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Thursday, 19 October 2017

Unstable Blood Flow in Autistic Brains?





Today’s post is complicated, but may be of interest to those people interested in Nitric Oxide therapies (Agmatine, Cocoa Flavanols, Beetroot, Taurine, Citrulline etc) and those who think they are treating earlier hypoxia/ischemia.
As usual, I am making simplifications, but the science behind the general ideas already exists. When it comes to the details regarding VEGF and autism, there are big gaps in the science. 
We have already seen that something as simple as improving blood flow appears to be therapeutic in some people with autism. Perhaps there should even be a post called “cold feet and autism”. 
One reader of this blog, Seth, has commented before that he sees autism as essentially vascular in nature.  Today’s research suggests it does indeed include microvascular abnormalities.
Rather than simply reduced blood flow, the problem, in at least some autism, appears to be unstable blood flow, which is much more complex.
I do take a leap in logic to suggest that this is likely linked to the known abnormalities in Vascular Endothelial Growth Factor (VEGF) and in VEGF receptor 1 (VEGFR-1).  It also appears that the VEGF anomalies that lead to angiogenesis may be part of the reason for the increased prevalence of chronic inflammatory diseases including asthma, atopic dermatitis, psoriasis, and rheumatoid arthritis.
Ideally you might want to normalize VEGF, even later in life. The use of anti-angiogenic drugs has been suggested.  Angiogenesis inhibitors were once seen as potential wonder drugs to treat cancer.
It does seem that just simply targeting vascular resistance is helpful for some people with autism.   
VEGF is regulated by many things, some are highly complex and are usually studied with regard to cancer, like Wnt signaling and Ras. Recall that both Wnt and Ras are relevant to autism. One simple thing that influences VEGF is nitric oxide (NO), but it is not a simple relationship. As highlighted by our reader Tyler, intermittent fasting (IF) can also be used to increase VEGF. Research suggests that intermittent fasting (IF) is actually a simple but potent tool to both prevent and treat metabolic disorders, including but not limited to type 2 diabetes.


In the case of autism, where both VEGF and NO are likely to be low, it does seem quite likely that by increasing the production of NO you will increase the expression of VEGF. So the amino acid L-citrulline is likely to increase VEGF.
In the rat study below, L-citrulline increased eNOS and VEGF; we presume NO also increased. 


Blood Flow in Autistic Brains
Now we get to the autism-specific research.


A team of scientists has found evidence that people with autism have unstable vessels in the brain which prevents the proper delivery of blood flow, according to research published in the Journal of Autism and Developmental Disorders
“In a typical brain, blood vessels are stable, thereby ensuring a stable distribution of blood,” said Patricia Whitaker-Azmitia, PhD, professor in the Department of Psychology and director of the Graduate Program in Integrative Neurosciences at Stony Brook University, N.Y.,  in a statement. “Whereas in the autism brain, the cellular structure of blood vessels continually fluctuates, which results in circulation that is fluctuating and, ultimately, neurologically limiting.”



Sustained angiogenesis may contribute to prolonged neuroplasticity in the ASD brain. We propose the sustained splitting angiogenesis is a necessary component to maintain the heightened neuronal activity reported in ASD patients. Many biological and functional indicators are increased in ASD including cerebral metabolic rate, regional synchronous electrical activity sensitivity to sound; cortical activity in deactivation centers at rest, low-level visuospatial processing, visual-tactile interactions; attention to low-level perceptual information and over-connected, redundant cortical networks. It can be suggested that sustained rearrangement of microvasculature permits excessive shorter and local connections to be maintained and prevents the growth of longer and more complex brain connections required for language and social interactions. Use of anti-angiogenic drugs may provide a novel treatment strategy for reducing neuronal activity in ASD patients by inhibiting vascular plasticity.








Brain tissue from children (left) and adults (right) with autism (top) but not controls (bottom) shows dividing cells lining blood vessels.


Angiogenesis and Lymphangiogenesis
It looks like, at least in today’s subgroup of autism, we want less angiogenesis but more lymphangiogenesis.  The ideal way to do this is via VEGF/VEGFRs.
Here it may be helpful to explain the meaning of some new terminology.

Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels
Angiogenesis is a normal and vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, it is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer.”
Lymphangiogenesis is the formation of lymphatic vessels from pre-existing lymphatic vessels in a method believed to be similar to angiogenesis (blood vessel development).

Lymphangiogenesis plays an important physiological role in homeostasis, metabolism and immunity. Impaired or excessive lymphatic vessel formation has been implicated in a number of pathological conditions including neoplasm metastasis, oedema, rheumatoid arthritis, psoriasis, lymphangiomatosis and impaired wound healing.”


Lymphatic system and the Brain 
As highlighted recently by our reader Tanya, a pretty basic gap in science’s understanding of how the brain works has just been addressed. It is all about where do the waste products produced in the brain go to.
Scientists have found evidence that the brain is connected to body’s central lymphatic system.
This then begs the question of what happens when this system does not work well. Is this a feature of some neurological disease? If that were the case, it would likely be associated with reduced lymphangiogenesis.

Running through your body is a network of channels and junctions called the lymphatic system, which siphons off waste and fluids like a biological sewer.
It was long thought the brain was excluded from this web of anatomical plumbing. After being spotted in mice brains two years ago, researchers have now confirmed the presence of lymphatic vessels in human brains, fueling speculation over the kinds of diseases they might be responsible for.




VEGF and VEGF receptors 
There are four types of VEGF and they act through three types of receptors. Confusingly, the receptors have been given multiple names.


In severe autism there is reduced VEGF, but we do not know which type(s) but there is increased expression of the receptor  VEGFR-1 also known as Flt-1. VEGFR-2 expression is normal, this is the best understood receptor.

This receptor VEGFR-1 is activated by VEGF-A and VEGF-B.  

Objective:

To study vascular endothelial growth factor (VEGF) and its soluble receptors sVEGFR-1 and -2 in autism.

Design and methods:

We measured serum levels of angiogenic molecules in 22 patients with severe autism and 28 controls.

Results:

Patients and controls had similar sVEGFR-2 levels, but VEGF levels were lower and sVEGFR-1 higher in patients with autism.

Conclusion:

The imbalance between VEGF and its receptor sVEGFR-1 may be involved in the pathophysiology of autism.


Hypoxia related autism 
It is well known that hypoxia-ischemia insults early in life can cause cognitive dysfunction and likely autism.  In the very recent paper below, it is suggested that altered VEGF signaling is the mechanism that causes the damage to the brain. 

Neurovascular dysfunction and the role of vascular endothelial growth factor (VEGF) have been explored in neurodevelopmental disorders including schizophrenia, bipolar disorder, major depressive and mood disorders, and autism. These disorders are correlated with hypoxia-ischemia insults during early life and are strongly associated with cognitive dysfunction. This review focuses on the hypoxia-regulated protein, VEGF, to discuss its crucial roles in brain development and function. These data implicate that alterations to VEGF signaling during early life can impair neural development, underlying the severe cognitive deficits observed in neurodevelopmental disorders.
Recent Findings
VEGF has been linked to neurological processes that influence learning and memory. VEGF is advancing towards being a novel biomarker and possible therapeutic for neurological disorders. Prenatal environmental enrichment positively impacted neurotrophic factors, brain structure, and memory in rodent models.
Summary
Understanding the molecular mechanisms of VEGF in neurodevelopment will create intervention strategies for at-risk children born to adverse early-life events. By proactively working with those in a pliable neurodevelopmental state, we hope to ameliorate cognitive deficits to increase their chance to develop into high-functioning adults with disabilities. 

Hypoxia-Induced Angiogenesis - Good and Evil


Hypoxia promotes vessel growth by upregulating multiple pro-angiogenic pathways that mediate key aspects of endothelial, stromal, and vascular support cell biology. Interestingly, recent studies show that hypoxia influences additional aspects of angiogenesis, including vessel patterning, maturation, and function.
VEGF, considered a master regulator of angiogenesis in its own right, causes endothelial cells to detach from the parent vessel and migrate into the neighboring stroma. Hypoxia is the principal regulator of VEGF expression, as it is a direct transcriptional target of both HIF-1α and HIF-2α.



Allergy and inflammation resulting from angiogenesis 
It appears that in some people another consequence of too much angiogenesis is allergy and other inflammatory disease; these are of course often comorbid with autism.  This suggests anti-angiogenic and pro-lymphangiogenic therapies.


Angiogenesis and lymphangiogenesis, the growth of new vessels from preexisting ones, have received increasing interest due to their role in tumor growth and metastatic spread. However, vascular remodeling, associated with vascular hyperpermeability, is also a key feature of many chronic inflammatory diseases including asthma, atopic dermatitis, psoriasis, and rheumatoid arthritis. The major drivers of angiogenesis and lymphangiogenesis are vascular endothelial growth factor- (VEGF-)A and VEGF-C, activating specific VEGF receptors on the lymphatic and blood vascular endothelium. Recent experimental studies found potent anti-inflammatory responses after targeted inhibition of activated blood vessels in models of chronic inflammatory diseases. Importantly, our recent results indicate that specific activation of lymphatic vessels reduces both acute and chronic skin inflammation. Thus, antiangiogenic and prolymphangiogenic therapies might represent a new approach to treat chronic inflammatory disorders, including those due to chronic allergic inflammation.



Figure 1: VEGF-binding properties and distinct VEGF receptor expression on lymphatic and blood vascular endothelium. VEGFs bind to the three VEGF receptor tyrosine kinases, leading to the formation of VEGFR dimers. Blood vascular endothelial cells express VEGFR-1 and VEGFR-2, whereas lymphatic endothelial cells express VEGFR-2 and VEGFR-3. VEGF-A—which binds both VEGFR-1 and VEGFR-2—can directly induce blood and lymphatic vascular remodeling. VEGF-C and -D bind VEGFR-3 and, after proteolytic processing, also VEGFR-2, thus inducing angiogenesis and lymphangiogenesis.


There is clear evidence that in humans, vascular remodeling occurs in many chronic inflammatory disorders. Even though different anti-inflammatory drugs are on the market, there is no specific therapy that interferes with the pathological vascular changes that occur during inflammation. Angiogenesis and lymphangiogenesis are tightly linked to chronic inflammation, and targeting the blood vessels and lymphatic vessels has been shown to be an effective strategy in different experimental mouse models of chronic inflammation. One has to keep in mind, however, that in most conditions the vascular activation likely represents a downstream event that maintains the inflammatory process, but not the pathogenetic cause of the respective disease, which often has remained unknown. Nonetheless, antiangiogenic and prolymphangiogenic therapies might represent new approaches to treat chronic inflammatory disorders, including those due to chronic allergic inflammation.


Conclusion
I did start this post by saying this subject is complicated.
From the previous post on nitric oxide, it looked like L-citrulline, L-norvaline, Agmatine and other NO increasing substances could be therapeutic. Cold hands and feet seem to be very common in autism.
It seems likely that the NO increasing therapies will likely also increase VEGF, which I think is a good thing.
From today’s post we see that rather than just a single VEGF we have five broad types (A,B,C, D and PIGF), but even just VEGF-A has various different forms. We do not have detailed research on autism and specific subtypes of VEGF. 
We have the four different VEGF receptors and we know VEGFR-1 is over expressed. We do not have a clever way to counter this. More VEGFR-3 expression would be helpful and that is again a case of changing the balance between inflammatory cytokines, which as we know is usually disturbed in autism.
The inflammatory cytokine IL-6 induces VEGF-C production which leads to both angiogenesis and lymphangiogenesis; this is why people with cancer and high IL-6 may have a poor prognosis.
Regarding VEGF and autism we clearly lack 95% of the science. Strange things are afoot and we are just guessing.
For the time being, I see increasing vascular permeability via eNOS as therapeutic, even though today’s post suggests that antiangiogenic therapies could be helpful, which may seem contradictory.
The kind of drugs that would reduce the activity of VEGFR-1/Flt-1 would be very expensive cancer drugs.  Hypoxia also downregulates VEGFR-1/Flt-1.
Inflammatory cytokines regulate VEGFR-3/Flt-4 and hence control of lymphangiogenesis.  Interferon gamma (IFNγ) upregulates VEGFR-3/Flt-4, while Interleukin 1 beta (IL1β) down regulates it. 
So more IFNγ and less IL1β might help.
Although expensive, interferon gamma (IFNγ) has been shown to be effective in treating severe atopic dermatitis. This would make sense since it induces lymphangiogenesis and the research suggests this should improve inflammatory disease.


CONCLUSIONS:


We conclude that rIFN-gamma appears to be a safe long-term therapy for patients with severe atopic dermatitis.



So perhaps interferon-gamma (IFNγ) for some autism? Quite possibly, just look for the ones with asthma, atopic dermatitis, psoriasis or juvenile arthritis.






51 comments:

  1. It seems cordyceps has potent antiangiogenic effects,

    Extract of Cordyceps militaris inhibits angiogenesis and suppresses tumor growth of human malignant melanoma cells.
    https://www.ncbi.nlm.nih.gov/pubmed/24789042

    "In this study, we aimed to elucidate the biological role of Cordyceps militaris extract in tumor cells, especially in regulating angiogenesis and tumor growth of a human malignant melanoma cell line. We demonstrated that Cordyceps militaris extract REMARKABLY suppressed tumor growth via induction of apoptotic cell death in culture that links to the ABROGATION OF VEGF PRODUCTION IN MELANOMA CELLS."

    We demonstrated that Cordyceps militaris extract remarkably suppressed tumor growth via induction of apoptotic cell death in culture that links to the abrogation of VEGF production in melanoma cells. This was followed by mitigation of Akt1 and GSK-3β activation, while p38α phosphorylation levels were increased.
    Extract treatment in mouse model xenografted with human melanoma cells resulted in a dramatic antitumor effect with down-regulation of VEGF expression. The results suggest that suppression of tumor growth by Cordyceps militaris extract is, at least, mediated by its anti-angiogenicity and apoptosis induction capacities. Cordyceps militaris extract may be A POTENT ANTITUMOR HERBAL DRUG FOR SOLID TUMORS.

    Now this is in melanoma cells (these are skin cancer cells I think?) and it also does not say which vegf receptors are affected.

    Oddly enough I thus seem to benefit both from VEGF activation aswell as inhibition

    Pharmacological and therapeutic potential of Cordyceps with special reference to Cordycepin
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909570/

    AN ENTOMOPATHOGENIC FUNGUS, Cordyceps sp. has been known to have numerous pharmacological and therapeutic implications, especially, in terms of human health making it a suitable candidate for ethno-pharmacological use.

    Cordycepin: mechanism of action

    * Inhibition of purine biosynthesis pathway
    * Cordycepin provokes RNA chain termination
    * Cordycepin interferes in mTOR signal transduction
    * The product from wild type and cultured Cordyceps has also been shown to significantly decrease blood viscosity and fibrinogen levels preventing myocardial infarction
    * In general, researchers demonstrated that 3–4.5 g of Cordyceps/day is sufficient except in patients suffering from severe liver disease
    * Cordyceps dosage up to 80 g/kg body weight/day for 7 days was injected intraperitonealy in mice and even then it did not cause any fatality
    * It is suggested that CAUTION SHOULD BE TAKEN WHILE TAKING CORDYCEPS BY PATIENTS WHO ARE UNDERDOING ANTI-VIRAL OR DIABETIC DRUG TREATMENTS AS CORDYCEPS CONTAINS HYPOGLYCEMIC AND ANTI-VIRAL AGENTS, which can further affect the dosage of these drugs

    The usage of natural/herbal medicines over the synthetic ones has seen an upward trend in the recent past. Cordyceps being an ancient medicinal mushroom used as a crude drug for the welfare of mankind in old civilization is now a matter of great concern because of its unexplored potentials obtained by various culture techniques and being an excellent source of bioactive metabolites with MORE THAN 21 CLINICALY APPROVED BENEFITS ON HUMAN HEALTH including anti-diabetic, anti-tumor, anti-oxidative, IMMUNOMODULATORY, sexual potentiator and anti-ageing effects (Das et al. 2010b). Cordycepin alone has been widely explored for its anti-cancer/anti-oxidant activities, thus, holding a strong pharmacological and therapeutic potential to cure many dreadful diseases in future. Further investigations need to be focused on to study the mechanistic insight into the MYSTERIOUS POTENTIAL of this medicinal mushroom on human health and promoting its cultivation strategies for commercialization and ethno-pharmacological use of this wonderful herb.

    Seems it as a huge range of potential benefits, Id be interested to see how cordyceps acts on VEGF outside tumor cells.
    Inhibiting VEGF in tumor cells is a good thing, it stops them from growing as far as I know?

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  2. Hi Peter and community,

    First, thank you Peter for another great post. I will be adding beetroot powder and L-Citrulline to my daughters list of supplements, as well as Trehalose shortly so we'll see how that goes.

    Also, I should be getting the results back shortly of mitochondrial testing, OAT, and caseomorphin / geluteomorphin testing, so lots of new info that will hopefully be helpful.

    Speaking of helpful, the following paper just came out recently and I wanted to share:

    "Modeling the interplay between neurons and astrocytes in autism using human induced pluripotent stem cells"

    "Results
    Our results revealed that ASD-derived neurons had a significant decrease in synaptic gene expression and protein levels, glutamate neurotransmitter release and, consequently, reduced spontaneous firing rate. Based on co-culture experiments, we observed that ASD-derived astrocytes interfered with proper neuronal development. In contrast, control-derived astrocytes rescued the morphological neuronal phenotype and synaptogenesis defects from ASD neuronal co-cultures. Furthermore, after identifying IL-6 secretion from astrocytes in our ASD individuals as a possible culprit for neural defects, we were able to increase synaptogenesis by blocking IL-6 levels.

    Conclusions
    Our findings reveal astrocytes contribution to neuronal phenotype and confirm previous studies linking IL-6 and autism, suggesting potential novel therapeutic pathways for a subtype of ASD individuals. This is the first report demonstrating that glial dysfunctions could contribute to non-syndromic autism pathophysiology using iPSCs modeling disease technology."

    http://www.sciencedirect.com/science/article/pii/S0006322317320097

    Very interesting stuff, certainly another piece of the puzzle. What I loved is that when ASD neurons we co-cultured with WT astrocytes, they essentially became normal.

    I believe I'm already tackling IL-6 in several ways, but the key may be to find ways to tackle astrocyte derived IL-6.

    I've posted the self-hacked site on IL-6, and will post any info I find on IL-6 and astrocytes. If anyone finds anything of interest, please share.

    https://selfhacked.com/blog/interleukin-6/

    AJ

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    Replies
    1. Very interesting and seems to intreplay well with the MIA model of autism. Perhaps in the future an Interleukin-6 inhibitor or else an intervention that indirectly reduces Interleukin-6 in at risk mothers such as the obese, those at risk of gestational diabetes, and those with diabetes could be prescribed.

      Here in America you won't find politicians tackling the issue since 70% of us adults are overweight and around 35% are obese, with obesity rates of 40% in adult women. It is getting so bad that only about 25% of 18 year olds can serve in the armed forces, mostly due to obesity disqualifications now. The first politician who says there is an obesity crisis is going to be swiftly voted out of office as a body shamer.

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    2. Yes super interesting indeed. It has been known for a while that prenatal IL-6 is harmful to developing brain and that is is one of the mechanism through which maternal immune activation/inflammation can lead to autism and/or brain injury.

      But what is even more interesting here is that it is the actual neurons of ASD individuals producing endogenous IL-6.

      It is very likely that prental exposure to stressors, including immune ones, changes baby's long-term gene expression, and so more Il-6 is produced later on life.

      I would put all my money on endogenous retroviruses being the central mechanism linking these two things - ie prenatal infection/MIA/stress and screwed immune and brain function in the offspring.

      This further solidifies my long-held suspicion that we won't get to the bottom of treating 'autism', esp more severe types, until we find ways of controlling and/or reversing HERV activation.

      Some further reading: "Activation of the innate immune response by endogenous retroviruses"

      http://www.microbiologyresearch.org/docserver/fulltext/jgv/96/6/1207_vir000017.pdf?expires=1508501596&id=id&accname=guest&checksum=0A2E8191CAD9894C79CD465B329C97FF

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    3. Hi Tyler and Natasa,

      Thank you both for reading the paper, and your comments!

      Tyler - The MIA model certainly seems to have some merit.

      You're absolutely right about an intervention targeting IL-6 for at risk mothers, this would make a lot of sense.

      What I am really intrigued by, and honestly excited by, is the fact that ASD neurons "normalized" when healthy Astrocytes were co-cultured with them.

      If we can ideally find a way to reduce Astrocyte IL-6 expression, then hopefully we can see some improvement in our kids. I did see a paper saying that Resveratrol does this, but because its an estrogenic properties, I'm very hesitant to do so. I'll keep looking, but the fact that ASD neurons (via IPSCs) normalized in normal conditions gives me a lot of hope.

      Have a wonderful day Tyler! And I'll keep you posted on your Trehalose recommendation once I've started using it.

      Natasa - It certainly does look like IL-6 is at least one culprit, and the fact that ASD astrocytes are continuing to produce IL-6 tells us something is going on with our kids' immune systems.

      As I noted to Tyler, my great hope stems from the fact that the ASD neuron phenotype transformed to a normal phenotype when it was co-cultured with a non-ASD astrocytes. That is, if we can find a way to significantly reduce the IL-6 from our kids' Astrocytes, we may see significant improvement.

      I haven't yet delved into the biology of Astrocyte IL-6 production, but the ideal intervention would (in my opinion) have to cross the BBB and either reduce astrocyte IL-6 production, or somehow intervene in the subsequent steps in the neurons once the Astrocyte derived IL-6 interacts with them.

      This paper actually makes me hopeful, since it does appear to allow for normalization of ASD neurons.

      Have a great day Natasa!

      AJ

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    4. Sorry meant to say that it is the astrocytes of ASD individuals producing endogenous IL-6, not neurons.

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  3. Hi Aj,

    Very interesting about the the caseomorphin and geluteomorphin, are there any therapies available or under way that specifically target this?

    Also where can you get these test you are talking about, is it from the 23andme thing? or? would love to know some details if you could share.

    With regards to interleukin-6, allthough high IL-6 is definatly very bad, we still need it to some degree, its very crucial in the response to exercise for example.

    Some scientists believe that very low/absent IL-6 is one of the reasons why excessive amounts of antioxidants diminish/remove the positive effects of exercise.
    However I think it is pretty save to say that adding antioxidants/vitamins that lower IL-6 would only be beneficial for autism as we have way too high IL-6 at baseline. However overdoing it would probably be not a good idea either.

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    Replies
    1. Hi Aspie,

      I know its a controversial theory about the caseomorphin and gluteomorphin impacting ASD, but I always think about that doctor who tried for a long time to convince the medical community that ulcers were caused H. Pylori versus stress, and how at first he was looked at as a quack and then finally people realized he was right.

      So I'm taking the approach that if my daughter's test does indicate that she has caseomorphin or gluteomorphin issues, I will at least try to treat it and see if it makes any impact.

      So the test itself is a urine test, and we're getting it done via Great Plains Labs (through our integrative medicine doc).

      As far as I know, there are really only two ways to try to treat this issue, one being a gluten free casein free diet (this will be a real challenge) or digestive enzymes supplements with DPP IV (DPP4) to help better digest gluten and / or casein.

      My strategy, if the test comes up positive, will be to try to get as close to a gluten free casein free diet and to also use the digestive enzymes in those situations where I can't, and see what the impact is over a period of time (likely about 6 months).

      In terms of IL-6, I agree that we will likely need some, my hope is to find a supplement, drug, or method to really focus on astrocyte-derived IL-6, since that seems to be the issue.

      As I've noted to Tyler and Natasa, the fact that ASD neurons normalized in the absence of the ASD astrocytes, and that astrocyte IL-6 appeared to be the culprit gives me great hope.

      The key question is, which supplement / drug can cross the BBB + inhibit astrocyte IL-6 (or blunt its impact on neurons downstream). If we can find this, it would be worth a shot. I believe I found Resveratrol does this, but an estrogenic compound is not ideal for a 4 year old girl, so I'm looking for something else that impact IL-6 production / impact in the brain.

      I know you do a lot of good research Aspie, so if you find something, kindly share.

      Have a great day Aspie!

      AJ

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    2. Thanks AJ,

      And I do not think its controversial at all, especially since my mother has had crohn's all her life and was bombed with opioids to soften her pain basically all her life and others painkillers.

      Im in the Netherlands, I have no clue where to get the test that you mention but I will definatly dig deeper into it and ask my psychiatrist who I now only see once per 2months on average instead of twice a week a couple of years ago (yes this shows permanent progress is possible and my progess seems maintained).


      With regards to digestion, I tried this product in the past to see how I would respond to it:
      https://nl.iherb.com/pr/Enzymedica-Digest-Gold-with-ATPro-10-Capsules/62940

      My bottle had 30 or 60 pills (been about a year ago, so hard to remember what I was taking then, I do try to journal things now) I was taking 3-4 pills with every meal and I had absolutely zero bloating at all or discomfort! This was before I started clostridicum butyricum and biogaia gastrus (the probiotics Peter recommended on here).
      I believe clostridicum butyricum that 'fixed' my gut *knock wood as I cant look inside my gut what is actually happening :)*. It is available from ebay through japanese sellers and all the times I ordered it (from different sources) always arrived, did take about 3-4 weeks though so keep that in mind.

      Now, through diet I have accomplished great results and once again these seem to be maintained, for example if I eat junk for now once a week I will not get residue headaches the next day and such.
      However I do still notice I get headaches from food that has MSG (monosodium glutamate).
      Out of all the type of grains and carb sources I have tried throughout the years I have found the north african couscous to be the winner.
      It has a somewhat medium-ish fibre content and seems to digest very well, also it is so easy to cook.

      Betaine HCL also helped rebuild my stomach acid levels and I do not need it now anymore.

      Another thing that has helped is going from 5 semi large meals a day to 3 meals a day (and very important no more food after dinner, besides maybe a very small snack if im really hungry in the evening).

      So usually my last meal is at like 6.30pm and my breakfast is at like 7.30am, some of results may also be that when fasting as others have mentioned induces autophagy and cleans the crappy cells out, once again I cannot look in my body what is happening, but the protocol I just mentioned seems to work for me.

      With regards to the digestive enzymes, I simply cannot afford that at the moment (especially the digest gold ones which seem to be very expensive yet effective) with all the other supplements im taking and are on the way.
      Im slowly adding more supplements to my current regime 1 by 1, so it will be easier for me to tell what is beneficial and whats not.

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    3. AJ,

      If you decide to go gluten free you may consider ruling out coeliac in your daughter before. Coeliac disease seems overrepresented in 'autism population', can present atypically and after you go gluten free common coeliac tests will become unreliable. Dietary approach is different in coeliac. I would say the same about gluten and cow's milk allergy as well (this is based on the history of own mistakes).

      As cytokines rather work in network than alone I would be curious about the counter-regulatory and anti-inflammatory IL-10, which, as far as I remember, is able to decrease IL-6 expression among other things.

      A subgroup of children with autism was found to be deficient in IL-10 production capacity (see PMID: 25344730 as an example). I always wondered if naturally occurring IL-10 boost during infectious fever might contribute to fever effect.

      On my search for boosting IL-10 I found corydcepin among few agents able to increase it. It is listed here, at the top of table 1:

      https://www.ncbi.nlm.nih.gov/pubmed/16375698

      The only thing that makes me hesitate to try Cordyceps is that I know too little about it's potential for interactions.

      Delete
    4. Hi Agnieszka,

      Spot on and very good find, it also lists vitamin d3 (I was having also a very good response to this but my blood levels gone too high so had to stop it) and omega3's (also good response).
      On top of that it also confirmed my profound personal experience with cordyceps militaris (also contains cordycepin).
      I ordered it earlier today again from amazon yay and also inositol.

      Ive tried L. Reuteri atcc 6475 as recommended by Peter and also discussed on longecity alot, I do feel like it had a somewhat pro-social effect, but honestly the cordyceps I very strongly feel.

      On top of that I was taking 4-8 gastrus tablets (thats l.reuteri atcc 6475) a day for like 2 months (this is very expensive).

      There does indeed seem to be some proper science behind this particular strain (not just any reuteri strain) in increasing oxytocin and IL-10, but my guess is it is poorly colonized in humans, and would either need an insane dose or another way to permanently colonize it.
      In other words it seems easily overpowered by the allready living colony in the gut and these easily get rid of the positive effects of reuteri atcc 6475.
      Adding a pre-biotic that specficially enhances this strain could be beneficial (I remember I searched for this in the past but was lost in the maze of information lol).

      Probiotic ‘glow of health’: it’s more than skin deep
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354898/

      Human-derived probiotic Lactobacillus reuteri strains differentially reduce intestinal inflammation
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2993169/

      What I remember from the studies they did with this strain is that they could large replicate it with anti IL-17a agents.

      Which makes me wonder if indeed IL-17a reduction is the reason we benefit from raising IL-10, wouldnt it just be easier to find things that lower IL-17a?

      Keep in mind this is speculation though.

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    5. PROGESTERONE INCREASES APOPTOSIS AND INTERLEUKIN 10
      SECRETION BY MATURE MONOCYTE DERIVED DENDRITIC CELLS
      http://www.tandfonline.com/doi/pdf/10.1080/13102818.2007.10817496

      This could also explain the lack of social capacity that happens in autism?

      Females have more progesterone than males (males still have progesterone, but pregnenolone seems to prefer to feed the testosterone producing pathways).
      I wonder if I (and those with similar symptoms as myself) could benefit from a low dose of progesterone (only for adults obviously! it is still a hormone after all!).

      Another one that I have also recommended and have had good experience with, even recommended it the other day to I believe it was Tanya and warned her about the awefull taste of it though:

      Damiana (turnera diffusa/turnera aphrodisiaca):

      Gastroprotective activities of Turnera diffusa Willd. ex Schult. revisited: Role of arbutin
      https://doi.org/10.1016/j.jep.2012.02.030

      * very powerfully lowered interleukin-6 in stomach tissue
      * very powerfully increase interleukin-10 in stomach tissue
      * Administration of arbutin normalized the levels of AST and ALT
      * lowers tnf-a
      * looks very protective of the gut
      * damiana is used as a herbal alternative to progesterone, possibly by binding to its receptors (use google and you will find dozen of pages about it)
      * and what a surprise it also a diuretic.

      Delete
    6. Hi Agnieska and Aspie,

      Agnieszka - thank you for noting that celiacs is more difficult to diagnose in tests after one goes gluten free. I honestly don't believe my daughter has celiac as she has never had any digestive issues, nor issues related to impact from foods.

      As you know, the gluteomorphin hypothesis relates to incomplete digestion of gluten, leaving an opioid-like version of gluten in the person's system, as opposed to an allergic-like reaction to gluten itself, so I am extremely curious to see how my daughter's test results look for both gluten (gluteomorphin) and casein (caseomorphin). If she does have high levels of these incompletely digested proteins in her system, they must be having some negative impact I would imagine. I'm hoping this isn't an issue - my daughter loves her milk and cookies.

      Good point on IL-10! I checked Self-Hacked to see if there were other options to increase IL-10 (I looked at the table in the paper you noted and Cordycepin was the only reasonably accessible one, but the paper was from 2005, so more options may have been discovered in the meantime):

      https://selfhacked.com/blog/il-10/

      I just added Ceylon cinnamon, have been using black cumin seed oil for a long time, and also use Niagen (after reading about it from Tyler). I may look to add Olive Leaf to find yet another mechanism.

      Hopefully we can find an effective IL-6 inhibition mechanism that crosses the BBB.

      Aspie - the doctor who I went through is an integrative medicine doctor, so basically a doctor who uses alternative methods (i.e. supplements, tests). I don't know how easy it is to find one in the Netherlands, but that may help.

      If you want, you can apparently order tests internationally from Great Plains Labs, but I have to be honest, the tests we did (Urine - OAT and casein / gluten) require that the urine sample be frozen, and shipped with a frozen pack to keep the sample cool in shipping. To get the sample from the Netherlands to the US on a rush basis may be extremely expensive.

      The link is as follows:

      http://healthlinkpartners.com/intl_testkits/index.php?cPath=3

      Hopefully someone in Europe offers the same test(s).

      Have a wonderful night both of you!

      AJ

      Delete
    7. Hi AJ,

      Thanks for the detailed explanation, I will definatly look into it allthough im afraid it might be too expensive for me.

      I see you mention Olive Leaf (extract), I have used natures way in the past when my blood pressure was still high and it did seem to help a bit with this.
      However I had an absolute horrible response to it, I felt very ill and off (If you search for olive leaf extract there have been dozen of reports for herxheimer/die-off reaction and apparantly it is well known for possibly causing this), on top of that my obsessive like behaviour, quadrupled, I noticed I didnt go out of my house anymore and even developed some aversion to eating while on it!!!
      It is not to be taken lightly, just a warning.

      With regards to the information selfhacked provides, most of it seems correct, however they often post many many contridicationairy things, so keep that in mind.
      That being said, their list on IL-10 seems to be a decent one.
      SelfHacked has articles written by dozen of authors now, and it seems these days that website is all about making money and not so much about helping people, so once again, keep that in mind.

      Have a nice weekend.

      Delete
  4. Peter and possibly others who know more or have tried Trehalose,

    Seems swanson has it in bulk, what would be a good dosing regimen for it, also does it tend to build in the body after time?
    Im going to systematically work my own list of supplements (yes i know i still have austim after all :) ), ill definatly be trialing this, it seems to affect autophagy which is dysfunctional aswell in autism.

    Just read that its also in alot of medicinal mushrooms, seems these things are so underrated eventhough they are becoming more popular these days (thank god).

    ReplyDelete
    Replies
    1. For oral dosing in humans as much as 100 grams per day was used with positive results related to autophagy. 1 gram of trehalose equates to 4 calories so that is 400 calories in glucose at some point. The high dosage is used to overwhelm the trehalase enzyme which exists in copious amounts in the small intestine (most other sugars are broken down and absorbed in the stomach) as well as in the liver and the blood itself.

      You are not going to see immediate results as it's utility is more related to creating more lysosomes which improves autophagy housekeeping processes. Also the issue of trehalase is a big matter of debate, even though there are human studies suggesting that at least enough trehalose makes it past the intestines to have biological utility beyond being simply a more expensive form of glucose.

      We use the Swansons trehalose but BulkSupplements has it as well. I have no idea which one is best in terms of quality, but for some reason the BulkSupplements product was literally bulkier.

      Delete
  5. Wow at 100grams a day that would be quite expensive im not sure If I can afford that on top of all the other things im using.

    What would be the minimal time to use it to expect some results (assuming I do benefit from autophagy)?
    Also what about all the glucose, Im sure this could lead to insulin resistance with prolonged use?

    ReplyDelete
  6. Insulin resistance happens for many reasons and fructose is one of the main culprits as your intestinal tract and liver only have so many enzymes to process it. Excess fructose gets processed more or less like a poison in the way alcohol does and gets converted straight to fat.

    Trehalose does not seem to do that. Also since it is broken down into glucose in the small intestine, it will cause a much lower rise in blood sugar as it is rate limited by that process which makes it a good natural sugar for diabetics.

    On top of that, trehalose itself blocks the glucose 2 transporter, which increases autophagy in the liver and can help reverse non-alcoholic fatty liver disease via this unique mechanism.

    It is not that expensive compared to other supplements and it has caloric value so in a way it counts as food. It is incompatible with ketosis dieting of course but the 100 grams is.just what was used in that study. I have no idea how much you need for its therapeutic purposes and I suppose part of that involves how many copies of DNA you have for producing the trehalase enzyme.

    As for the results, it is the same you might find for resveratrol in the sense you won't notice it consciously, rather you will have to measure changes in biological function like blood pressure or results from blood tests.

    ReplyDelete
  7. Great post! Add inlammatory bowel disease to this list as well. Another connection for the ASD "gut kid" sub type

    ReplyDelete
  8. I would not worry about resveratrol being a strong estrogenic. When you read a study saying substance X has A,B, and C properties you always have to ask yourself, relative to what?

    ReplyDelete
    Replies
    1. Very true, Im pretty sure resveratrol even has aromatase inhibiting properties aswell, though probably very weak.

      Alot of flavonoids in vedgies/food have some affinity to mildly alter estrogen binding/activity.

      Even sulforaphane has an effect on estrogen, most likely by enhancing its metabolism, on top of that sulforaphane is also being research for prostate cancer and other androgen related cancers.

      Delete
  9. Peter,

    I have noticed there are alot of people who see autism as one problem and have no idea of the subcatagories.
    It might be good to bring to attention of people who visit the blog.

    I notice alot of people just say my son/daughter has autism, then no further description of symptoms of whatsoever.
    Allthough I absolutely hate labeling or catagorizing (lets be honest nobody wants themselves labeled or stickered), I do think it is important to raise awareness of the subtypes.

    Also I think science needs to do more meta studies and try to put all the pieces of the puzzle together, lets be honest there is allready a gigantic amount of information available. Yet connecting the dots hasnt really been done yet. I believe the science is there but the cooperation has been poor in the research world.

    Also how do you feel about making a 'document' section where links to papers (and possibly the .pdf files) are posted.
    Obviously these should should be catagorized under things such as immune function, brain, etcetera.

    ReplyDelete
    Replies
    1. Aspie1983, the regular readers are fully aware that autism has many subtypes, but most visitors to the blog are new ones. The blog already has far too many papers for most people, who really just want to know what supplement will help.

      In reality, it is only by going into details that you can hope to figure out what to do. This can take years, even for the cleverest.

      Delete
    2. Hi Aspie1983,
      I do appreciate your comments, especially those regarding your own experience. Some of them are though repeating stuff already in this blog. Not surprising, since there is so much written that it is really time-consuming to go through it all. A very friendly tip from me is to try anyway. You seem really interested and I can promise that it's worth it. You will get many answers and the community will get not only another clever mind but also a very well educated one! :)

      /Ling

      Delete
    3. Aspie, pretty much nobody in my extended family can name the core three symptoms of autism used for a diagnosis in the United States or at least get close to it and their empathy for my children, my wife and I is just as low. On top of that, I have never asked someone who does not have a child with ASD what the symptoms of autism are without them making comparisons to "Rain Man" or saying something even more ignorant like "people with autism are really smart but not good with people". This in spite of all the "Autism Awareness" in the last decade. Of course, most people here in the United States can't find their own country on a world map (this is sadly true), but they all know who Kim Kardashian and Lebron James are, so maybe it is just a symptom of generalized ignorance on anything not sensational.

      Nevertheless, to even get halfway up to speed on some of these topics requires a monumental amount of effort and time for a lot of parents (such as myself). My wife doesn't understand any of this science even though I try and discuss it with her sometimes, but I would never say I love the kids more than she does (her job had good health care so I had to quit software engineering to deal with this autism stuff as it is near impossible to have a severely autistic child at home and have both parents with full-time jobs). Many parents love their kids but simply don't have the time or the background education to understand a lot of this stuff. Peter tries to simplify things as much as practically possible, but much of the time the truth or at least discussing possible truths is far from simple. Better to not be elitist and hold out a helping hand for those less informed, because everybody in this quest starts out clueless.

      My personal time investment in all of this came pretty early after our first diagnosis and really accelerated after second two children got a diagnosis which to a parent at that time in your life is more or less a death sentence to your family (or at least that is how it feels). I am much more optimistic now, but at the time it did not take too many internet searches to find the true grim statistics for autism diagnoses and expected outcomes. I also, first put my trust in people who professed themselves to be experts because of their "experience" which I bet just about every other parent on this blog has done before reading this blog or similar forums concerning autism treatments. Pretty soon red flags popped up which suggested these "experts" were clueless and were really just in the business of being employed off of the misery of others. That is what led me to learn as much as I could to see if anything could be done other than cede myself and my children to those grim statistics.

      Several years later, I came across something (not medicine, supplements, or anything like that) from luck, curiosity, and experience from hobbying around with a technology a half a decade before, and have since been working on this project for the last 4-5 years nonstop which I hope will make a big difference in the lives of many people (soon).

      Delete
    4. This is a one man show at the moment so things have taken longer than expected because real life gets in the way with four kids and three diagnoses and my oldest who is on the more severe end of things as well as the fact I want to be as thorough as practically possible in getting things right before going public with this. I was hoping to have everything nailed down literally over a year and a half ago, but discovered some new stuff that makes what I have work a lot better and have now have much more scientific understanding in why it works.

      So knowing what I know for better or worse about autism or anything else for me is just a side-effect of having to know a lot about the kind of stuff I have been working on, that is if you care about solving problems and helping people, especially your own kids.

      Also, even though there is a big difference between non-verbal autism (the more severe kind) and high-functioning autism, I think it is a great benefit to hear the perspectives of various autism treatments from "the horses mouth" such as yourself, especially older people such as yourself who may have had to deal with some really bad interventions in the past that for whatever reason are still used for many people who don't have the cognitive capacity to advocate for themselves.

      Since you are outside the purview of the United States (Netherlands) and have high-functioning autism, I would be especially interested in you or any one else not from the USA who is an adult and has an autism diagnosis, "beta-testing" the generally vague "stuff" I have just described here that I hope will improve autism symptoms, and much more for many, many people. America has more lawyers than anywhere else on earth, so bringing this to fruition and navigating the legal minefields relating to anything that is intended to help treat a condition which does not also grow in the ground is not impossible, but still super challenging without the millions in investment capital to start with even though the technology I have developed is completely safe. In fact in much of the USA now you can now sell medical marijuana without actually being a real doctor or pharmacist, but you are nevertheless not allowed to do much more than that when it comes to health care if you are not dues paying member of a medical guild that requires hundreds of thousands of dollars to belong to.

      Also for legal reasons, I can't at this time do anything for children, at least in the United States unless I followed all the red-tape you have to follow for any business concerning health care in this country (especially if you are not an M.D. yourself) and that requires insane amounts of money. I will get over those roadblocks eventually, but in the meantime if you or any other adult with high functioning ASD/Aspergers who lives outside of the United States would like to help out, let me know.

      Delete
    5. Thanks for that Peter, maybe I overreacted in my previous post, but as you probably understand we can only come to solutions through working together.

      As having parents who easily gave up during my youth in trying to improve my situations you can see how this brings up alot of emotions, and it is heartwarming to see that there are tons of people out there that do actually try.

      Delete
  10. Hi Peter and community,

    This post is an extension of the comments on the Naviaux post, but I wanted to post it in this latest article so that it is seen by the community.

    So, I always really believed in Naviaux's hypothesis, and watching the latest vimeo video of his recent talk at TACA made me an even bigger believer.

    I actually learned a few things in his talk, and one was the result of a cartoon he put on the screen. It showed a cell releasing ATP (as a result of CDR) which becomes known as eATP (extracellular ATP) by virtue of it leaving the cell. This eATP then becomes the ligand for various purinergic receptors, which is why my focus on a natural version of the antipurinergic therapy was focused on the P2X and P2Y receptors.

    But today, as I watched the video, a thought struck me - in the video, Dr. Naviaux talked about the benefit of maintaining ATP in the cell, which makes perfect sense as it is the main source of energy for the cell. He noted that Suramin both acts as an antagonist for the puringeric receptors (i.e. P2Xs and P2Ys) but also blocks the channels from which ATP is released into the extracellular space due to CDR.

    The issue of blocking the purinergic receptors, while important, appears to me to be less important than the issue of having ATP secreted from the cells in the first place. If ATP isn't secreted (or if this is reduced significantly), the purinergic receptors are going to get far less signaling.

    I looked for a good image to help illustrate the impact of Pannexin 1:

    https://en.wikipedia.org/wiki/Pannexin#/media/File:Purinergic_signalling.jpg

    To be honest, when I was doing my research on antipurinergic signaling, especially P2X7R, Pannexin 1 would always pop up in the papers. It is the channel through which cells affected by CDR release ATP.

    Therefore, maybe the better target isn't the purinergic receptors, but Pannexin 1! Obviously both would be great, as Suramin does this, but if we can also widen our net to also look for antagonists / inhibitors of Pannexin 1 (or the pathway in CDR that leads Pannexin 1 to allow ATP to be secreted), we may find some good opportunities to treat our kids in the meantime.

    Just a thought, but I wanted to share, as I think it may be a good pathway to pursue.

    I'll share what I find about Pannexin 1 (and its pathway), and I ask that others kindly do this too.

    I hope some will find this of interest!

    AJ

    ReplyDelete
  11. I made a post about Pannexin-1 not too long ago:

    https://epiphanyasd.blogspot.com/2017/01/the-purkinje-rora-estradiol-neuroligin.html?showComment=1485848313964#c5205803367817571798

    ReplyDelete
  12. AJ& Tyler, Probenecid was proposed in an earlier post because as well as blocking Pannexins, it is also an OAT3 inhibitor. As an inhibitor of OATs (organic anion transporters) it affects how drugs are excreted, it increases their plasma concentration and prolongs their effects. This makes an OAT3 inhibitor the perfect partner of bumetanide.

    It would be very interesting to hear from anyone who uses bumetanide and probenecid.

    I think AJ would probably like to hear feedback from anyone using just Probenecid. Many people with autism have high levels of uric acid and Probenecid is mainly used to treat gout, because its effect on OATs will reduce plasma uric acid.

    ReplyDelete
    Replies
    1. Hi Peter,

      As mentioned before my bloodtests indeed show approx. 2 times the tollerable uppper limit of urea.
      Is uric acid the same as urea? I see so many things, BUN? (blood urea nitrogen), uric acid and urea? Are these all the same? I notice some tests are also done with urine, my tests have been bloodtests only so far.

      I have allready found an online source to order this, not saying I will directly order it, but I would be able to obtain it (Bencid - 500mg).
      Its also currently out of stock.

      Delete
    2. Aspie1983, uric acid and urea are both found in urine, but they are different things.

      Uric acid is produced in the body from food that contains purines and from the purines that your body itself produces. Sometimes you body produces too much uric acid or does not excrete it.

      High levels of uric acid cause gout/arthritis.

      Too little uric acid in your blood would suggest a liver or kidney problem.

      It has been known for decades that people with autism can have odd levels of uric acid.

      People with Down Syndrome have high levels of uric acid (and so gout) and this has been suggested to be driven by high levels of oxidative stress (also a feature of autism). High levels of uric acid are protective against MS (Multiple Sclerosis). MS and gout are almost mutually exclusive.

      Uric acid is also a scavenger of peroxynitrite, which should help people with mitochondrial dysfunction.

      There is an old post:-

      The Hyperuricosuric Subtype of Autism, Uridine and Antipurinergic Therapy
      https://epiphanyasd.blogspot.com/2015/11/the-hyperuricosuric-subtype-of-autism.html

      Uric acid is usually tested by a blood test.

      Delete
    3. Hi Peter and Tyler,

      Thank you both for your responses!

      As I looked for a Pannexin-1 inhibitor, Probenecid did pop up, so if anyone has used this, kindly provide your insights (whether its with or without bumetanide).

      I'm assuming that if probenecid alone would be as effective as Suramin, Dr. Naviaux would have used it instead of Suramin, but I am curious to see if it has a positive impact, so that we can use it in the meantime until either Suramin is made available for ASD or another compound is found / developed that mimics Suramin.

      Thanks everyone!

      AJ

      Delete
  13. Tyler and AJ,

    I have just read both your posts about pannexin1, this seems to perfectly fit me (permanent high opioid state), also this seems very common in autism, especially what we see in kids with autism, not showing distress by maternal seperation due to opioid blunting the response.

    As odd as it may sound I think I might benefit from opioid type of withdrawal (from what ive read Pannexin1 activation induces withdrawal?).
    Ofcourse Im not going to touch opioids in any form.

    ReplyDelete
  14. The best alternative to strong mu-opioid antagonists like nalaxone and naltrexone that I have found is L-Aspartic Acid. I have posted extensively about it here so just search the comments section and it might help you and it might not. The science behind it is quite old, but it seems to help my son a lot. Just remember too much opioid antagonism leads to anhedonia so if you notice this you may want to reduce the dose. If you don't notice any anhedonia then you will want to increase the dose and once you notice anhedonia, you will want to decrease it again little by little till the anhedonia goes away which is where you want to be as far as opioid signaling equilibrium is concerned.

    ReplyDelete
  15. Hi Tyler,

    Despite knowing of myself that I have nmda/glutamate dysregulation (probably a mix of both hyper and hypo in differen brain areas) I might try D-AA again, I have done so in the past and it definatly made me feel mentally alive in a different way than regular mitochondria supplements, however I seem to get severe insomnia on D-AA (also had this when I tried ZMA as a source of magnesium in the evening).
    Not to mention very vivid dreams and extremely poor sleep quality (im talking waking up every 20min/30mins then drifting back to sleep in a half awake/half dream state).

    Would you have any idea to counter the sleep problems that it brings to me.

    By the way D-aspartic acid definatly gets stronger with daily use and it seems to build up in the body.

    ReplyDelete
    Replies
    1. D-Aspartic Acid is much different than L-Aspartic Acid. D-Aspartic as you likely well know for a while was thought to increase testosterone, which is not a goal for most people with autism.

      D-Aspartic Acid is synthesized in the body but in very small amounts and does have direct neurological effects. L-Aspartic Acid is much different and seems to have indirect effects in down regulating the opioid system which also indirectly downregulates dopaminergic reward pathways as well.

      Delete
    2. Hi Tyler,

      Yes im aware of its proclaimed uses for testosterone boosting properties, it is just hyped for that and doesnt do anything for that as proven by multiple studies, all my blood tests show normal for testosterone, all I want is more normal hedonic tone.

      Delete
    3. Well then try L-Aspartic Acid which is the best I can suggest for modulating the opioid system besides naltrexone/naloxone which is are strong opioid antagonists. There are also Kappa Opioid receptor agonists as they act kind of like the brake for hedonism tone while mu-opioid receptors act like the gas.

      Agmatine also has indirect effects on the opioid system via a2a adrenergic receptors. One small chinese study used a combination of agmatine and yohimbine in a push/pull mechanism for moderating withdrawal effects in rats. It was a small study from an obscure journal and the level of fraud in Chinese science is quite staggering so that is why I am mentioning that study with an asterisk. Nevertheless, it could be useful information to you in modulating your hedonic tone.

      Delete
  16. Emoxypine, a vitamin b6 structure like russian drug, has anyone tried this?:

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

    "In Russia, emoxypine has a wide range of applications in medical practice. It purportedly exercises anxiolytic,[4][5] anti-stress, anti-alcohol, anticonvulsant, nootropic, neuroprotective and anti-inflammatory action.[citation needed] Emoxypine presumably improves cerebral blood circulation, inhibits thrombocyte aggregation, lowers cholesterol levels, has cardioprotective and antiatherosclerotic action."

    http://photos.imageevent.com/diydefense/awakebrain/MexidolPaper.pdf

    "Thus, not having the direct affinity to benzodiazepine and GABA receptors, mexidol
    exercises the modifying action by intensifying their binding ability. These data together
    with the results of the analyses of mexidol's anxiolytic action with the help of analyzers bring the idea that mexidol's anxiolytic mechanism is determined by its modulatory effect on the benzodiazepine CHLORINE-IONOPHORE receptor complex."

    https://cosmicnootropic.com/products/mexidol

    "The drug has a positive effect on cellular energy production, as it diminishes the effect of free radicals and restores the activity of antioxidant enzymes. Mexidol ® also improves the intracellular protein synthesis, helps the enzyme processes in the citric acid cycle, and facilitates glycose utilization, as well as synthesis and intracellular storage of the ATP. This can prevent pathomorphological changes in the brain caused by ischemia and hypoxia"

    "Mexidol ® has the following effects: anti-ischemic, anti-hypoxic, neuroprotective, and anxiolytic. Many people report strong anxiolytic effects developed during the course of treatment with Mexidol ®"

    Now the claims listed on cosmicnootropic I have not looked up to for reference, but this nootropic website has been around quite long, so Id say its pretty save to assume the information they provide their is based on papers.

    Not sure what it does to chlorine levels and if it has something to with how bumetanide has positive effect for some people with autism.

    ReplyDelete
    Replies
    1. Aspie1983, it is interesting just how many cognitive enhancing and sport performance enhancing drugs are produced in Russia. Undoubtedly some might be helpful for certain types of autism.

      Pantogam works for some people with Asperger's. Mildronate works for tennis stars and my guess is some with mitochondrial disease.

      Delete
  17. Hi Peter,

    Thanks for highlighting that, I have read up once again a bit on it, seems that it is a cns depressant and theres been some reports of people comparing it effects somewhat to baclofen (which made me a crying sleeping zombie), so im kinda carefull with this as you can imagine, that is not to say I wont try it sometime.

    ReplyDelete
  18. So my inositol and cordyceps militaris arived today, I tried 10gram inositol earlier today and now 15gram in the evening, this stuff puts a smile on my face, it allows me to experience joy from social interactions, Im very intrigued what its mechanism of action would be.

    I know IP3 (inositol triphosphate) is a messenger molecule and is involved in oxytocin signalling, but I lack the knowledge to pin it down to its exact mechanism, but from what I understand protein kinase c is involved.

    Anyway the alpha gpc has also arrived but to avoid just creating an insane stack and losing track of whats effective im only adding inositol and cordyceps.

    I'll be visiting the doctor tomorrow and asking for a bloodtest paper for my liver values and urea (will save the paper and get bloodwork drawn start of december), be interesting to see if cordyceps can bring my urea down to 'normal levels' and more importantly allowing me to be socially open, inositol clearly does this, but its effect lasts a few hours, if anything like an inositol agonist exists, PLEASE PLEASE PLEASE let me know.

    ReplyDelete
  19. Inositol increase adiponectin too:

    The effect of myoinositol supplementation on insulin resistance in patients with gestational diabetes.
    https://www.ncbi.nlm.nih.gov/pubmed/21414183

    "There were 69 evaluable patients, 24 in the study group and 45 in the control group. Fasting glucose and insulin, and consequently homeostasis model assessment of insulin resistance, decreased in both groups (50% in the study group vs. 29% in the control group), but the decline in the study group was significantly greater than that in the control group (P = 0.0001). Adiponectin increased in the myoinositol group while it decreased in the control group (P = 0.009)."

    This is in diabetes, but P=0.009 is quite notable.

    Inositol lowers urea?:

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

    "Xanthine oxidase inhibitors are of two kinds: purine analogues and others. Purine analogues include allopurinol, oxypurinol,[2] and tisopurine. Others include febuxostat,[3] topiroxostat, and inositols (phytic acid and myo-inositol[citation needed])."

    Inositol treatment of autism.
    https://www.ncbi.nlm.nih.gov/pubmed/9203092

    "Recent studies suggest that serotonin reuptake inhibitors are helpful in at least some symptoms of autism. Inositol is a precursor of the second messenger for some serotonin receptors, and has been reported effective in depression, panic disorder and obsessive-compulsive disorder. However a controlled double-blind crossover trial of inositol 200 mg/kg per day showed no benefit on 9 children with autism. Since biochemical studies could evaluate inositol in children already receiving serotonin reuptake inhibitors."

    Note this study was done in 1997, which is long ago, and also has never been tried again? plus maybe inositol is only effective in aspergers?

    For those wondering if inositol feels anything like an SSRI, the answer is NO! I absolutely hate how inositol makes me feel, inositol puts a smile on my face, it makes me appreciate life, opens me up, I actually cant think of anything else besides cordyceps that effects me in such a positive way.

    Alpha gpc can also increase adiponectin but I will try that later on.

    Have a nice evening all !!

    ReplyDelete
    Replies
    1. Thoughts on Resveratrol? Mg? Vimpat?

      Delete
  20. Hi AJ,

    Want to talk once more about gluten (gluteomorphin) and casein (caseomorphin) that we talked about a bit earlier, im pretty sure you have tried it before, but im going to ask you anyhow.

    Have you tried using digestive enzyme therapy on your daughter before?

    I came accross the following that might interest you:

    doi.org/10.1054/mehy.2001.1513

    now they do use the product by kirkman called enzymaid in this study (not sure if it is a sponsored study or not but they do mention the product a lot..)

    They go into detail about how their specific combination of enzymes is beneficial for reducing exorphins, especially "analogs of the Dipeptidyl peptidase IV enzyme".

    Another study:
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4540030/

    This one talks about lactase being the main enzyme that is very low in autism.
    Also talks about exorphins (i.e., casomorphins and gluteomorphins or gliadorphin)

    They used Papain 1.6 g and pepsin 0.8 g in this study.

    ReplyDelete
  21. Found an enzyme product that specificially contains DPP IV
    https://nl.iherb.com/pr/Enzymedica-Digest-Spectrum-30-Capsules/74623

    Their digestgold pro is what I used in the past, only done the trial packs, so it was hard to make a judgement as those only contains 10 pills each.

    ReplyDelete
  22. Hi Aspie,

    So I have not yet tried any digestive enzymes, as I ran the gluteomorphin / caseomorphin just recently (through Great Plains Lab) and I'm hoping to get the results this week.

    As it is extremely difficult to exclude gluten and casein from one's diet (especially a little girl who loves milk and cookies), I was going to wait until the test results come back. Hopefully no issues with gluteomorphin or caseomorphin.

    But if there are, our plan is to significantly reduce gluten and casein (ideally eliminate, but this is very tough), and also supplement with a digestive enzyme product so that if something gets through, very little (relative to today) caseomorphin or gluteomorphin will be in my daughter's system.

    The key will be use a product that has DPP IV to help improve digestion of gluten and casein beyond the point where they become gluteomorphin / caseomorphin.

    Having said that, I will ensure that I look for a formula that also has lactase, thanks to the info you provided. If many with ASD are low in lactase, why not ensure that this is also part of a formula.

    I will keep you and the board updated on the test results (should be this week, if not tomorrow) and the subsequent impact of the enzymes combined with a dramatic reduction in gluten and casein if my daughter's levels turn out to be high on the test results.

    Thanks for providing the additional info my friend!

    AJ

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    Replies
    1. Not a problem AJ, it might be worth taking 2 enzyme supplements and take like half the recommended dose one of each.

      Atleast you will have all necesarry enzymes covered then, ofcourse there might also be a dose dependant response.

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  23. Tyler, I will do the Homovanillic and Vanillymandelic acid test to my son,do you think it is woth to have a clearer picture about his dopamine imbalance? Valentina

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  24. Peter, do you know if anything is happening on the research for H4 histamine receptor antagonists? Is this something we should put up on our wishlist to Santa, or uninteresting?
    Actually, I would like to know what treatment options are on your wishlist - that is, medicines that are not available today but at least somewhere in the pipeline.

    /Ling

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