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Friday 19 January 2024

Cerebral Folate Deficiency – increasing cerebral folate without increasing plasma/blood folate, via activating the reduced folate carrier (RFC)

 


Source: https://autism.fratnow.com/blog/folate-transport-systems-i-transmembrane-carriers/


Two readers of this blog have been telling me about the fundamental role of brain energy and metabolism in autism. Marco sent me a book called Brain Energy by a psychiatrist at the Harvard Medical School. He stumbled upon this subject when he encouraged a patient to lose weight using the ketogenic diet. As well as losing weight, the patient’s decades-long psychiatric disorders seemed to vanish. The author, Dr Palmer, now believes that many of his patients actually have metabolic disorders as the underlying basis of their psychiatric symptoms. 

Our reader Natasa is approaching with a similar idea, essentially that autism features a brain running on empty.

Today’s post is about increasing the level of folate within the brain, by targeting similar metabolic pathways to those that will boost “brain energy.”

Low levels of folate within the brain will cause varying degrees of neurological disorder.

There are three ways folate can cross into the brain.

1.     Folate receptor alpha (FRA)

2.     Proton-coupled folate transporter (PCFT)

3.     Reduced folate carrier (RFC)

Autoantibodies to the FRA have been linked to neurodevelopmental diseases, particularly cerebral folate deficiency, schizophrenia and autism. Recent studies have shown that these neurodevelopmental disorders can be treated with folinic acid (leucovorin).

Dr Frye, Professor Ramaekers and others are targeting the problem of low folate in the brain by supercharging the level of folate in the bloodstream and hoping more squeezes through the blood brain barrier.

In my previous post I mentioned that Agnieszka has pointed out the idea of using the supplement PQQ. This targets the third transport mechanism above, it is aiming to get more folate across via  the Reduced Folate Carrier (RFC).

Somebody recently wrote their PhD thesis on exactly this topic:- 

Regulation of Folate Transport at the Blood-Brain Barrier: A Novel Strategy for the Treatment of Childhood Neurological Disorders Associated with Cerebral Folate Deficiency

Camille Alam, Department of Pharmaceutical Sciences, University of Toronto 

Additionally, we provided in vitro and in vivo evidence that RFC expression and transport activity is inducible by another transcription factor, NRF-1. These findings demonstrate that augmenting RFC functional expression through interaction with specific transcription factors could constitute a novel strategy for enhancing brain folate delivery. Modulating folate uptake at the BBB may have clinical significance due to the lack of established optimal therapy for neurometabolic disorders caused by loss of FRα or PCFT function. 

What Camille is saying is that if folate transport mechanism number 1 and/or number 2 are not working, we can reinvigorate mechanism number 3.

So if you have Dr Frye’s folate receptor antibodies, or PCFT isn’t working then you might focus on Reduced Folate Carrier (RFC).

The good news is that we have lots of ways to target Reduced Folate Carrier (RFC).

We do not, it seems, have any clever ways to target PCFT. 

NRF-1 and PGC1-alpha

There is a lot in this blog about PGC1-alpha, because it is the master regulator for biogenesis of mitochondria.

All those people with impaired “brain energy” would love to activate PGC1-alpha.

NRF-1 is an activator of mitochondrial respiratory chain genes. NRF-1 specifically targets genes encoding subunits of the mitochondrial respiratory chain complexes, particularly complexes I, III, and IV. By binding to their promoters, NRF-1 directly stimulates their transcription, leading to increased synthesis of these critical protein components and enhanced oxidative phosphorylation (OXPHOS) capacity.

Synergy between NRF-1 and PGC-1alpha

PGC-1alpha acts as the upstream regulator. Various stimuli, such as exercise, cold exposure, and certain hormones, can trigger PGC-1alpha expression. Once activated, PGC-1alpha directly interacts with and co-activates NRF-1, enhancing its binding to target gene promoters and amplifying its transcriptional activity.

NRF-1 as the downstream effector.  NRF-1 fine-tunes the expression of specific mitochondrial genes, ensuring a balanced and efficient OXPHOS system. This synergy between PGC-1alpha and NRF-1 optimizes mitochondrial function and cellular energy production.

So for Natasa, trying to boost energy production in the brain and in the rest of the body, it would be ideal to have more NRF-1 and more PGC-1alpha

What has optimized mitochondrial function got to do with more folate in the brain?

It turns out that you can increase expression of Reduced Folate Carrier (RFC) via activating NRF-1 and/or PGC1alpha.

So what is good for your brain energy is likely to also be good for your brain folate.

Nuclear respiratory factor 1 (NRF-1) upregulates the expression and function of reduced folate carrier (RFC) at the blood-brain barrier

Folates are important for neurodevelopment and cognitive function. Folate transport across biological membranes is mediated by three major pathways: folate receptor alpha (FRα), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC). Brain folate transport primarily occurs at the choroid plexus through FRα and PCFT; inactivation of these transport systems results in suboptimal folate levels in the cerebrospinal fluid (CSF) causing childhood neurological disorders. Our group has reported that upregulation of RFC at the blood-brain barrier (BBB) through interactions with specific transcription factors, that is, vitamin D receptor (VDR) could increase brain folate delivery. This study investigates the role of nuclear respiratory factor 1 (NRF-1) in the regulation of RFC at the BBB. Activation of NRF-1/PGC-1α signaling through treatment with its specific ligand, pyrroloquinoline quinone (PQQ), significantly induced RFC expression and transport activity in hCMEC/D3 cells. In contrast, transfection with NRF-1 or PGC-1α targeting siRNA downregulated RFC functional expression in the same cell system. Applying chromatin immunoprecipitation (ChIP) assay, we further demonstrated that PQQ treatment increased NRF-1 binding to putative NRF-1 binding sites within the SLC19A1 promoter, which encodes for RFC. Additionally, in vivo treatment of wild type mice with PQQ-induced RFC expression in isolated mouse brain capillaries. Together, these findings demonstrate that NRF-1/PGC-1α activation by PQQ upregulates RFC functional expression at the BBB and could potentially enhance brain folate uptake.

The hugely simple intervention mentioned above is to just take vitamin D. This has nothing to do with brain energy.

Upregulation of reduced folate carrier by vitamin D enhances brain folate uptake in mice lacking folate receptor alpha

Folates are critical for brain development and function. Abnormalities in brain folate transport have been implicated in a number of childhood neurodevelopmental disorders, including cerebral folate deficiency syndrome, hereditary folate malabsorption, and autism spectrum disorders. These disorders have devastating effects in young children, and current therapeutic approaches are not sufficiently effective. In this study, we demonstrate that functional expression of the folate transporter, reduced folate carrier, at the blood–brain barrier and its upregulation by the vitamin D nuclear receptor can remarkably increase folate transport to the brain. These findings provide a strategy for enhancing brain folate delivery for the treatment of neurometabolic disorders caused by folate transport defects.

 Low vitamin D correlates with poor health, dementia, and death from all causes

Taking vitamin D has become popular in recent years.

A correlation does not guarantee causality.  It was thought that vitamin D might be the silver bullet to improved health in older people. It has not proved to be.

Low vitamin D also correlates with less time outdoors, doing some physical activity. Taking vitamin D does not mean you will live longer, but we know for sure that exercise improves many medical concerns that will improve healthy life expectancy.

The concern many people now have regarding skin cancer leads to some healthy active people having low vitamin D. Put on that sunscreen and your exposed skin will not be able to produce your vitamin D.

Vitamin D is important to health and is easy to maintain in the normal range, but it is just one element of good health. It might be one way to increase folate in the brain, for those who need it. 

 

Conclusion

How do you increase folate in the brain?

The obvious way is to put more folate in your blood, this is the standard therapy. You either take calcium folinate tablets or, very rarely, the more potent infusions.

If you have antibodies blocking transport via FRA, you could follow the hypothesis that these antibodies are from a reaction to cow’s milk and try going dairy-free. There is a complex relationship between milk and folate receptor alpha antibodies (FRAA), but direct evidence of milk causing FRAA production is limited.

Milk, particularly cow's milk, contains proteins similar to folate receptor alpha found in humans. Some individuals, mainly those with a genetic predisposition, could develop FRAA that cross-react with these milk proteins. This cross-reactivity would not necessarily mean the milk directly caused FRAA production but might trigger an existing immune response. Some studies, though not all, have found an association between higher milk consumption and increased FRAA levels.

If you want to increase folate transport via our third mechanism, Reduced Folate Carrier (RFC) you have many options:

The obvious first step is to take a vitamin D supplement to raise levels to the high end of normal. This can be done by taking a larger supplement just once a week, because vitamin D has a long half-life.

As you can see from the study below in children there is a correlation between low vitamin D and low folate in children.

 

Evaluation of correlation between vitamin D with vitamin B12 and folate in children

The present study reported a positive correlation between vitamin D and vitamin B12 and folate levels. Regular measurement of these two micronutrient levels in children with vitamin D deficiency is important for public health.

Vitamin D is low in much of the population, even more so in wintertime. It seems particularly low in children with autism, perhaps because they are spending less time playing outside than other children.


Activate NRF-1 and/or PGC1alpha:

1.     Exercise, particularly endurance training

2.     PQQ supplement

3.     Perhaps resveratrol/pterostilbene

4.     Butyric acid / sodium butyrate

5.     The very safe old drug Metformin

6.     Other type 2 diabetes drugs like Pioglitazone

Metformin has been shown to raise IQ in Fragile-X by about 10 points and has a range of metabolic benefits and even cancer preventative effects. This common diabetes medication primarily targets AMPK, an energy sensor molecule upstream of PGC-1alpha. By activating AMPK, metformin indirectly stimulates PGC-1alpha and subsequently NRF1, leading to enhanced mitochondrial function.

Pioglitazone has been researched in autism and is my choice for peak risk spring/summer aggression and self-injury. Pioglitazone can potentially upregulate PGC-1alpha expression through several pathways:

                    Pioglitazone activates AMPK, an important energy sensor molecule. AMPK can then stimulate PGC-1alpha expression through various signaling pathways.

                    Pioglitazone activates PPAR-gamma and PPAR-gamma directly interacts with PGC-1alpha, potentially increasing its activity.

I think Metformin has a better safety profile than Pioglitazone and so better for every day use.

Butyric acid does have the potential to activate PGC-1alpha. Butyric acid is produced in the gut by fermentation. You need “good” bacteria and fiber. People with healthy diet naturally produce it. You can also buy it as a supplement (sodium butyrate) since it has numerous benefits – everything from gut health, bone health to a tight blood brain barrier.

According to a doctor I was talking to recently, nobody wants to hear that exercise is a key part of health. It is free and the side effects are generally all good ones. Endurance exercise will boost NRF1 and PGC1alpha. Many people with autism are overweight, often due to the psychiatric drugs they have been put on.

Sirtuin activators boost NRF1 and PGC1 alpha. There are drugs and foods which can do this, but a potent way is through exercise.

I hope Dr Frye is checking his patients’ vitamin D levels and supplementing to the safe upper limit.

Those taking I/V calcium folinate might want to look at the more potent ways to activate NRF1 and/or PGC1alpha.

 



65 comments:

  1. Hi Peter,

    Excellent post as usual. I can contribute to this post as my daughter is a patient of Ramaekers.

    She was prescribed 14g of Isovorin (Pfizer’s version of Leucovorin which happens to be double the strength) per day and you’ll be happy to know 800IUs of Vitamin D3 per day. He also initially added B2 as precaution to my daughter carrying the MTHFR gene but later dropped it when it was found she was not a carrier.

    Unfortunately it hasn’t been the game changer it is for some but there is still a noticeable effect that both her teachers and therapists have noticed.
    We tried going up a dose but she developed severe OCD so we dropped back.

    Ramaekers did mention something about the method behind using the high dose being the use of different transporters across the blood brain barrier, but I forget the exact one.

    ReplyDelete
    Replies
    1. It might be worth trying PQQ, which is an OTC supplement, and see if it gives a benefit without causing OCD.

      Delete
  2. Thank you for this information!

    My son seems to respond well to folinic acid supplements I've been giving him for a year at 5mg a day. He has also been taking vitamin D, and we will trial pqq. In utero, and as a baby he was very low energy, but things have really changed since I've been treating him with folinic acid and several supplements geared towards mitochondria as well as some targeting specific SNP's he has (I review them through Promethease).

    We trialed pqq for about a week and didn't notice a difference, but maybe we will try it for longer.

    ReplyDelete
  3. Dr. Frye's labs-

    CBC (w/plts/ & autodiff)
    TSH
    Ferritin
    25 hydroxy vitamin d
    antimitochondrial antibodies
    cmp
    carnitine
    lactic acid
    creatine kinase
    acylcarnitine profile
    coEnzyme q10
    IgG with subclasses
    rbc zinc
    homocysteine
    amino acids analysis (all) plasma quantitative
    rbc copper
    organic acids, full panel, quantitative urine
    Whole sequence genome

    -Stephen

    ReplyDelete
    Replies
    1. Opps, I forgot to add the FRAT test which I already had done and GI mapping by Dr. Data.

      Delete
    2. Yes, I was wondering why the FRAT test was not on the list.

      Delete
  4. As of my understanding, overexcitability in the brain will inevitably lead to a higher metabolic demand. If that demand can't be met, you're in trouble.
    IMHO autism and many disorders that are considered "neurological" are in reality made up of that vortex of neuro/immune/metabolic issues triggering each other. (Sure, one could add oxidative/nitrosative stress and barrier breakdowns etcetera to the equation too. It's still a vortex.)
    While some parents will actually find out the underlying cause of their child's autism and can work from that point, the most useful strategy in general would be to test interventions for each dysfunction above. For example: If epilepsy is not treatable with the usual drugs targeting ion channels, then try something that works do dampen inflammation and/or something that helps up metabolic supply. Some people will see that the E/I imbalance gets better from this, almost like a side effect.

    There's so many tools in the toolbox.

    /Ling

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    Replies
    1. Hi Ling,

      "are in reality made up of that vortex of neuro/immune/metabolic issues triggering each other. (Sure, one could add oxidative/nitrosative stress and barrier breakdowns etcetera to the equation too. It's still a vortex.)"

      Yes, this is well phrased, imho.

      I've been reading quite a bit about me/cfs and long covid recently, and your description is how I've been thinking about those conditions. It seems like a combination of events (usually including an infection) pushes the body into a state where the immune activation / oxidative stress / lack of energy are all feeding each other, and the body fails to recover by itself.

      Perhaps this is a generic description that applies to many, many conditions? The requirement is then to figure out the useful kinds of anti-oxidants, immune system adjustments (anti-histamines / mcas / boosters / ???), metabolic changes (fat/carb diet, rest/exercise), drug interventions that minimise symptoms* and help the body get itself back to a healthy state.

      * assuming that minimising symptoms is the way forward, may not always be??

      Aspie2

      Delete
    2. I wonder why it seems so easy to get stuck in this vortex where the body harms itself, and why it is so hard to escape it. It doesn't make sense really, our bodies are designed to strive for balance, not escalation. Sure, in parts of autism you can point to genetic mutations that continuously will keep the body off balance... But in ME/cfs and long covid it's really odd that otherwise healthy adults are suddenly trapped in this nasty loop and stay there for eternity.

      While addressing parts of the vortex (like E/I balance, oxidative stress, metabolic issues, inflammation) helps relieve symptoms, I don't know if it really helps escaping the whole 'vortex state'. At least for brain inflammation we know that overactivated brain immune cells live on for around 4 years, which gives a hint of the time it takes to escape just that certain part of the vortex.
      It echoes the ideas of Naviaux of different stages of (impaired) healing. If I recall him correctly, he's suggesting that the path to healing is not necessarily the reverse of pathology.
      No, I don't really understand what he means... :-)

      One of the most recent findings for ME/cfs that I'd like to mention here is the impaired phosphorylation of something called eIF2a. This in turn is a crucial mechanism of the body's response to any kind of stress (keywords: Integrated stress response and Unfolded protein response, Peter has some great posts on it). If it doesn't work properly or the mechanism is overloaded, it will have detrimental effects on protein production, oxidative stress and metabolic output. All at once.
      It's definitely more heavy science than most people care to read up on, but having traversed a lot of literature I'd say a lot of roads are leading to this vicinity also in autism, schizophrenia, Alzheimer's and so on. And it's not impossible to find molecular interventions that target this area. TUDCA/Salubrinal are implicated for ME/cfs, just to take an example.

      /Ling

      Delete
  5. Thanks Peter, what do you mean by one large dose of vitamin D once a week? 5000m or more?

    ReplyDelete
    Replies
    1. I mean you take the whole week's dose in one go.

      How big the dose is depends on the individual. Some people have consistently low vitamin D and it is hard to increase it. Some people react badly to vitamin D. So there is no one size fits all solution.

      Monty takes 15,000 IU once a week. I do the same.

      Delete
    2. Hi Peter -
      My son takes 5,000 iu every day. We have darker skin and where we live, consistently sunny days are not always guaranteed. Should he still take a high dose once a week or continue as is? thanks!

      Delete
    3. Mo, it is simply a matter of what is most convenient. You can take it once a day or once a week. 5,000 IU is high for a daily dose. You can do a blood test to see where he is in the reference range. You do not want to be way above it.

      Delete
    4. Thanks Peter. I will definitely have him retested. We are of African descent and when we lived in Washington state - our pediatrician recommended dosage of 1,000 iu for all the kids because WA doesn't get a ton of sun and we just needed more. Then I read research and article from a Dr. Cannell showing efficacy of high doses of vitamin D for autism. We really saw significant improvements after this.
      https://pubmed.ncbi.nlm.nih.gov/25876214/
      https://www.vitamindcouncil.org/health/autism/autism-information.shtml

      Delete
  6. hi, i inject leucovorin to my kid because i cant find capsule or tablet big enough. is this save?

    ReplyDelete
    Replies
    1. Leucovorin can be administered into muscle or intravenously, or as a tablet.

      Is it safe? For people with low folate in their brain, it is a good choice. Some people do not tolerate large doses. There should be a behavioral or cognitive or speech improvement. There is no point giving it to people with normal levels of folate in the brain.

      Delete
    2. Also, Leucovorin works with the reduced folate carrier so make sure vit d is on the high side of normal.

      -Stephen

      Delete
    3. Stephen, it did occur to me that you might be able to increase the absorption of oral folate by taking it with a betaine HCl capsule. This reversibly lowers pH (increase stomach acidity) for a couple of hours.

      PCFT is the primary transporter for folates in the small intestine, where most absorption occurs. Estimates suggest it could be responsible for up to 80% of folate uptake in this region.

      Folate uptake through the proton-coupled folate transporter (PCFT) is pH-dependent, increasing in acidic environments. A slightly more acidic duodenum could theoretically improve PCFT-mediated absorption of folate supplements.

      While PCFT plays a crucial role in intestinal folate absorption, its contribution to crossing the BBB is negligible. FRα and RFC are the predominant players at the BBB, highlighting the importance of these transporters for ensuring adequate brain folate supply.

      Evidence suggests PCFT plays a minimal role in direct folate transport across the mature BBB. Its primary function at the BBB seems to be facilitating intracellular folate recycling. This recycling process helps maintain adequate folate levels for brain function.

      The relationship between blood pH and PCFT function at the blood-brain barrier (BBB) is an unexplored area. While we know that PCFT plays a minor role in direct folate transport at the BBB, it's possible that blood pH could indirectly influence its activity through various mechanisms.

      Lowering blood pH is possible using the “autism drug” Acetalozamide/Diamox. I was interested to hear from Dr Boles, that he uses it for other reasons.

      The betaine HCl idea is the easy one to test, because it is OTC and widely used for digestive problems.

      Delete
    4. Interesting, Dr. Frye also uses Diamox. Thank you for the tip. Dr. Boles probably uses it for central sleep apnea or idiopathic intracranial hypertension.

      Delete
    5. Peter, I had a strange thought. Could the folate autoantibodies be the reason for increased neuro inflammation? The brain just lost 2/3 of the folate pathway makes sense it would be inflammed.

      Folate deficiency resulted in increased expression of inflammatory and oxidative stress markers in vitro and in vivo, with increased cellular ROS levels observed in mixed glial cells as well as a reduction of mitochondrial DNA (mtDNA) content observed in FD mixed glial cells.

      -Stephen

      Delete
    6. Stephen, yes, I think it would be an addition cause of inflammation.

      Every biological process that is operating sub-optimally is going to increase inflammation and oxidative stress.

      The good news is that you can get beneficial results targeting inflammation and oxidative stress without really knowing its origins.

      Delete
    7. I don't know if anyone has studied a correlation between inflammation at birth and Autism, but my Autistic son was born with his cheeks and face extremely swollen and inflamed. If I could upload a picture I would. A few hours after birth it came all the way down, but I can't help but wonder if that inflammation contributed to his Autism.

      Delete
  7. Peter, thoughts on this...

    Proteostasis defects: Medicinal challenges of imperfect aging & neurodegeneration

    https://www.sciencedirect.com/science/article/pii/S2468501123000111

    Itraconazole Confers Cytoprotection Against Neurodegenerative Disease-Associated Abnormal Protein Aggregation

    https://www.sciencedirect.com/science/article/pii/S2468501123000111

    ReplyDelete
    Replies
    1. Interesting how many anti-fungal and anti-parasite drugs have useful secondary effects.

      Delete
    2. Now if I could only find a Keap-1 inhibitor to prolong the half-life of nrf-1.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808764/

      Delete
  8. Hi Peter,
    This is a separate comment to the thread, but I was curious if you have tried suvorexant for Monty? Or if you know anyone who has? I was looking for sleep meds that could also help cognition and came across it.

    https://journals.lww.com/annals-of-medicine-and-surgery/fulltext/2024/01000/improvement_of_autistic_like_behaviors_in_adult.34.aspx

    https://www.medpagetoday.com/neurology/alzheimersdisease/104137

    Thanks,
    Shana

    ReplyDelete
    Replies
    1. Hi Shana, the idea to use suvorexant is recent. I doubt anyone has tried it for autism (in humans).

      Given that this is an approved drug for sleep you would think that it would be interesting to many with autism. It is quite a new drug so there is no cheaper generic version.

      I will take a deeper look into it.

      Delete
  9. Hi, so now my wife pregnant the 2nd kid. my firsd kid autism and ,should my wife use Bumetanid about 7-10 days after the kid was born, is it safe ?

    ReplyDelete
    Replies
    1. There are many ideas about preventing autism. The use of NAC in the pregnant mother actually has been trialed for other reasons and was shown to be safe.

      Delete
    2. I would suggest 81mg ASA and fish oil. If she has elevated il6 levels it will help decrease her inflammation.

      https://www.sciencedirect.com/science/article/abs/pii/S0301211517300039#:~:text=Both%20aspirin%20and%20omega%2D3,only%20for%20achieving%20this%20effect.

      Delete
    3. Also folic acid during pregnancy can reduce the chance of ASD by 40% https://www.publichealth.columbia.edu/news/folic-acid-supplements-early-pregnancy-may-reduce-risk-autism-40#:~:text=Mothers%20who%20took%20folic%20acid,did%20not%20take%20folic%20acid.

      Delete
    4. "The timing of a mother’s intake of folate appears to be a critical factor. Her child’s risk of autism was reduced only when the supplements were taken between 4 weeks before to 8 weeks after the start of pregnancy."

      Delete
    5. Guy, i want to say about gaba . use bumetanid before born maybe help kid?

      Delete
    6. Hi Peter,

      I think you mentioned a study once in Scandinavia where a small sample of newborns(?) were given a small amount of yogurt (perhaps weekly?) and none of them developed asd? I've searched for it, but can't find it, did I dream this?! I remember thinking it sounded too good to be true, but it seemed like something to look out for in the future, hoping there would be followup studies.

      Aspie2

      Delete
  10. Hi Peter, I would like to report positive results from the PQQ front. Since I have two boys with FRAA I thought I would give it a shot. For the child that has had no vaccines, no antibiotics, and no GI disfunction it works great paired with Leucovorin. Better language and dialog. However, the son with GI issues it just makes him more hyper and he just runs back and forth. Just an interesting observation I've had.

    ReplyDelete
    Replies
    1. Thanks for the update
      Anvesh

      Delete
    2. Stephen, interesting and clearly very useful to others taking Leucovorin/ calcium folinate. Thanks for sharing.

      Delete
    3. No problem. The version I've been using is seeking health pqq. They make it in a lozenge form that taste like candy. I got it off of iherb.

      Delete
  11. Even more interesting data just released on the Folate front by Frye & co;
    https://www.mdpi.com/2075-4426/14/1/62?fbclid=IwAR0hj0I6oHzYXMhEC2sT-RNSD7xFxPSYI3UDr5d6BkparUKEpKRZsHN6i5g

    ReplyDelete
  12. Hi Peter
    Please is Monty still taking tavegyl and where have you been sourcing it from?I can't find it anywhere and we have just about 3 weeks supply left.Do you know any EU country where I can get it from?
    Please can you recommend any good brand for spermidine?I can see so many online so I am a bit confused on what brand to go for.Thank you

    ReplyDelete
    Replies
    1. You have to look online for both Tavegyl and Tavegil. I see it for sale in Germany. It was also common in the Baltic states. I bought mine in the UK. It is quite often unavailable for a month or two, since they run out. We used it for several years.

      I do not think the brand of spermidine matters.

      Delete
    2. Thank you.Its not been in the Uk for about 2 years now and I have been buying from nigeria but I can’t find anywhere .Will check for tavegil as you suggested .
      Thank you

      Delete
    3. You can check amazon.de, they have some in stock

      Delete
  13. Weird question Peter, do you recall if anyone has ever said that their ASD child acts better after general anesthesia?

    A general anaesthetic propofol inhibits aquaporin-4 in the presence of Zn²⁺

    https://pubmed.ncbi.nlm.nih.gov/23772702/

    ReplyDelete
    Replies
    1. Not a weird question at all. I have come across this more than once. I think once was after a dental operation under anesthetic and one was after a minor surgery.

      On the other hand some people have been reported to have got worse after anesthetic.

      Delete
    2. Yea, probably the best procedure would be sedation with propofol for an MRI. Since there would be no inflammation involved from surgery.

      Delete
    3. I can confirm this happened with us too. Once my son had an ear tube insertion and the other time when he had his eyes straightened. His eye contact was steady, he used his words more and was very regulated - however we chucked it down to lethargy from the anesthesia.

      Delete
    4. The Estradiol Synthesis Inhibitor Formestane Diminishes the Ability of Sevoflurane to Induce Neurodevelopmental Abnormalities in Male Rats

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498728/

      Use can use bumetanide to protect the brain during anesthesia fyi

      -Stephen

      Delete
  14. Itraconazole also increases nrf-1 through activation of ampk pathway.

    Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells - PubMed
    https://pubmed.ncbi.nlm.nih.gov/26655341/#:~:text=Inhibition%20of%20VDAC1%20by%20itraconazole,an%20upstream%20regulator%20of%20mTOR.

    Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis - PubMed
    https://pubmed.ncbi.nlm.nih.gov/11701451/

    -Stephen

    ReplyDelete
  15. Peter, do you have any tricks to increase nk cells?

    Stephen

    ReplyDelete
  16. Hi Peter,

    Now I'm going to throw yet another supplement at your scrutiny, one that I haven't seen mentioned anywhere on the blog or in the comments yet. Maybe it's irrelevant for autism, but looking at the properties I wouldn't be surprised if it actually helped some kids (and for different reasons).

    First I'll say that it seems very safe, as it has been used even for pre-term babies. The exception is people who are allergic to milk protein, who probably should avoid using it (lactose intolerance seems ok).
    It is on the more expensive side of supplements though, which is a pity. I've tested it myself (not autistic) for some time, and it has an obvious positive impact on my immunity and on mucosa, notably in the gut and in the eyes.
    Additionally literature suggests it works as a prebiotic, is antibacterial, acts as a non-conventional antioxidant, modulates immunity in complex ways (making it hard for me to tell who would benefit and who wouldn't), regulates appetite, is anti-fungal (candida), is neuroprotective, regulates iron (almost like an adaptogenic), has a positive role in bone building, has anti-cancer properties and... the list never ends. There's a lot of papers out there on it's effects in various conditions. In autism literature it is mostly mentioned in conjunction with gut issues, but I think the effects reach more far than that.

    Oh, I almost forgot to mention what I'm talking about.
    It's lactoferrin!

    /Ling

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    Replies
    1. Ling, lactoferrin is a biomarker for gut inflammation. As you point out it has lots of anti-inflammatory properties, so it is an example of the body trying to heal itself.

      The question is whether giving it as a supplement to people will help them. There is no consensus, but for most people it would be very safe. Lactoferrin is found at high concentrations in mother's milk.

      I think you would have to make a trial to find out if it helps.

      Delete
    2. Hi Peter,

      Here is an interesting article on Lactoferrin and Antabuse combination. I guess it can help with sepsis.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461433/

      -Stephen

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  17. Hi, Has anyone here done a 24 hour ambulatory EEG? This is one of the recommended tests for a MAPS physician that we will seeing later this year. My almost 14 year old is non-verbal "tough" kid who has not responded to much so far. The child had a febrile seizure as a toddler and one "barely abnormal" EEG but that was over a decade ago. Medication was not recommended by the neuro. The kid has gets aggressive and wanted to see if 24 hour EEG monitoring has yielded anything useful - this will not be easy and I wanted to see if signing up for this is worth it. Any suggestions from parents here to make this easier will be incredibly helpful. Thank you

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  18. Hello Peter, Hope you are well. Have you done any research on peptides? I have recently come across a blog post on it's great benefits and wanted to try. You can check this out on diaryofrecovery.com

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    Replies
    1. Someone else asked about KPV peptide. It is not very stable, but before it breaks down it does have potential benefits. There is no harm in trying it.

      Delete
    2. Interesting, but I often get suspicious when a substance/product has a mountain of claimed benefits. Often it’s too good to be true.
      But back on topic it appears the women in the linked blog has also used PQQ with success.

      Delete
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  20. Interesting, article on dietary fat and lps transportation across the gi tract.

    https://lipidworld.biomedcentral.com/articles/10.1186/s12944-022-01754-3

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  21. Dragos pls email me. I have a question about Antabuse.

    Sjkilij@gmail.com

    Stephen

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  22. Hello, A bit off topic for this post. I wanted to check if anyone has insight into Naltrexone (not low dose) usage for autism. Our doctor is recommending trying 25mg dose to help with regulation(no SIB, but has aggression)for our teen. I have heard of LDN usage and a bit worried about its sedation effects full dose

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  23. In the field of autism's big brother, schizophrenia, I found an article that truly impressed me. If autism research looked like this - then wow!
    ------------------------------------------------

    So, what this group of scientists/clinicians did was that they first chose a subset of symptoms in schizophrenia (in this case: hallucinations and delusions).

    Then they identified genetic biomarkers in patients' blood that predicted future psychiatric hospitalization due to the symptoms. Each symptom got a specific set of biomarkers that was re-validated in patients. The biomarkers were paired with personal data, like gender and diagnosis, which increased the predictive accuracy even more.

    "the best biomarkers were more predictive than the standard or new rating scales [used to evaluate patients]"

    For the top biomarkers, they next uncovered a range of existing drugs and substances (read: supplements) that are known to target the affected pathways.

    Did they stop here? No!

    Last but not least, they developed a personalized lab report (I assume based on a blood test and personal data such as gender) that a doctor can use for a patient to get
    a) a risk assessment for each symptom and
    b) a list with the best matching treatments for this specific individual
    --------------------------
    I'm blown away that this work was done by just one group of researchers and presented in just one article. To me, it looks more like the summary of many years collective advancements in the field.

    Article (paywalled): https://www.nature.com/articles/s41380-024-02433-8
    Summary of the findings: https://neurosciencenews.com/schizophrenia-blood-test-25585/

    /Ling

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    Replies
    1. Ling, I also saw that paper and made a note of it. It is like from another world.

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    2. Here is the link to the above published paper.

      https://drive.google.com/file/d/1BP5Fax50x0zcWTTYWjTR4Sc14j8NxFiw/view?usp=drivesdk

      Stephen

      Delete

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