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Wednesday 10 January 2018

A RORα Agonist for Autism?


Today’s post is again about RORα, which was suggested to be a nexus where different biological dysfunctions that lead to autism may converge. I think you can consider RORα like a dimmer switch on your lights, you need to adjust the brightness to give the effect you want.



Fine tuning RORα to tune autism gene expression

I recently came across some research where the scientist clearly has the same idea. He has been working on a synthetic RORα/γ agonist for some years and has investigated its use as both a cancer therapy and an autism therapy.
I have become rather interested in cancer therapies because there are so many overlaps between what can lead to cancer and what exists in autism. The big research money is of course in cancer research.
Tumor suppressor genes/proteins like PTEN and p53 have been shown to be disturbed in autism, as is Bcl-2. The Bcl-2 family of proteins regulate cell death (apoptosis); some members induce cell death and other inhibit it; the balance is important.
Generally it seems that most people with autism might benefit from more PTEN and Bcl-2. 

Autism is a developmental disorder of the nervous system associated with impaired social communication and interactions as well excessive repetitive behaviors. There are no drug therapies that directly target the pathology of this disease. The retinoic acid receptor-related orphan receptor α (RORα) is a nuclear receptor that has been demonstrated to have reduced expression in many individuals with autism spectrum disorder (ASD). Several genes that have been shown to be downregulated in individuals with ASD have also been identified as putative RORα target genes. Utilizing a synthetic RORα/γ agonist, SR1078, that we identified previously, we demonstrate that treatment of BTBR mice (a model of autism) with SR1078 results in reduced repetitive behavior. Furthermore, these mice display increased expression of ASD-associated RORα target genes in both the brains of the BTBR mice and in a human neuroblastoma cell line treated with SR1078. These data suggest that pharmacological activation of RORα may be a method for treatment of autism. 
The RORs have been linked to autism in human in several studies. In 2010, Nguyen and co-workers reported that RORα protein expression was significantly reduced in the brains of autistic patients and this decrease in expression was attributed to epigenetic alterations in the RORA gene. Additional work from this group demonstrated that multiple genes associated with autism spectrum disorder are direct RORα target genes and suggested that reduction of RORα expression results in reduced expression of these genes associated with the disorder leading to the disease. Independently, Devanna and Vernes demonstrated that miR-137, a microRNA implicated in neuropsychiatric disorders, targets a number of genes associated with autism spectrum disorder including RORA. There are also additional links between RORα and autism. Deficiency of Purkinje cells is one of the most consistently identified neuroanatomical abnormalities in brains from autistic individuals, and RORα is critical in development of the Purkinje cells. Significant circadian disruptions have also been recognized in autistic patients, and RORs play a critical role in regulation of the circadian rhythm., Additionally, the staggerer mouse displays behaviors that are associated with autism including abnormal spatial learning, reduced exploration, limited maze patrolling, and perseverative behavior relative to wt mice.

SR1078 is a relatively low potency compound with limited RORα efficacy (3–5 μM EC50Emax 40%), but the efficacy compares favorably to other classes of compounds that have been optimized such as a 38% decrease in the same model induced by the mGluR5 allosteric modulator GRN-529 and a 47% reduction by the mGluR5 antagonist MPEP. Both of these compounds have been optimized and display high potency (single digit nanomolar range at mGluR5) and strong efficacy., Thus, we believe that focused optimization of RORα ligands will provide compounds that will have improved efficacy in this model. It should also be noted that SR1078 has both RORα and RORγ agonist activity and a RORα selective agonist has not yet been developed. Thus, it is possible that the RORγ activity of this compound may also play a role in its efficacy in this model of autism. In summary, we have demonstrated that a synthetic RORα/γ agonist is able to increase the expression of key genes whose decrease in expression is associated with ASD both in cell culture and in vivo. Furthermore, the agonist decreases repetitive behavior in an animal model of autism suggesting that it is possible that ROR agonists may hold utility in treatment ASD. 

Activation of p53 function leading to cell-cycle arrest and/or apoptosis is a promising strategy for development of anti-cancer therapeutic agents. Here, we describe a novel mechanism for stabilization of p53 protein expression via activation of the orphan nuclear receptor, RORα. We demonstrate that treatment of cancer cells with a newly described synthetic ROR agonist, SR1078, leads to p53 stabilization and induction of apoptosis. These data suggest that synthetic ROR agonists may hold utility in the treatment of cancer.  

Results showed that levels of Bcl-2 decreased by 38% and 36% in autistic superior frontal and cerebellar cortices, respectively when compared to control tissues. By the same token, levels of P53 increased by 67.5% and 38% in the same brain areas in autistic subjects vs. controls respectively. Calculations of ratios of Bcl-2/P53 values also decreased by 75% and 43% in autistic frontal and cerebellar cortices vs. controls respectively. The autistic cerebellar values were significantly reduced (p < 0.08) vs. control only. There were no significant differences in levels of β-actin between the two groups. Additionally, there were no correlations between Bcl-2, P53, and β-actin concentrations vs. age or PMI in either group.
These results confirm and extend previous data that levels of Bcl-2 and P53 are altered in three important brain tissues, i.e. frontal, parietal, and cerebellar cortices of autistic subjects, alluding to deranged apoptotic mechanisms in autism.  

Conclusion
Increasing PTEN and Bcl-2 is already part of my Polypill, via the use of Atorvastatin.
There are of course many other genes miss-expressed in autism and we cannot give a drug for each one. We need to identify a handful of nexus, where multiple anomalies can be resolved with a single intervention.
It is good that Thomas Burris, the lead researcher, has been working on SR1078 for at least 6 years, let’s hope he continues to persevere.
I think it highly likely that some types of autism will need the opposite therapy, a RORα antagonist.
My method of attempting to modulate RORα will be different. I come back to my earlier gross simplification of autism :- 

As we have seen in earlier posts, the hormonal dysfunction, this time the balance between testosterone and estradiol, has a direct effect on RORα (and vice versa).



The schematic illustrates a mechanism through which the observed reduction in RORA in autistic brain may lead to increased testosterone levels through downregulation of aromatase. Through AR, testosterone negatively modulates RORA, whereas estrogen upregulates RORA through ER.

androgen receptor = AR 

estrogen receptor = ER

As you might know, many hormones are interrelated, so what are thought of as male/female sex hormones have much wider effects. They impact growth hormones and play a big role in calcium metabolism. They also affect serotonin.
We know that in most autism aromatase is reduced, estradiol is reduced and that there is reduced expression of estrogen receptor beta.
In the ideal world it might indeed be best to use an agonist or antagonist to fine tune RORα.
We have a chicken and the egg situation. Is RORα out of tune in autism because the hormones are disturbed, or vice versa?
We do know that hormones generally have feedback loops, but we also know that increasing a hormone like estradiol via obesity is not fully matched by a corresponding reduction in aromatase. So it looks highly plausible that you can tune RORα via estradiol, and that this could be a long term strategy, not just a short term strategy.
In the case of people with low T3 thyroid hormone centrally (in the brain), giving exogenous T3 may help initially, but in the long term it does not because feedback loops to the thyroid will reduce production of the pro-hormone T4. In the extreme you will make the thyroid gland shut down, this does happen to people using thyroid hormones for depression and even weight loss. 
T3 is quite commonly prescribed by alternative practitioners in the US for autism and also for depression in older people. In Europe this hormone is rarely even available. 
Many phytoestrogens are used as OTC autism therapies. These are dietary estrogens that are structurally similar to the human hormone estradiol and so produce estrogen-like effects. They include soy products, fenugreek, kudzu, EGCG etc.







62 comments:

  1. Thank you for another great post. Peter, can you give me alternatives to statins for increasing PTEN and BCL-2?

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    1. I think I found one in your posts -- sulforaphane (broccoli). Thanks!

      Delete
  2. Peter, would a regular (non contrast) MRI show a deficiency of Purkinje cells? Thanks !

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  3. I an the anonymous above with another question - what types of autism would need a RORa antagonist ? My son has had multiple MRIs and they have all been deemed "normal" which is why I asked if Purkinje cell deficiency would show up in an MRI. Does this mean that he may have the type of autism (he's totally non verbal and has severe cognitive and fine motor deficits, and suspected global dyspraxia). At the risk of sounding immensely stupid (please bear with me as I am new to all this) would a RORa decrease PTEN and BCL-2 ?

    Please advise. Thanks !

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  4. Ugh ! I am so sorry for the incomplete comment above. I am reposting (after editing it) so it sounds coherent !
    -----------------------------------

    I am the anonymous above with another question - what types of autism would need a RORa antagonist ? My son has had multiple MRIs and they have all been deemed "normal" which is why I asked if Purkinje cell deficiency would show up in an MRI ? Does this mean that he may have the type of autism that might benefit from a RORa antagonist ? He's totally non verbal and has severe cognitive and fine motor deficits, and suspected global dyspraxia (he's 8 years old).

    At the risk of sounding immensely stupid (please bear with me as I am new to all this) would a RORa antagonist decrease PTEN and BCL-2 ? Would my son's type of autism be the type to need the antagonist ?

    Apologies for the multiple posts. Thank you so much for any advice you might have for me.

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    1. I would not have great expectations from an MRI, unless it is analyzed by someone with a strong interest in autism and detailed knowledge of the research. Otherwise, they will likely only notice big differences and miss any small ones.

      The paper below shows an MRI can potentially be used to look at Purkinje cells.

      In vivo detection of reduced Purkinje cell fibers with diffusion MRI tractography in children with autistic spectrum disorders
      https://www.frontiersin.org/articles/10.3389/fnhum.2014.00110/full

      If you are new to all this, the place to start is to use drugs that have already shown promise in animal and human trials.

      If your son has no identifiable syndrome; he is 8 years old and has had multiple MRIs and so he likely has idiopathic autism (ie of no known origin), start with bumetanide.

      This will take around two weeks to show effect and you likely have a 50:50 chance of your son responding. If he is a responder, it will change his life.

      That is the best place to start.

      RORa is complex and nobody has proved anything in humans.

      Bumetanide was first shown to work in animal models of autism, then in humans and is now in the later stages of approval as a drug for autism in Europe. Bumetanide is a decades old drug that is very cheap in most countries.

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  5. Peter, thank you ! Do you know if bumetanide can be used in kids who have subclinical epileptiform discharges ? My son has these and is on Topimirate 100 mg twice a day.

    Thanks for your feedback.

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    1. I think it may well resolve these epileptiform discharges. Some people report being able to stop anti epileptic drugs (AEDs). There are reports on this in comments in this blog. Bumetanide shifts the excitatory-inhibitory balance towards inhibitory, which should help reduce excess firing of neurons, but each person is slightly different, so I would keep your Topimirate while you trial bumetanide. If you find bumetanide works, later on do an EEG without Topimirate and see what it shows.

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  6. Thanks, again.

    One other question - an earlier post here in this blog said that if there is very high intracellular levels of chloride due to high inflammation then the child may not respond to the Bumetanide. In that case, it is better to spend time resolving the inflammation first and then trial the Bumetanide ? I mentioned before that my son has chronic urticaria -- is it better to do the Verapamil first ? And if so then how long ?

    For the first time I have hopes for my son and don't want to mess it up. Please advise ? Thanks !

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    1. Please give yourself a name or initials, otherwise it is not possible to know one anonymous from another.

      Yes, if you have any chronic inflammatory condition you have to get that resolved to the extent that it is possible. Some people with mast cell activation do benefit from bumetanide, but as the mast cell problem gets worse, so does the autism and then "bumetanide stops working".

      A very good experienced mainstream physician should be able to treat chronic urticaria. He will not make the connection that an inflammatory condition can make your son's autism worse, or stop it getting better. One reader was prescribed Azithromycin by a senior physician for their son's mast cell problems and had great success, this is an off-label immuno-modulatory therapy.

      Verapamil may indeed help, the effect would be within a few days. Histidine (OTC) at a higher dose than I use, for example 4g a day is now being used widely in supplement for skin conditions.

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  7. Hi I am anonymous above (now with initials).

    Just to confound the situation my boy also has mitochondrial dysfunction - specifically, he has Complex 1 hyperactivation and Complex 4 deficiency, resulting in an abnormal Complex 1 to Complex 4 ratio.

    I live in California and a lot of mainstream doctors do not Rx Bumetanide or Verapamil to patients off-label, unless they are MAPS ($$$$$$) doctors.

    Pretty sure that getting the meds would not be an issue but my question is - are any of the above (verapamil or bumetanide) contra indicated in a child with Mito dysfunction and should these best be done under the guidance of a physician (for my son's and my protection). Thanks !

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    1. Hi GRT, they are prescription drugs so ideally you would use a doctor, but clearly many people do not.

      Some kind of mito dysfunction apparently shows up in many people with autism if tested. I have not heard of anyone suggesting this would limit the use of verapamil or bumetanide.

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  8. Quercetin, I was looking back at Peter's posts and there is quite a bit on Quercetin. I was wondering if anyone has had any success (or otherwise) and what the benefits were for you or your child. Thank you, Maria

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    1. Quercetin turned out to be at least as good as my standard pollen allergy meds, and I have severe pollen allergy since early childhood. This spring I will probably ditch the usual drugs and only go with quercetin. That said, it didn't take away pollen-related raging in my otherwise NT 5 year old. But, it made tantrums a milder and allergy symtoms in general were under control.
      It is easy to try, a lot of people praise it and for using it 2-3 months a year seems harmless.

      /Ling

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  9. Peter, what is your opinion on using Spiranolactone over Bumetanide ? I am asking because it appears to "spare" potassium and my little man (code named Fella) is very hard to get supplements into and also has a rather self-limited diet of rice, more rice, yet more rice and lots of rice.

    For this reason, if I can skip out on the potassium supplements (get away with one less), it's huge for me.

    Thanks !

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    1. GRT, Spironolactone will not reduce intracellular chloride, which is the goal. Some doctors combine Spironolactone with Bumetanide when treating older people, this avoids the potassium problem, but Spironolactone has some other additional effects.

      The effect we want from bumetanide is not the diuresis, that is just the side effect. It blocks NKCC2 giving diuresis and blocks NKCC1 in the brain lowering chloride levels inside neurons. We only really want the second effect.

      There are many ways to give potassium, it is also sold in the form of bulk powder which can be added to food or drink.

      You can add potassium to rice. People use potassium chloride instead of sodium chloride as low sodium table salt.

      I think getting your Fella to increase his potassium intake is not a big challenge, he will likely not even notice.

      Delete
  10. off topic for this entry: Mold mycotoxin and mood disorders
    Asking here if anyone has experience with Great Plains Labs mycotoxin panel. We just received my son's results, and according to their testing, the one mycotoxin that is elevated is Verrucarin A at a level of 11.5 with reference range .5-1.2. Just how bad is that 11.5 reading? Anyone I can compare notes with?

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    1. did you find out anything? My sons came back as 19.8 and trying to learn more. We were told black mold, but we can't find out a source.

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  11. Peter, thank you ! Will stick to the Butanemide with a liberal helping of potassium.

    BTW, I came across this article :

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC320967/

    I am still learning but this makes it seem like the action of Furosemide is identical to the action of the Butanemide ? What is your opinion ?

    Thanks !

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    1. GRT, Furosemide is widely seen as very similar to Bumetanide, but there is one critical difference. Furosemide is an inhibitor of KCC2, which is the transporter that lets chloride exit neurons. So while Furosemide, like Bumetanide reduces the in flow of chloride into neurons, it also reduces the out flow. The net effect of Furosemide is that it can trigger seizures.

      At the moment Bumetanide is the best option, except for those with an allergy to it. They could use KBr, but that does cause acne as a side effect.

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    2. Peter, is potassium bromide as effective? Any case reports on just using it?

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    3. Tanya, it was reading a case report from 150 years ago that triggered my initial interest in KBr. I read a case report about a girl with epilepsy, MR/ID and apparent autism. When her epilepsy was treated with KBr she started to exhibit appropriate play with her doll for the first time. There are no modern case reports in autism. KBr lowers chloride by substituting bromide, it does not inhibit any ion transporter, it us just that bromide crosses more easily than chloride into the neurons. Bromide is very similar to chloride, but more inert.

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  12. Peter and Tyler, is it possible my little trial of mirtazapine (i read here short course can re set sleep cycle) combined with the higher dose of inositol I was tryng for anxiety was the "flipped switch" effect for my son - triggering the mania? Or almost like a serontonin syndrom reaction? Or just mania effect for those susceptible to bi polar (bi polar dx for a cousin).

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    1. and should add susceptible *adolescent* brain

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    2. Tanya, I found this:-

      "Bipolar disorder: Mirtazapine should not be used in treating bipolar disorder unless mood stabilizers are also being used. It can precipitate manic episodes that may be mild or severe, and can lead to delusions, psychosis and rapid cycling."

      www.anti-depressants.com/drugs/snri/mirtazapine/

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    3. oh my. Thanks Peter. Had I had the slightest inkling bi polar being in the gene pool might possibly pose a risk for my son with ASD, I would have never given the mirtazapine a try. Toubling the doctor who prescribed it must not have known either, but that isn't surprising I guess.

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  13. Hi Peter,

    I'm definitely going to campaign to get a Bumetanide script in the near future - a cognitive boost would make such a big difference for us. I'm thinking of starting at 0.5mg X 2 for a month just to make sure we're OK with the drug and then move on to 1mg X 2 with appropriate hydration and potassium supplementation. Any thoughts?

    Also Peter, I'd appreciate your input on the NKCC aspect of the following paper - While I'm waiting on the Bumetanide script I was interested in anything above and beyond Astaxanthin that may help, and found this recent paper, but can't quite decipher the NKCC aspect of it. Hemp Seed Oil looks like it will cross the BBB, but would it potentially have the desired effect on NKCC1?

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698249/

    Thanks very much in advance for your input Peter!

    AJ

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    1. AJ, I found 1mg once a day more effective than 0.5mg twice a day and much more practical.

      Your paper relates to NKCC2, blocking that is one way for a diuretic to work. We want to block NKCC1. I did check and hemp oil is a diuretic, there is no mention on the web of NKCC1 and hemp oil.

      Bumetanide creates a lot of diuresis, I have no idea if hemp oil has this level of potency.

      I think bumetanide is the safest and most reliable choice, whether you get it in Canada or Mexico.

      Delete
    2. Thanks Peter! I'm going to go back to my daughter's doctor armed with the Bumetanide trial info to see if we can get a script. I'll ask for 1mg X 1 - my fingers are tightly crossed as my daughter is at a point where even a moderate boost cognitively will make a big change in her schooling.

      One more question for you - would I then be looking at 1mg X 1 as the initial dose, and then I would look to move up? If so, would I be looking at 2mg X 1 or 1mg X 2?

      Have a great day Peter!

      AJ

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    3. AJ, your daughter is still young and most likely 1mg will work just fine. As she gets older you might later increase to 2mg once a day. The first thing is find out if she is a responder,

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    4. Hi Peter,

      Thanks very much Peter!

      Yes, she is very young and skinny (about 40 pounds), and I think that 1mg per day would be a more palatable recommendation to the doc than 2mgs when the doc doesn't have any experience with Bumetanide for ASD.

      Hoping she is a responder - that would be a game-changer for us.

      AJ

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    5. Hi Peter and community,

      Just an update on two fronts:

      The one doc who would even have considered Bumetanide, will not prescribe it despite the info on the drug (safety, efficacy, etc.). Of course, when I tried a while ago to get it from a Mexican pharmacy, I found out Canadian credit cards do not allow such purchases, and even if I use a money order, it's almost certain to be stopped at the border. Translation - back to the drawing board.

      BUT - I do have another avenue I am pursuing. We did not get funding for a genetic test, so we are paying for it ourselves out of pocket. I'm hoping to get results back in a few weeks. Hope its something that we can address using either approved meds (assuming a doc is willing to write the script) or supplements, assuming the test even finds anything.

      AJ

      On

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    6. I usually get it from Asia but several times I got bumetanide from Ebay (some ship from USA, others from Mexico). Search "Miccil water pills". I never lost a package due to Canadian borders.. yet.

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    7. Thanks Christi!

      I'll see what sources I can find - I have to admit, even buying from a reputable online Mexican pharmacy made me a bit uneasy given the big business that fake pharmaceuticals have become in the world. I'll look into Ebay as you've noted to see how reputable potential sources are.

      Appreciate the comment Christi!

      AJ

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  14. Hi Peter and community,

    I was going through an old (May 2017) Life Extension Magazine when I saw an article on a new test they were adding at the time - a Neurotransmitter panel.

    To me, this would be of great interest, and I was quite pleased to see that it is urine based.

    The specs for the test are here, as well as a PDF sample report:

    http://www.lifeextension.com/Vitamins-Supplements/itemLC100058/Neurotransmitter-Panel

    For me, even if there is one parameter that is outside the norm, the test could be very helpful.

    I wanted to check in with the community to see if anyone had any thoughts on this or if anyone had actually ever run a Neurotransmitter panel, to see what value you may have gotten out of it.

    At $199, it looks like a good option from my standpoint. Again, if I find that even a single parameter is way out of the norm, it would be well worth the cost.

    I'm leaning very heavily towards doing it.

    Thanks for any input!

    AJ

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    1. Hi AJ, We did urine neurotransmitter testing back in our early days of biomed and my understanding is that urine testing is useless. I think even the OAT might give you a better idea of what NTs might be doing.

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    2. Hi Tanya, Thanks for providing the additional insight. There were a few neurotransmitter markers in the OAT testing we did, but I was intrigued by this one as there were a few items that weren't in the OAT test.

      It's too bad if this urine test isn't indicative of what is happening in the CNS with respect to neurotransmitters, as that would be really helpful.

      Thanks for your insights Tanya!

      AJ

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    3. We ran the OAT on Fella 4 years ago and all was in range, except vanillac acid. At the time, I was told it was due to him eating vanilla flavored foods (which he could not have) but my concerns were dismissed.

      I have recently learned that vanillac acid could be a metabolite of adrenalin and this warrants a repeat of his OAT. However, he has also had a lumbar puncture about 5 years ago (OAT was a year later) which also showed normal values for all neurotransmitters but elevated values of neopterin and biopterin ,(inflammation markers) and low normal values of folate.

      So we may as well as just repeat a lumbar puncture as that may be a more accurate representation of what is happening than an OAT.

      JMO.

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    4. Oh yes definitely I just meant as far as least invasive urine tests go. The OAT can shed light on NT cofactors status -like riboflavin and b6 etc. Tyler will come to the rescue to answer this :)

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    5. Hi everyone,

      Further to Tanya's comments, I searched around via Google and she is 100% right...there do appear to be some issues with the accuracy of urine testing for neurotransmitters. As those of you who remember my requirements will know, I'm only looking at non-invasive testing like urine testing.

      When I read the article in the LE magazine about urine NT testing, I thought it would be useful but didn't realize it was unreliable. Too bad, it would have been helpful.

      AJ

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  15. Peter, I followed Aspie's idea of activating sigma 1 receptors and asked a Greek-Russian friend to bring me some Afobazole from Russia. Since my son shows a moderate but clear response to Fluoxetine, which is a sigma 1 receptor agonist, I thought I might have similar results with Afobazole without the side effect of fluoxetine.
    "Are fluoxetine's effects due to sigma-1 receptor agonism?"
    https://www.ncbi.nlm.nih.gov/pubmed/27262678
    I have been using 1(10mg) tablet daily for 10 days. The recommended dose is 10mg three times a day, but not having much and not having clear instructions on how to use it I just remained there.
    I have some similar results with fluoxetine in terms of "freezing" and "learned helplessness" response. Cognition seems fine. My son told me that it helps with making decisions more easily and quickly.
    "σ1 receptor ligands control a switch between passive and active threat responses."
    https://www.ncbi.nlm.nih.gov/pubmed/27239788
    So, Peter, If you happen to know anything useful about Afobazole, please let me know because I would like to continue with it. Also I need to source some more and maybe find an experienced specialist, probably in eastern Europe, to give me instructions. Do you know countries registered with the drug?
    Petra

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    1. Petra and Aspie, could pregnenelone be a sufficient substitute if unable to get afobazole? I plan to research afobazole now for my son and talk to the doctor. Thanks for this tip. I look forward to reading your updates. Petra, is your son still using bumetanide?

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    2. Hi Tanya, pregnenolone, DHEA, fluvoxamine, sertaline, fluoxetine can agonise sigma 1 receptors, as far as I know. I don't use Bumetanide for the time being but have it handy to restart at any time I feel my son needs it.

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    3. Petra, I think Afobazole is only used in Russia and maybe some parts of the former Soviet Union. It is sold online from Russia, but I expect at a much higher price than in a pharmacy.

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  16. Peter, I know you have found great success with bumetanide for classic autism. Have you found that bumetanide helps those with regressive autism? Aspergers? Other than potassium bromide, are there other interventions that work similarly to the effect desired for bumetanide.? Martin

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    1. Martin, bumetanide does not work for everyone, but it helps some people with Asperger's, some with Schizophrenia, some with Down Syndrome and in theory it might help in Alzheimers. Regressive autism means different things to different people, late regressive autism caused by mitochondrial disease is not something the bumetanide seems to help. The best thing is to just try it, a paradoxical response to valium is an indicator that someone is likely to be a responder.

      I suggested that Diamox should also reduce intracellular chloride, via the AE3 exchanger. Diamox does indeed help some readers of this blog.

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  17. Peter, in your opinion / experience, what are the characteristics / profile of the individuals most likely to respond to Bumetanide ?

    Thanks !

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    1. GRT, if I was a doctor and had treated 50 patients, I think I could answer your question. It seems people from severe to mild autism can respond, so anyone with troubling autism should give it a try. The same applies to NAC, which is available everywhere, yet most people do not try it.

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  18. Hi Peter,
    We started back on bumex recently after couple of years and it has been 2 weeks, what we see mostly is more affection almost immediately after he takes it. But not much else.
    My wife wants to really try adhd meds like concerta, guanfesin (10X), one of the developmental peds we see suggested that we can try them and see how they will work, as one of the major issues my son is facing is severe hyper activity, which inhibits his ability to learn.
    Wanted to know your thoughts on these adhd meds, he turned 5 late summer.
    Thanks
    BK

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    1. BK, there are very many drugs for ADHD and people's experiences vary greatly.

      Here is a very long list with reviews:-

      https://www.drugs.com/condition/attention-deficit-disorder.html

      There are numerous possible underlying causes of ADHD and some do overlap with causes of autism.

      It is a case of trial and error with these ADHD drugs, some may help, but others may make things worse.

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  19. I wonder if the same effect of RORa agonist would have natural compound neoruscogenin

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    1. Quite possibly, but you will struggle to get hold of neoruscogenin.

      Ruscogenins were identified among other biologically active compounds in extracts of Radix Ophiopogon japonicus and Ruscus aculeatus, plants that are known for their medicinal properties.

      That suggest Ruscus Aculeatus root extract and Radix Ophiopogon japonicas extract, both of which do exist.

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    2. It is actually easy to get hold of Butcher's Broom Extract Powder, if you are in the US. This is another name for Ruscus Aculeatus.

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    3. Hi all,

      Just to add confirmation of Los-Palos's valuable insight via a pubmed paper:

      https://www.ncbi.nlm.nih.gov/pubmed/23896689

      Abstract
      Plants represent a tremendous structural diversity of natural compounds that bind to many different human disease targets and are potentially useful as starting points for medicinal chemistry programs. This resource is, however, still underexploited due to technical difficulties with the identification of minute quantities of active ingredients in complex mixtures of structurally diverse compounds upon raw phytomass extraction. In this work, we describe the successful identification of a novel class of potent RAR-related orphan receptor alpha (RORα or nuclear receptor NR1F1) agonists from a library of 12,000 plant extract fractions by using an optimized, robust high-throughput cell-free screening method, as well as an innovative hit compound identification procedure through further extract deconvolution and subsequent structural elucidation of the active natural compound(s). In particular, we demonstrate that neoruscogenin, a member of the steroidal sapogenin family, is a potent and high-affinity RORα agonist, as shown by its activity in RORα reporter assays and from its effect on RORα target gene expression in vitro and in vivo. Neoruscogenin represents a universal pharmacological tool for RORα research due to its specific selectivity profile versus other nuclear receptors, its excellent microsomal stability, good bioavailability, and significant peripheral exposure in mouse.

      AJ

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    4. Yes this one research document was the impulse that give me the idea about Butcher's Broom.
      By the way the Butcher's Broom one can buy even here in east EU part, but only as a part of multicompound supplement for treating of varices :-(.
      The pure Butcher's Broom extract powder I'm not possible to buy here. Maybe I didn't dig enough.
      Anyway I'm decided to give it a try since our 6y old son don't respond to bumex anymore. I thing it helped him a lot and he did really good progress but now he's like stuck and waiting for next development nudge.

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    5. Hi Los Palos,

      I figured that's where you got it from. Good find!

      Los_Palos, have you tried Swanson Vitamins or IHerb? They deliver virtually anywhere.

      For Iherb, click on the following link, then use the drop-down menu on the top left to see if they deliver to your country. I've used them a few times.

      https://eu.iherb.com

      For Swanson, check out this page and look at their drop-down menu:

      https://www.swansonvitamins.com/international.html

      Both are good, reliable, good selection, and if they deliver to your country, you're likely to find many good options at good prices (I don't know how much they may charge for delivery to the Eastern EU).

      Best of luck, and thanks for adding real value to the community!

      AJ

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    6. Thanks a lot for the hint with iHerb. I took many times from them - MTHF, broccoli sprouts extract, etc. But I wouldn't suppose I will find butchers broom there.
      Have somebody experience with it? Which one should I order? What dosage should I start with? If there is supposed effect on behaviour what should I await and for how long should I wait to see some outcome?

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    7. Hi Los Palos,

      I suspect there will be very few who have tried it, since the best reason I've heard to try it for ASD is the reason you just found.

      If someone has tried it, I agree with Los Palos, please provide some insights.

      Los Palos, if you try it, kindly share your experience. I checked Iherb and all 4 brands are good ones as far as I know. I usually go with capsules versus tablets so I can easily measure doses by pulling apart the capsule and emptying the amount I want into juice, and then putting the capsule back together again.

      I am not an expert on dosing, certainly for Butcher's Broom, but I usually try to give a dose of something given my child's size. So my child is 5, but skinny (40 pounds or 18 Kg), so I may use 1/3 of the adult dose. I usually start with just a sprinkle for a day or two to ensure that are no allergy issues or other issues

      I usually start a new supplement on the weekend so I can keep an eye on my daughter for any adverse events.

      Again, I am not an expert, only sharing my approach. I am also considering this option based on your finding. I have just done a genetic test so I'm now going to wait for the results before I start anything new, as the test results (if any relevant) may lead me to targets I haven't even considered yet.

      Los Palos, if you haven't already done so, I would highly recommend Organic Acid Testing:

      https://www.greatplainslaboratory.com/organic-acids-test/

      Sample report looks like this:
      https://static1.squarespace.com/static/560ac814e4b067a33438ecea/t/56157053e4b074e29ffe5209/1444245587632/OrganicAcidsSampleReport.pdf

      Tanya on this site informed me about it, it's a urine test that will tell you a lot. It really helped us identify some issues.

      We also ran the Gluten / Casein one, leading us to cutting both of these out of my daughter's diet.

      https://www.greatplainslaboratory.com/glutencasein-peptides-test

      Between knocking out the bad yeast + bugs in her GI tract using an antibiotic and Nystatin, replacing them with good bugs (e.g. Sac Boulardii, others) and also cutting out casein and gluten, we saw one of the best improvements we have seen with anything. Not a cure by any means, but solid improvement in all areas.

      For international orders, you would order here:

      https://healthlinkpartners.com/intl_testkits/

      Hope this is helpful.

      AJ

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    8. Butcher's Broom contains more than just neoruscogenin. It looks like many people find Butcher's Broom helpful for hemorrhoids and varicose veins; apparently neoruscogenin can cause the blood vessels to narrow or constrict.

      Some autism therapies are trying to widen blood vessels.

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  20. The sad thing is that there are a lot of "snake oil salesmen" out there, looking to take advantage of desperate parents looking for some hope and reassurance.

    Forget quacks -- many MAPS *doctors* are extremely pricey but who knows what their success rate really is ? How do they justify their charges / rates ? But don't you dare criticize them or you will have their hencewomen on your back.

    Autism is a big business and desperate parents are ripe for the picking.

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  21. Hey Peter,

    Can we have the scam e-mails from "KATE JOHNSON" removed from the site at your earliest convenience? It would be a shame if even 1 ASD parent fell for this scam - who knows what is in "Dr. Williams" Herbal concoction, and how much "Dr. Williams" will charge (or if the credit card details are all this likely scammer is after)

    Thanks,

    Concerned for desperate but easily scammed parents

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  22. Looks like autismweb.com stopped and autismweb2.com started

    ReplyDelete

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