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Friday 2 October 2015

Is dysregulated IP3R calcium signaling a nexus where genes altered in ASD converge to exert their deleterious effect?





Place de l'Étoile in Paris and the avenues radiating from it.  The Arc de Triomphe in the centre would be the IP3 receptor



There are a small number of researchers in the field of autism who really do seem to know what they are talking about;  one of those is Jay Gargus, from University of California at Irvine.  He is one of the few well versed on ion channel dysfunctions (channelopathies).  Today we look at his recent paper relating to the IP3R calcium channel in something called the endoplasmic reticulum (ER).

Gargus’ recent findings relate to calcium signaling, which we have seen previously in this blog to be dysfunctional in autism.  Blocking one type of calcium channel, with Verapamil, has had a remarkable effect in the children of some of those reading this blog; this has included resolving aggressive behavior, resolving GI problems and, most recently, greatly reducing seizures.  An interesting side effect of this drug is that it protects older people from Type 2 diabetes.

We will also encounter yet another kind of stress, ER stress (endoplasmic reticulum stress), which plays a role in many disorders including Type 2 diabetes and is suggested by some Japanese researchers to play a role in autism.  Interestingly some of my pet autism interventions are known to affect ER stress.

As usual in this blog, I will skip some of the complexities, but we do need to know some new words.  The explanation is mainly courtesy of the remarkable Wikipedia.


Organelle

In cell biology, an organelle is a specialized subunit within a cell that has a specific function.  Individual organelles are usually separately enclosed within their own lipid bilayers.  These lipid bilayers are also extremely important and need to be perfectly intact.  It does appear that these lipid bilayers are a little different in autism.











Components of a typical animal cell:

  1.     Nucleolus
  2.     Nucleus
  3.     Ribosome (little dots)
  4.    Vesicle
  5.    Rough endoplasmic reticulum
  6.    Golgi apparatus (or "Golgi body")
  7.    Cytoskeleton
  8.   Smooth endoplasmic reticulum
  9.   Mitochondrion
  10.   Vacuole
  11.   Cytosol (fluid that contains organelles)
  12.    Lysosome
  13.    Centrosome
  14.    Cell membrane



Endoplasmic Reticulum (ER) and ER Stress

The endoplasmic reticulum (ER) is the cellular organelle in which protein folding, calcium homeostasis, and lipid biosynthesis occur. Stimuli such as oxidative stress, ischemic insult, disturbances in calcium homeostasis, and enhanced expression of normal and/or folding-defective proteins lead to the accumulation of unfolded proteins, a condition referred to as ER stress.


Inositol trisphosphate receptor (InsP3R) or IP3R

IP3R is a Ca2+ channel activated by inositol trisphosphate (InsP3). InsP3R is very diverse among organisms, and is necessary for the control of cellular and physiological processes including cell division, cell proliferation, apoptosis, fertilization, development, behavior, learning and memory. Inositol triphosphate receptor represents a dominant second messenger leading to the release of Ca2+ from intracellular store sites.

It has a broad tissue distribution but is especially abundant in the cerebellum. Most of the InsP3Rs are found in the cell integrated into the endoplasmic reticulum.


Genes and autism

It is a widely held view that autism is essentially a genetic condition with some environmental triggers.

What is strange is that many hundreds, and later I suspect thousands, of genes are known to be implicated.  Do these lead to thousands of unique dysfunctions that ultimately manifest themselves as what we, rather clumsily, describe as “autism”?  This appears to be unlikely, more likely is that a much smaller number of downstream dysfunctions are involved.  This is behind what is suggested later by Gargus.

What I have always found odd is that siblings with idiopathic autism do NOT generally share the same genetic variations.  Most autism is called idiopathic, which means of unknown cause.  This is why I have not done any genetic testing on my son.

If siblings have Fragile X, then of course they do have the same genetic defect; the brother will likely be much more severely affected than the sister.

It occurs to me that unless the idiopathic autistic siblings live under some high voltage power cables, next to a TV transmitter or a chemical factory, the genetic testing must be missing something.  We have seen that sequencing the exome, the current “ultimate genetic test”, in fact only looks at 5% of genome.  We have also seen that in the remaining 95% are the so called enhancers and silencers of the genes in the exome.  We have also seen that overexpression of a perfect gene (as in Down syndrome) can do as much damage as a faulty gene.

My advice is to look in the remaining 95% of the genome.



Gargus, IP3R and Autism

Having completed the introduction now we can move on to the Gargus paper.

He is suggesting that a dysfunction at a specific calcium channel in the ER may be the common dysfunction triggered by “autism genes”.

So far he has only tested his idea on some single gene autisms, fragile X and tuberous sclerosis.
 





Autism spectrum disorder (ASD) affects 2% of children, and is characterized by impaired social and communication skills together with repetitive, stereotypic behavior. The pathophysiology of ASD is complex due to genetic and environmental heterogeneity, complicating the development of therapies and making diagnosis challenging. Growing genetic evidence supports a role of disrupted Ca2+ signaling in ASD. Here, we report that patient-derived fibroblasts from three monogenic models of ASD—fragile X and tuberous sclerosis TSC1 and TSC2 syndromes—display depressed Ca2+ release through inositol trisphosphate receptors (IP3Rs). This was apparent in Ca2+ signals evoked by G protein-coupled receptors and by photoreleased IP3 at the levels of both global and local elementary Ca2+ events, suggesting fundamental defects in IP3R channel activity in ASD. Given the ubiquitous involvement of IP3R-mediated Ca2+ signaling in neuronal excitability, synaptic plasticity, gene expression and neurodevelopment, we propose dysregulated IP3R signaling as a nexus where genes altered in ASD converge to exert their deleterious effect. These findings highlight potential pharmaceutical targets, and identify Ca2+ screening in skin fibroblasts as a promising technique for early detection of individuals susceptible to ASD.


This part I found interesting:-

Because of the ubiquitous nature of IP3R signaling and its diverse roles in almost all cells of the body, deficits in IP3-mediated Ca2+ signaling may not be limited to neurological correlates of ASD, but may also explain other characteristic ASD-associated heterogeneous symptoms, such as those of the gastrointestinal tract and immune system.  Furthermore, since the ER serves as a sensor of a host of environmental stressors, this same mechanism may contribute to the known environmental component
to the ASD phenotype, and holds the potential to reveal relevant stressors.

Is it a coincidence that the Verapamil therapy I propose also benefits autism symptoms linked to the gastrointestinal tract and immune system (mast cells/allergy) and also now seizures (hyper excitability)?  I think not,



Here is the rather easier to read press release from the University:-

UCI researchers find biomarker for autism that may aid diagnostics




Irvine, Calif., Sept. 22, 2015 — By identifying a key signaling defect within a specific membrane structure in all cells, University of California, Irvine researchers believe, they have found both a possible reliable biomarker for diagnosing certain forms of autism and a potential therapeutic target.

Dr. J. Jay Gargus, Ian Parker and colleagues at the UCI Center for Autism Research & Translation examined skin biopsies of patients with three very different genetic types of the disorder (fragile X syndrome and tuberous sclerosis 1 and 2). They discovered that a cellular calcium signaling process involving the inositol trisphosphate receptor was very much altered.

This IP3R functional defect was located in the endoplasmic reticulum, which is among the specialized membrane compartments in cells called organelles, and may underpin cognitive impairments – and possibly digestive and immune problems – associated with autism.

“We believe this finding will be another arrow in the quiver for early and accurate diagnoses of autism spectrum disorders,” said Gargus, director of the Center for Autism Research & Translation and professor of pediatrics and physiology & biophysics. “Equally exciting, it also presents a target of a molecular class already well-established to be useful for drug discovery.”

Study results appear online in Translational Psychiatry, a Nature publication.

Autism spectrum disorder is a range of complex neurodevelopmental disorders affecting 2 percent of U.S. children. The social and economic burden of ASD is enormous, currently estimated at more than $66 billion per year in the U.S. alone. Drug development has proven problematic due to the limited understanding of the underlying causes of ASD, as demonstrated by the recent failure of several much anticipated drug trials.

There are also no current, reliable diagnostic biomarkers for ASD. Genetic research has identified hundreds of genes that are involved, which impedes diagnosis and, ultimately, drug development. There simply may be too many targets, each with too small an effect.

Many of these genes associated with ASD, however, have been found to be part of the same signaling pathway, and multiple defects in this pathway may converge to produce a large functional change.

The UCI scientists detected such a convergence in the IP3R calcium channel in an organelle called the endoplasmic reticulum. Organelles are membrane structures within cells with specialized cellular functions. According to Gargus, diseases of the organelles, such as the ER, are an emerging field in medicine, with several well-recognized neurological ailments linked to two other ones, the mitochondria and lysosomes.

The IP3R controls the release of calcium from the ER. In the brain, calcium is used to communicate information within and between neurons, and it activates a host of other cell functions, including ones regulating learning and memory, neuronal excitability and neurotransmitter release – areas known to be dysfunctional in ASD.
“We propose that the proper function of this channel and its signaling pathway is critical for normal performance of neurons and that this signaling pathway represents a key ‘hub’ in the pathogenesis of ASD,” said Parker, a fellow of London’s Royal Society and UCI professor of neurobiology & behavior, who studies cellular calcium signaling.

To see if IP3R function is altered across the autism spectrum, clinical researchers at The Center for Autism & Neurodevelopmental Disorders – which is affiliated with the Center for Autism Research & Translation – are currently expanding the study and have begun to examine children with and without typical ASD for the same signaling abnormalities. These patients undergo complete behavioral diagnostic testing, and sophisticated EEG, sleep and biochemical studies are performed. This includes the sequencing of their entire genome. Also, skin cell samples are cultured and made available to lab-based researchers for functional assays.

In the area of drug discovery, scientists at the Center for Autism Research & Translation continue to probe the IP3R channel, specifically how it regulates the level of neuron excitability. The brains of people who have autism show signs of hyperexcitability, which is also seen in epilepsy, a disorder increasingly found to be associated with ASD. Cells from individuals who have autism exhibit depressed levels of calcium signaling, and this might explain why these patients experience this hyperexcitability. By restoring the release of calcium from the IP3R, the researchers believe, they can apply a “brake” on this activity.




ER Stress

As we saw above, the endoplasmic reticulum (ER) is the cellular organelle in which protein folding, calcium homeostasis, and lipid biosynthesis occur. Stimuli such as oxidative stress, ischemic insult, disturbances in calcium homeostasis, and enhanced expression of normal and/or folding-defective proteins lead to the accumulation of unfolded proteins, a condition referred to as ER stress.
We know that we usually have oxidative stress in autism and we know that calsium homeostasis is disturbed, so it is not surprising if we found ER stress in autism.

The following paper is not open access but it does suggest that ER stress leads to impaired synaptic function and specifically GABAB dysfunction.  If you respond well to Baclofen, you likely have a GABAB dysfunction.  Based on anecdotal evidence I would suggest that people with Asperger’s and anxiety might well have ER stress, since they are the ones that respond well to baclofen.




The molecular pathogenesis of ASD (autism spectrum disorder), one of the heritable neurodevelopmental disorders, is not well understood, although over 15 autistic-susceptible gene loci have been extensively studied. A major issue is whether the proteins that these candidate genes encode are involved in general function and signal transduction. Several mutations in genes encoding synaptic adhesion molecules such as neuroligin, neurexin, CNTNAP (contactin-associated protein) and CADM1 (cell-adhesion molecule 1) found in ASD suggest that impaired synaptic function is the underlying pathogenesis. However, knockout mouse models of these mutations do not show all of the autism-related symptoms, suggesting that gain-of-function in addition to loss-of-function arising from these mutations may be associated with ASD pathogenesis. Another finding is that family members with a given mutation frequently do not manifest autistic symptoms, which possibly may be because of gender effects, dominance theory and environmental factors, including hormones and stress. Thus epigenetic factors complicate our understanding of the relationship between these mutated genes and ASD pathogenesis. We focus in the present review on findings that ER (endoplasmic reticulum) stress arising from these mutations causes a trafficking disorder of synaptic receptors, such as GABA (γ-aminobutyric acid) B-receptors, and leads to their impaired synaptic function and signal transduction. In the present review we propose a hypothesis that ASD pathogenesis is linked not only to loss-of-function but also to gain-of-function, with an ER stress response to unfolded proteins under the influence of epigenetic factors.



I was surprised how much is known about ER stress, there is even a scientific journal devoted to it.

As is often the case, the literature is again full papers like the one below suggesting something, ER stress in this case, is a good drug target, but then do not suggest any drugs.





Abstract
Cardiovascular disease constitutes a major and increasing health burden in developed countries. Although treatments have progressed, the development of novel treatments for patients with cardiovascular diseases remains a major research goal. The endoplasmic reticulum (ER) is the cellular organelle in which protein folding, calcium homeostasis, and lipid biosynthesis occur. Stimuli such as oxidative stress, ischemic insult, disturbances in calcium homeostasis, and enhanced expression of normal and/or folding-defective proteins lead to the accumulation of unfolded proteins, a condition referred to as ER stress. ER stress triggers the unfolded protein response (UPR) to maintain ER homeostasis. The UPR involves a group of signal transduction pathways that ameliorate the accumulation of unfolded protein by increasing ER-resident chaperones, inhibiting protein translation and accelerating the degradation of unfolded proteins. The UPR is initially an adaptive response but, if unresolved, can lead to apoptotic cell death. Thus, the ER is now recognized as an important organelle in deciding cell life and death. There is compelling evidence that the adaptive and proapoptotic pathways of UPR play fundamental roles in the development and progression of cardiovascular diseases, including heart failure, ischemic heart diseases, and atherosclerosis. Thus, therapeutic interventions that target molecules of the UPR component and reduce ER stress will be promising strategies to treat cardiovascular diseases. In this review, we summarize the recent progress in understanding UPR signaling in cardiovascular disease and its related therapeutic potential. Future studies may clarify the most promising molecules to be investigated as targets for cardiovascular diseases.


However all is not lost, a little digging uncovers several existing substances that affect ER Stress.

Atorvastatin, long part of my autism Polypill, is quite prominent.  Atorvastatin is lipophilic statin, which means it can better cross the blood brain barrier.  By chance it is the statin with the least side effects.




Statins inhibit HMG-CoA reductase, target mevalonic acid synthesis, and limit cholesterol biosynthesis. HMG-CoA reductase is expressed in the membrane of the endoplasmic reticulum (ER). Statins are prescribed to prevent cardiovascular events.
In cultured neonatal mouse cardiac myocytes the lipophilic statin atorvastatin and the hydrophilic statin pravastatin both up-regulated PDI, indicating unfolded protein response (UPR) meant to relieve ER stress. Only atorvastatin increased ER stress, growth arrest, and induced apoptosis via induction of CHOP, Puma, active Caspase-3 and PARP. Dose-dependent release of LDH was only observed in atorvastatin treated cells (1–10 μM). Hearts of mice treated with atorvastatin (5mg/kg/day for 7 months) showed protein aggresomes and autophagosomes when compared to vehicle treated controls. While atorvastatin changed mitochondrial ultrastructure, no differences in cardiac function, exercise ability or creatine kinase levels were found.
We show differential activation of ER stress by atorvastatin and pravastatin in cardiac myocytes. Our results provide a novel mechanism through which specific statins therapeutically modulate the balance of UPR/ER stress responses thereby possibly influencing cardiac remodeling.






Cerebral ischemia triggers secondary ischemia/reperfusion injury and endoplasmic reticulum stress initiates cell apoptosis. However, the regulatory mechanism of the signaling pathway remains unclear. We hypothesize that the regulatory mechanisms are mediated by the protein kinase-like endoplasmic reticulum kinase/eukaryotic initiation factor 2α in the endoplasmic reticulum stress signaling pathway. To verify this hypothesis, we occluded the middle cerebral artery in rats to establish focal cerebral ischemia/reperfusion model. Results showed that the expression levels of protein kinase-like endoplasmic reticulum kinase and caspase-3, as well as the phosphorylation of eukaryotic initiation factor 2α, were increased after ischemia/reperfusion. Administration of atorvastatin decreased the expression of protein kinase-like endoplasmic reticulum kinase, caspase-3 and phosphorylated eukaryotic initiation factor 2α, reduced the infarct volume and improved ultrastructure in the rat brain. After salubrinal, the specific inhibitor of phosphorylated eukaryotic initiation factor 2α was given into the rats intragastrically, the expression levels of caspase-3 and phosphorylated eukaryotic initiation factor 2α in the were decreased, a reduction of the infarct volume and less ultrastructural damage were observed than the untreated, ischemic brain. However, salubrinal had no impact on the expression of protein kinase-like endoplasmic reticulum kinase. Experimental findings indicate that atorvastatin inhibits endoplasmic reticulum stress and exerts neuroprotective effects. The underlying mechanisms of attenuating ischemia/reperfusion injury are associated with the protein kinase-like endoplasmic reticulum kinase/eukaryotic initiation factor 2α/caspase-3 pathway.





ABSTRACT
The nuclear receptor peroxisome proliferator-activated receptor γ (PPAR-γ) is an important target in diabetes therapy, but its direct role, if any, in the restoration of islet function has remained controversial. To identify potential molecular mechanisms of PPAR-γ in the islet, we treated diabetic or glucose-intolerant mice with the PPAR-γ agonist pioglitazone or with a control. Treated mice exhibited significantly improved glycemic control, corresponding to increased serum insulin and enhanced glucose-stimulated insulin release and Ca2+ responses from isolated islets in vitro. This improved islet function was at least partially attributed to significant upregulation of the islet genes Irs1, SERCA, Ins1/2, and Glut2 in treated animals. The restoration of the Ins1/2 and Glut2 genes corresponded to a two- to threefold increase in the euchromatin marker histone H3 dimethyl-Lys4 at their respective promoters and was coincident with increased nuclear occupancy of the islet methyltransferase Set7/9. Analysis of diabetic islets in vitro suggested that these effects resulting from the presence of the PPAR-γ agonist may be secondary to improvements in endoplasmic reticulum stress. Consistent with this possibility, incubation of thapsigargin-treated INS-1 β cells with the PPAR-γ agonist resulted in the reduction of endoplasmic reticulum stress and restoration of Pdx1 protein levels and Set7/9 nuclear occupancy. We conclude that PPAR-γ agonists exert a direct effect in diabetic islets to reduce endoplasmic reticulum stress and enhance Pdx1 levels, leading to favorable alterations of the islet gene chromatin architecture.


PPAR-γ agonist pioglitazone is known to have a positive effect in some autism, but it does have side effects.

Other PPAR-γ agonists include Ibuprofen and Tangeretin (sold as Sytrinol).

ER stress plays a key role in diabetes and some obesity.









Conclusion

So as to Gargus’ question and the tittle of this post:

Is dysregulated IP3R calcium signaling a nexus where genes altered in ASD converge to exert their deleterious effect?

The researchers are now looking at children with and without idiopathic autism to see if dysregulated IP3R calcium is indeed a reliable marker.

Given so many things can lead to behavior diagnosed as autism, I think they will just identify an IP3R cluster.  Hopefully it is a big one.  Then they can find a therapy to  release calcium from IP3R.

Where does ER stress fit into this picture?  Gargus briefly mentions stressors and unfolded protein responses:-

In addition to its role in Ca2+ homeostasis, the ER serves as a key integrator of environmental stressors with metabolism and gene expression, as it mediates a host of broad ranging cell stress responses such as the heat shock and unfolded protein responses

I think he is missing something here. 

The endoplasmic reticulum (ER) is the cellular organelle in which lipid biosynthesis occurs as well as protein folding and calcium homeostasis.

I suspect all three may be dysfunctional.  We have ample evidence of lipid abnormalities in autism and even lipid bilayer abnormalities. The Japanese research referred to above suggests protein folding dysfunction.  Note that what reduces ER stress (statins and tangeretin) also reduces cholesterol.

The good news is that plenty of therapeutic avenues already exist.

The other good news is that after 261 posts of this blog, so many pieces of the autism puzzle seem to be fitting together, not perfectly, but well enough to figure out how to treat multiple aspects of classic autism.

I did stumble across a recent quote by Ricardo Dolmetsch, formerly of Stanford and currently Global Head of Neuroscience at drug maker Novartis.  He also has a son with classic autism.  He was quoted again saying there are currently no drug treatments for core autism.  He knows a thousand times more about biology than me, but he is totally wrong to keep saying that there is nothing you can do beyond behavioral education and, if that fails, institutionalization.  I did write to him a while back and I do feel rather sorry for him, since it was his research on Timothy Syndrome that indirectly led to my Verapamil “discovery”.

Some people are just too clever (him, not me).





22 comments:

  1. Hi Peter, I'm 22 been diagnosed recently with Aspergers. I'm living a sad life where my social skills is just not intuitive, I'm dreadfully quiet, everything is messed up. I wish I don't have ASD because it's seriously debilitating. I'm in search of an off-label medication that could help with the social deficit and wondering if there's any you could suggest.

    ReplyDelete
    Replies
    1. There are many people with Asperger's, with similar issues and they do write about things that they try to make them feel better. Many of the things they use are more modern versions of LSD, so they are not legal substances. If you go on one of those forums you may find something legal and effective.

      The prescription drugs that do help some people include:- baclofen (anxiety), oxytocin (social behavior) you could even try bumetanide (1mg twice a day)

      If you have oxidative stress (highly likely) then NAC may very well make you feel better, try 600mg three times a day . In classic autism, the broccoli sprout powder that makes sulforaphane makes a big impact on mood. Only 2.5 ml /half a teaspoon is needed.

      http://www.supersprout.com.au/broccoli-sprout.html

      Many people also have found that additional potassium, say 250mg twice a day, as a supplement (not a banana) has a positive impact. This is being researched as a therapy and there are solid reasons to support it.

      None of my suggestions affect serotonin. In the Asperger's forums they are mainly talking about substances that do affect serotonin, but most have some big drawbacks, legal and biological.

      Delete
    2. Thanks. I'm from Australia, I guess I'd have to talk to my psychiatrist to try those off-labels.

      I remember when I had low doses of lexapro wow my senses changed. I became socially aware, reading social cues, was talkative, interactive, I had so much done, was not anxious, creative. After about 6 months of this I lost it after a falling into anxiety and depression from an event and could not figure out how to get back to that state that once made me feel normal!

      I wonder why it is taking so long for research into Autism? Is it just that there is low demand, thus few researchers? Because there's so many genetic defects, I hope they are able to trace it to one gene. Anyway, sorry about the rant.

      Thanks for the advice. I'll take a look into that.

      Delete
  2. Peter... I'm confused -- is this research suggesting calcium channel blockers? In parts it read like there wasn't ENOUGH calcium as opposed to too much?

    ReplyDelete
  3. It is confusing, but what the research is showing is that the calcium (and chloride, potassium and even zinc) is often in the "wrong place". Your bones are full of calcium, so there is enough of it. The research really shows that there is aberrant calcium signalling and does not go much further. Gargus' thoughts are quite new. Calcium ion channels are involved in everything all over your body, but since they are part of a dysfunctional system we know to be on the look out for any problems that we do no how to treat. So my Verapamil idea could be thought of as a lucky guess.

    ReplyDelete
  4. Hi Peter,

    Congratulations on reaching 261 posts on this blog. Please keep it going!

    I'm sure that although we're not always commenting I can speak for myself that I am always reading your posts. This really is my 'go-to' and 'starter' site for keeping up with recent developments and new insights.

    Ricardo's quote is disheartening for us parents. Clearly this is not what we want to hear from someone so well versed in biology. You've convinced me that Autism is a biological and not a behavioural disorder.

    Reading the research can be very frustrating at times. They initially show much promise as new vectors of hope but then fizzle-out and remain dormant in the archives of bloggers. The process of trial and error then becomes more fruitful.

    Our continuing administration of NAC and Propolis is serving our 9 year old very well but we really wanted to improve his focus at school. Against all advice I pressed our Doc for a trial of Ritalin. Feedback from the school was unexpected. Next to no improvement in focus/concentration in academic work ... but ... an explosion in social skills and language complexity. How? Why? We're also seeing this at home. It truly is wonderful to see at the shops and with other kids. Then there's the BUT. As the medication wears off the anxiety overshoots the original baseline.

    There just seems to be 'no free lunch' with this condition. To get something you want, you have to sacrifice something else. The Ritalin experiment was interesting though.

    Regards,
    D&G


    ReplyDelete
    Replies
    1. There are many studies I have read on dopamine dysregulation with regards to autism, especially in the frontal cortex. Most suggest that there is too much dopamine as a consequence of not enough serotonin in the brain (both serotonin and dopamine use the same enzyme AADC in converting 5-HTP to serotonin and L-DOPA to dopamine), and I have also read a study suggesting dopamine is high in the autistic brain because the dopamine transporter can function in reverse which means that dopamine builds up way too high (excessively high dopamine is associated with intellectual disability). Since ritalin increases the RELEASE of dopamine in the frontal lobes, I would imagine it would make things worse, rather than better, though I can see how hyperactive subtypes of autism could benefit if low dopamine levels happen to be the main problem as opposed to mutated transporter proteins, or damaged receptors.

      Here is a good overview:

      https://spectrumnews.org/news/diverse-dopamine-defects-found-in-people-with-autism/

      Delete
    2. Just so you know, I also trialed Ritalin. What a disaster!!! He became uber aggressive. I was very disheartened and frustrated. Nothing can make this kid focus! Everything I've tried seems to make him aggressive. NAC - no effect. I tried Bumetanide. I would argue that I didn't get a long enough trial out of my doc, but he was on it for a full month, and we didn't get anything. Then, one day he had an ear infection and he got put on amoxicillin. Dream behavior. He drew pictures and colored in coloring books. Hyperactivity was gone. Focus was there. It was AMAZING!!! Now, I'm quite puzzled. I don't know if I should push for Verapamil or what. But, in response to your quest for something that will help him focus, I just saw an article about atomoxetine working well for children with autism. The only scary side effect is suicidal ideology developing, but I kind of think if it's something your body needs, you won't get the "rare, scary" side effects. Cheers!!

      Delete
    3. Hi Tyler and thanks for the feedback on your Ritalin experience.

      We can really relate to your experience with the aggressive side-effects of Ritalin. We just needed to try something to help with his focus and concentration at school as like yourself we feel nothing can make our child focus at school and it's frustrating as hell. Increased anxiety and aggression were explained to us as likely side-effects.

      Where it gets further frustrating is when you see your child latch onto a topic of interest and research it to the n'th degree (almost always a product) where he is actually teaching you things about it you would never have known yourself. For example, researching a particular product to the extent that all conceivable features across that product range are known to the point where he drags you into the store to test/verify each individual feature to verify what he has researched online is true and then cunningly get you to buy that product.

      I get so confused about intellectual disability and happy to get someone to try and explain it to me qualitatively but not in terms of a so-called number range.

      If only we could get him to apply that tenacity and drive at school and with people but I can see it'll never happen. He just has no drive nor understanding of the need for academic work and never likely will even though we believe and seen he has the tools to do do.

      Will of course look at atomoxetine and thanks for the suggestion. He also is crippled by anxiety.

      Regards,
      D&G

      Delete
    4. Simply boosting dopamine in the frontal lobes won't necessarily improve focus in the brain of someone with autism (especially since dopamine seems to be high most of the time), rather the strategy should be to reduce activity in the hyperactive parts of the brain. In several imaging studies I have read the trend seems to be a hyperactive motor cortex, hyperactive sensory cortex, and hyperactive visual cortex, while the frontal cortex is often dysfunctional or hypoactive in one way or another with poor connections between the frontal cortex and the parietal cortex (the main connections in the default mode network). This is why I think drugs will only do so much because unless they are targeted to specific receptors for brain cells that are unique to a part of the brain, you are always going to have spillover effects. I have what you might call a targeted brain stimulation "therapy" I have been working on for quite a while now (its novel but I need to do a lot of work and source equipment to tease out the details and know for sure if it works as I believe it does) and have had success essentially through mildly retarding activity in the likely hyperactive regions of the brain while mildly stimulating the hypoactive parts of the brain. This is just my anecdotal report here, but really you might want to look into a strategy in tiring out the motor cortex and/or visual cortex somehow so that they don't dominate the activity relative to important cognitive areas like the frontal cortex and parietal cortex that compete with the sensory cortexes for accesss to lower brain areas like the cerebellum which have been shown to be highly irregular in autism.

      Delete
    5. Hi Peter (Tyler),

      In response to both of you in the above.

      We've managed to all but eliminate the laughing and hyperactive behaviour with a strict elimination diet with the Specific Carbohydrate diet based on the work of Elaine Gottschall. It's a right royal ($$$) pain to implement and after the second day we were ready to move on. As the text suggests, you either undertake the program with fanatacism or don't start at all. Bless my wife for her tenacity.

      After three weeks, almost complete cessation in laughing and hyperactive behaviour. No more jumping around and stimming after eating and that 'alocohol-delerious'effect is gone. I never would've believed.

      So for now, it's working. Please may it last as so often historically it hasn't. We are still giving biotin 10mg x2 and the magic Zyrtec on the odd occasion (never let's us down).

      My wife feels I am understating the benefits of the biotin supplementation. I will have to watch more closely.

      However, nothing is improving our child's fear/anxiety of proximity to people. He still goes into a trance when confronted by people. You could call it chronic shyness. Sentences become one word responses with his head down and no chance of any eye contact. It's a complete aversion to people. What's the mechanism behind this and what's the remedy?

      I can tell you what isn't...Zoloft, Risperdal, Ritalin, Vyvanse, Propranolol. We asked for Bumetinide and instead we were given Strattera.

      Our Doc isn't satisfied with the safety profile of Bumetinide in the pediatric population and is seeking further counsel on this before he will consider prescribing.

      I don't even want to start the Strattera. I've read no glowing endorsement rather platitudes at best and horror stories I would rather not contemplate.

      How can you dampen down the fear response? Ironically I've found by increasing it. We were at the beach the other day and our boy got knocked over by a shore wave and this triggered an immense fear response as he just lay on the shore after that. What was striking was the change in his expression. Immense engagement, free flowing conversation with me and others around the outdoor showers. Discussions off-topic as opposed to obsessive favourites. All at a level I would never dare ask for any more. As usual, it was short lived and within the hour it was all gone. Why?

      When our child is nervous, he has a slight stammer where he starts a word and before he finishes pronouncing he starts again. It's like he has to work so hard to draw on the words. In contrast when he is calm, then there is no stammer but rather full easy-flowing language that is coming to him with ease and very little exertion. This is the classical distinction between his two states of being. Very rarely is he in the middle.

      Regards,
      D&G

      Delete
    6. Peter,D&G, I am sorry to interfere with your discussion, but I am also concerned myself about social issues and anxiety. For one thing, I am absolutely convinced those drugs mentioned don't help, on the contrary they might deplete mitochondrial leves of energy when there is an underlying disorder. My son got really worse when he was on medication, before them he had issues and after intensive medication he started having meltdowns and SIB.
      I am going to trial vitamin A to see if we can have the oxytocin effect, or trial oxytocin itself when I find the right product.
      We are on biotin 20mg daily and in the beginning of supplementation we had big results which are not so obvious anymore.
      I am sure most of you have tried magnesium together with vitamin 6 which raises serotonin levels and decreases dopamins levels. The first few days I used it I had good results. I think his body and muscles work better now.
      I will also try other antioxidants in addition to Nac,such as, ALA, Lcarnosine, the second is supposed to improve sociality.

      Delete
    7. D&G, I would suggest you, or your doctor, writes to either Dr Lemmonier (the clinician) or Dr Ben-Ari (the scientist) and ask them about the safety profile of Bumetanide, since hundreds of children have now been treated in France, starting four years ago.

      Since your son is high functioning, there is quite a high chance that he would respond well to Baclofen. The UK pediatrician writing on this blog, was pretty much suggesting that those people who could not get it from their doctor, might as well buy it online. Pretty odd hearing it from a doctor.

      Delete
  5. I am interested if anyone has tried TUDCA (Tauroursodeoxycholic acid) to reduce endoplasmic reticulum stress. I have Asperger's (53) and am giving it a trial run. Sorry to place this comment here, but don't know where else it would suit.
    Peter--thanks very much for you blog... I am working through all the threads and am finding much useful information.

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    Replies
    1. It sounds very interesting, good luck and please keep us posted!

      Delete
    2. I have not heard of anyone trying TUDCA, apparently it lowers vascular endothelial growth factor.

      The drug that seems to help the majority of people with Asperger's is baclofen.

      Delete
  6. https://en.wikipedia.org/wiki/Sigma-1_receptor

    "The sigma-1 receptor (σ1R), one of two sigma receptor subtypes, is a chaperone protein at the endoplasmic reticulum (ER) that modulates calcium signaling through the IP3 receptor.[5] In humans, the σ1 receptor is encoded by the SIGMAR1 gene."

    "An endogenous ligand for the σ1 receptor has yet to be conclusively identified, but tryptaminergic trace amines, as well as neuroactive steroids such as dehydroepiandrosterone (DHEA) and pregnenolone all activate the receptor."

    " The σ1 receptor has been shown to appear in a complex with voltage gated K+ channels (Kv1.4 and Kv1.5), leading to the idea that σ1 receptors are auxiliary subunits.[20] σ1 receptors apparently co-localize with IP3 receptors on the endoplasmic reticulum.[21] Also, σ1 receptors have been shown to appear in galactoceramide enriched domains at the endoplasmic reticulum of mature oligodendrocytes.[22] The wide scope and effect of ligand binding on σ1 receptors has led some to believe that σ1 receptors are intracellular signal transduction amplifiers."

    Cough syrup/DXM (which I have done before to 'test' if I benefit from nmda antagonism, which I indeed did and it produced a pleasant afterglow though distinct from that of an alcohol hangover) is a NMDA antagonist aswell aswell a sigma1 agonist.

    Now another somewhat familiar med that also hits the sigma1 receptor is memantine:

    https://en.wikipedia.org/wiki/Memantine

    Memantine is a nmda antagonist, alpha7 nACHr antagonist, 5ht3 antagonist, d2 agonist and sigma agonist (its profile seems to perfectly fit me, allthough a drug can work different in reality than expected).

    "Alpha-7 nAChR upregulates quickly in response to antagonism, which could explain the cognitive-enhancing effects of chronic memantine treatment."

    I know you mention this before Peter, it makes me very eager to try memantine now, I suspect I will have to be on it atleast a few weeks to make a judgement on it though (need to give enough time for nicotinic receptors to upregulate).

    https://en.wikipedia.org/wiki/Methylphenylpiracetam

    Methylphenylpiracetam is another drug that targets sigma1, as a PAM, but this is impossible to get Im sure.

    My only concern with memantine would be that with long term use downregulation of the sigma1 receptor might occur? (not sure if this is possible though as nmda antagonists are often used to reverse tollerance to alot of drugs, agmatine also does this).

    ReplyDelete
  7. http://www.sciencedirect.com/science/article/pii/S1347861314000176

    http://www.anavex.com/my_uploads/Sigma-1-Receptor-Agonists-as-Potential-Treatment-Options.pdf

    https://en.wikipedia.org/wiki/ANAVEX2-73

    "ANAVEX2-73 acts as a muscarinic receptor and a moderate sigma1 receptor agonist."

    "Sigma1 activation appears to be only involved in long-term memory processes. This partly explains why ANAVEX2-73 seems to be more effective in reversing scopolamine-induced long-term memory problems compared to short-term memory deficits.[1] The sigma-1 receptor is located on mitochondria-associated endoplasmic reticulum membranes and modulates the ER stress response and local calcium exchanges with the mitochondria. ANAVEX2-73 prevented Aβ25-35-induced increases in lipid peroxidation levels, Bax/Bcl-2 ratio and cytochrome c release into the cytosol, which are indicative of elevated toxicity.[clarification needed] ANAVEX2-73 inhibits mitochondrial respiratory dysfunction and therefore prevents against oxidative stress and apoptosis"

    http://www.anavex.com/newlypublished_data_alzheimer/

    https://www.fraxa.org/anavex-data/

    "Anavex 2-73 is a sigma-1 receptor agonist being developed for autism spectrum disorders, including Rett syndrome and Fragile X syndrome, and for Alzheimer’s disease."

    https://globenewswire.com/news-release/2017/05/22/994557/0/en/Anavex-Life-Sciences-Reports-New-Data-for-ANAVEX-2-73-in-Neurodevelopmental-Disorders-Including-Angelman-Syndrome-Data-Presented-at-Antiepileptic-Drug-Trials-XIV-2017-Conference.html

    ReplyDelete
  8. AJ,
    I know your one of the readers who also has been looking into the opioid excess theory, after my first day on memantine and how I feel even on the very low dose of 5mg I feel as this is the direction I should be going, im not sure how much the nmda antagonism plays a role in the effect of memantine, but im very sure sigma receptors play a huge role.

    Im closing in to solving atleast my own problem and I suspect to most of those with aspergers that have ocd/adhd tendencies.

    The social wanting aspect as proven by other papers before is dysfunctional, now low opioids in the brain make one detect that one is vulnerable for threats, this in turn most likely (I am 99% certain on this) rewire/re-activate the social wanting pathways.

    Anti-opioid activity of sigma1 systems
    https://www.sciencedirect.com/science/article/pii/0167011594904693

    "(+)Pentazocine is a potent sigma1 ligand which antagonizes mu, kappa1, kappa3 and delta analgesia. This antagonism is reversed by haloperidol, which blocks both D2 and sigma receptors, but not by sulpiride, a selective D2 drug without sigma activity. Haloperidol (< 1 mg/kg) shifts the dose-response curves for morphine in CD-1 mice approximately 2-fold and is more effective against kappa analgesics. These shifts argue for a tonic activity of this anti-opioid system. This anti-opioid system also contributes to the differences in opioid sensitivity among strains of mice."

    Selective antagonism of opioid analgesia by a sigma system.
    https://www.ncbi.nlm.nih.gov/pubmed/7996472


    Sigma 1 receptor modulation of G-protein-coupled receptor signaling: potentiation of opioid transduction independent from receptor binding.
    Kim FJ, Kovalyshyn I, Burgman M, Neilan C, Chien CC, Pasternak GW. Mol Pharmacol. 2010 Apr; 77(4):695-703
    PMID: 20089882 DOI: 10.1124/mol.109.057083

    Modulation of brainstem opiate analgesia in the rat by sigma 1 receptors: a microinjection study.
    Mei J, Pasternak GW. J Pharmacol Exp Ther. 2007 Sep; 322(3):1278-85
    PMID: 17545312 DOI: 10.1124/jpet.107.121137

    Sigma1 receptor modulation of opioid analgesia in the mouse.
    Mei J, Pasternak GW. J Pharmacol Exp Ther. 2002 Mar; 300(3):1070-4
    PMID: 11861817

    Anti-opioid activity of sigma1 systems
    Pasternak G. Regulatory Peptides. 1994 Nov; 54(1):219-220
    DOI: 10.1016/0167-0115(94)90469-3

    Neurosteroids and sigma1 receptors, biochemical and behavioral relevance.
    Maurice T. Pharmacopsychiatry. 2004 Nov; 37 Suppl 3:S171-82
    PMID: 15547783 DOI: 10.1055/s-2004-832675

    Neuroactive neurosteroids as endogenous effectors for the sigma1 (sigma1) receptor: pharmacological evidence and therapeutic opportunities.
    Maurice T, Phan VL, Urani A, Kamei H, Noda Y, Nabeshima T. Jpn J Pharmacol. 1999 Oct; 81(2):125-55
    PMID: 10591471

    Modulation by neurosteroids of the in vivo (+)-[3H]SKF-10,047 binding to sigma 1 receptors in the mouse forebrain.
    Maurice T, Roman FJ, Privat A. J Neurosci Res. 1996 Dec 15; 46(6):734-43
    PMID: 8978508 DOI: 10.1002/(SICI)1097-4547(19961215)46:6<734::AID-JNR10>3.0.CO;2-U

    So sigma receptors regulate:

    * endoplasmic reticulum IP3 release
    * modulation of antinociception
    * possibly modulate neurosteroids

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  9. Hi Peter,

    Is there any feasible way to directly activate and/or inhibit IP3 receptor channels? I looked up agonists & antagonists and they seem to be mostly obscure chemicals only available to researchers (Xetospongin, 2-APB, Adenophostins, etc).

    You mention calcium channel dysfunctions quite frequently on this site and provide possible treatment options (Verapamil, Gabapentin, Amlopidine) for voltage-gated ones. But what about ligand-gated ones? Specifically IP3R. How would one go about targeting an IP3 Receptor channelopathy directly?

    Thank you for any information. This blog is an invaluable resource for many

    ReplyDelete
    Replies
    1. Greg , researchers are looking into how to target IP3R, but they have not found a good solution yet. Also there are 3 subtypes of IP3R, so it is not simple.

      The cancer and autism protein/gene BCL2 directly interacts with IP3R.

      Delete
    2. Greg, Bcl2 is known to be down regulated in autistic brains. Upregulating Bcl2 will affect IP3R, this should be possible with estradiol. Valproic acid resveratrol or EGCG.

      Delete

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