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Thursday, 19 April 2018

Modulation of IP3 receptors in Autism – Pancreatitis and Caffeine?



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

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

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

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

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

·      Glioblastoma, an aggressive and “untreatable” brain cancer

·      Alzheimer’s disease

·      Huntington’s disease

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

For detail, refer to this Japanese paper:- 


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

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


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

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

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

Pancreatitis IP3R and Caffeine 


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

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

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


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


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

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

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

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





7 comments:

  1. This looks like it could be an interesting paper. A genetic mouse model with ONLY intellectual dysfunction and without any ASD traits.
    https://www.ncbi.nlm.nih.gov/pubmed/29459374

    I wonder what the rescuing compound C is?
    /Ling

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    Replies
    1. Hi Ling,

      Compound C (AKA Dorsomorphin) appears to be a potent AMPK inhibitor.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954437/

      So anyone with a known loss of function mutation in CRBN (or maybe even epigenetic inhibition of its expression) may want to consider an AMPK inhibitor.

      Very interesting, thanks for sharing Ling!

      AJ

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  2. Peter, coffee affects blood sugar function of the liver and may help prevent these atypical diabets symptoms some of us notice right after meals.
    In addition, particularly for people who have to take drugs lifelong, it seems extremely hepatoprotective.
    I know some people cannot tolerate coffee, probably due to chlorogenic acid altering stomach acidity, but they might as well have something small to eat with, to counteract side effects.
    It's also interesting that coffee acts on thermoregulation in a dose dependent manner, raising the core body temperature a little and obviously this may be beneficial for my son feeling cold all the time, again right after meals mostly.
    As for cold feet syndrome we are dealing with,compression socks and troxerutins very much give comfort.I thought this may be useful for someone here whose daughter has jerky, numb legs.
    As you mention coffee has a good amount of flavonoids, troxerutins among them, very well researched for their vasoprotection and glucose metabolism.
    Petra

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  3. Peter, what do you suspect the variant for hypo-active IP3 receptors will be for autism? Also, question -- how should I read your yellow vs. green vs. red highlighting of posts?

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    Replies
    1. The red is the most important. Yellow and green are of equal importance.

      I think the hypo-active variant would be much less likely to show SIB, (no glutamate excitotoxicity, provoked by too much Ca2+)

      Reduced levels of intracellular Ca2+ will affect many things. For example research shows "the level of intracellular Ca2+ as a critical modulator of such NMDAR plasticity".

      Perhaps there would be a correlation between IP3R hyper/hypofunction and NMDAR hyper/hypofunction?

      Delete
    2. "Perhaps there would be a correlation between IP3R hyper/hypofunction and NMDAR hyper/hypofunction?" was what I was wondering. It still boggles me how many things trhoughout the body are not functioning in a nt way with autism. And, since it is early onset (or before) things are pervasively affected as things are growing. It does seem like you want to focus on some powerhouse interventions (like NAC, some of the cancer drugs???) which will affect multiple areas.

      Delete
  4. Peter, yesterday at night,after one dose of donepezil, my son woke up at 5, hyperactive, nonsense talking,hypomanic.It is clear that for my son, more acetylcholine means more dopamine, and will suspend the trial.I have already had a bad experience with Citicoline.For me is enough.Today,second trial, sarcosine. Stopped hyperactivity and after 40 minutes he went to sleep, actually he is sleeping now. I think that in normal circunstances, Sarcosine will have a calming effect and behavior improvement.I have magnesium glycinate for bedtime,with this experience,it should work,also magnesium is a dopamine antagonist.
    Valentina

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