interventions for high-functioning autistics to make that extra leap into mainstream social behaviors.

      Also, on a site called wrongplanet.org you can find a lot of testimonials from high-functioning autistics and aspies as to what they do to "address these acting like a NT problem". In my reading, some of them thought phenibut helps a lot (not my suggestion as it is strong and has tolerance issues like most potent gabaergics). Others suggested ecstasy and ketamine (I would avoid them for the same reasons as alcohol, especially ecstasy because of how it taxes serotonergic neurons). I would read it yourself because even though reading random comments from people on an internet forum is far from being scientific, you can glean from the information the perspectives of people on their pros and cons of a particular intervention who actually have to live with the choices they make. It is a big gray area, but how you weight that information is up to you.

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    2. Also, here is a new study on what alcohol does to the developing brain and why underage drinking is one of the worst things you can do if you care about long-term cognitive health.

      https://www.sciencedaily.com/releases/2017/01/170118082434.htm

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    3. Tyler, thank you for your views on alcohol.

      Both me and my husband feel deeply responsible for our son's well being, so we try to be prudent in our approaching treatment and behavioural issues.

      My son rarely drinks and hates the taste of alcohol, but during holidays with relatives we had a few drinks and noticed that his brain worked much better. This doesn't possibly mean that I am going to administrate alcohol for him, that's why I am trying to find alternatives.

      I just thought it has something to do with SCFA's dysfunction, maybe some kind of wrong ratio of propionic acid to acetic acid, or something which has to do with gut fermentation, so vinegar came to my mind. Lot's of people use it for NAFLD to break down fats.

      It is also well known that coffee, tea, wine in small to moderate amounts could help with gut fermentation, in adult population.

      Oxytocin seems a good option and I'll try to find a reliable product/source.

      I know "wrong planet" but it doesn't really help me, so I would stick to this blog's research.

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    4. Petra, if you google "GABAa subunits and ethanol" you will see how small amounts of alcohol affect alpha 5 and delta subunits among others. Since your son responds to bumetanide it is quite possible that he might have another GABA related dysfunction. The compostion of the GABA receptor is variable and he might not have the optimal make up of subunits. Therefore when he takes a modulator of these subunits, like ethanol, he might end up in a better place. I did write about this in one post and suggested that propylene Glycol might have a similar effect. This is a safe food additive not to be confused with ethylene Glycol, which is used in your car as anti freeze.

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    5. I think Peter has a much better reply than me on this. If you think alcohol has a paradoxical improvement in cognitive function in your child, then perhaps the ethylene glycol intervention is worth a shot.

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    6. Peter, Tyler, thank you for your suggestions.

      My son's "anxiety" could be described as a state of mind with running thoughts torturing him, cannot execute tasks, feels a great deal of pain and he tries to defend himself by stimming persistently (oxidative stress).
      I am quite sure that his brain/cognition malfunctions at that time. I can see him test himself in cognitive tasks by trying to study. When his brain works he overcomes his "anxiety", but when he realises that he cannot process then things are critical for him as nobody knows when/if he overcomes this.
      I believe this kind of anxiety is relevant to cell communication among different brain regions.
      Whatever helps at that time could be life saving.
      While in UK during the summer, we visited a good doctor to check him up if this is in fact schizophrenia with Asperger's. Doctor examined him for almost 3 hours and told us that "it's his rigid thinking" which makes running thoughts and meltdowns.
      Peter, how much Glycol should I trial? You also say a few drops of well aged whiskey, how much approximately would that be for him?
      He is an adult and he can have some well aged whiskey when times are critical. I know that tolerance can build up through alcohol but if this doesn't really help my son is going to quit it. He did that with antidepressants and olanzapine by himself with only a few withdrawal symptoms.
      Finally I should mention that he says that fasting from times to times makes things better.

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    7. Petra, this is all experimentation. In the Japanese study it was something similar to whiskey, but it was not the ethanol it was the aromatic substances that gave the effect. You could try 2ml and see if your son feels any positive effect.

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  5. Hey everyone,

    Some interesting reading on Neuregulins and ASD:

    "our research has revealed that microglia also express NRGs, levels of which are markedly increased in activated microglia."

    "Furthermore, we observed a positive correlation between NRG expression in microglia and peripheral blood mononuclear cells (PBMCs) in mice, suggesting that NRG expression in human PBMCs may mirror microglia-derived NRG expression in the human brain."

    "Levels of NRG1 type III expression in PBMCs were positively correlated with impairments in social interaction in children with ASD"

    "These findings suggest that immune cell-derived NRGs may be implicated in the pathobiology of psychiatric disorders such as ASD."

    https://www.ncbi.nlm.nih.gov/pubmed/28089559

    Have a great day!

    AJ

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  6. Here is some interesting research relevant to the aspartate therapy that may work via the opioid system that also intersects with immunity and pain sensitivity:

    Press Release:

    https://www.sciencedaily.com/releases/2017/01/170117140036.htm

    Paper:

    http://www.sciencedirect.com/science/article/pii/S088915911630109X

    Clonidine an alpha-2-adrenoreceptor (A2A) agonist has been used for a long-time as an autism drug and I recently trialed agmatine sulfate as an alternative (agmatine has many similarities in function and is not really considered a true drug as it is produced in the body).

    The general idea for agonizing A2A receptors is that they suppress noradrenaline which is involved in arousal and many autistics have hyperarousal issues. Opioid addicts who go cold turkey (abstinence) will often have hyperkinetic symptoms and my interest from in aspartate was based upon some very old and forgotten research and the therapy derived from it in treating opioid addicts trying to get through the withdrawal symptoms of abstinence as synthetic endorphins (endogenous morphine) cause A2A autoreceptor desensitisation as well as a reduction of naturally produced endorphins (the same general phenomena happens with steroid users and testosterone production).

    Now with this new research they showed that immune cells can be activated by opioid pain receptors which then secrete opioid peptides (enkephalins, endorphins, dynorphins, etc.) which then induce their pain suppression effects.

    What is really interesting here is that there are a ton of studies linking hyperactivity in the sensory cortex (obviously involved with pain) as well as dysfunction in the insula (also involved in pain) and the anterior cingulate cortex (also very involved in pain). So the question here is if some of the worst autism symptoms could be potentially driven by the opioid system via excessive pain signaling causing this chain of deleterious events leading to doctors and parents trying to address them all like a game of whack-a-mole.

    So for the sake of argument lets assume this hypothesis is correct, well then there are obviously multiple ways of addressing this as laid out in the paper. For one, you can treat decrease or eliminate the particular immune cells that are releasing massive amounts of endorphins either because they are too sensitive or else too numerous in the periphery of the body. You can use opioid blocker therapies like low-dose naltrexone which try and restore healthy opioid signaling or the aspartate therapy I have had success with, and then there is the manner of chelating excess intracellular calcium from the immune cells (I know nothing about this so it is probably one of those many methods you only find in animal research).

    It is also interesting to note that opioid addicts can have severely compromised immunity after chronic abuse. Inflammation is defined as the body's immunological response and chronic inflammation will actually desensitize the body to proper immunological signaling which will make those affected more likely to get sicker in the future. Chronic inflammation is a hallmark of autism, so maybe this research could be on to something in terms of knowing where the focus should be on possibly addressing some immunity compromised autisms at potentially its root level.

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