Thursday, 18 April 2019

Wnt, TCF4 and Pre-myelinating Oligodendrocytes

Cartoons in art class - Monty is getting ready for Easter break, but not in the Maldives

Today’s post may sound very complicated and narrow, but it is very relevant to people with the following: - 

·        Pitt Hopkins Syndrome (insufficient expression of the Transcription Factor #4  TCF4 gene)

·        Multiple Sclerosis

·        Some Mental Retardation/Intellectual Disability (MR/ID)

·        Schizophrenia

·        Impaired Wnt signalling

·        Perhaps PAK1 inhibitor responders

I do feel that Multiple Sclerosis could be treated very much better if some effort was made to translate the existing science, freely available to all, into therapy. You could greatly improve many people’s lives just by repurposing cheap existing drugs.
In simple terms, to produce myelin that you need to coat axons in your brain, you need a type of cell called an oligodendrocyte (OL).  You need a lot of these cells and you need them to get busy. They place tiny pieces of white insulation along axons of your brain cells, this produces the so called “white matter”.  These pieces of insulation are needed to make electrical signals flow correctly in your brain.
It has been shown that in some people the oligodendrocyte precursors (OLPs) do not “mature” and instead get stuck as premyelinated oligodendrocytes (pre-OL). That means reduced myelination and loss of white matter.

It is clearly shown in the graphic below: -

Tcf4 is expressed in oligodendrocyte lineage in human developmental white matter and in active areas of MS lesions. (A) Tcf4 is expressed in white matter tracts during myelination of human developmental brain at postnatal age 1 mo, 3.5 mo, and 16 mo, but is not expressed by 7 yr. Tcf4 colocalizes with Olig2 when expressed in the developing human corpus callosum. (B) Tcf4 protein expression is evident in active MS lesions, but it is not seen in normal-appearing white matter (NAWM) or in the core of chronic MS lesions. An illustrative MS case is shown with several lesion types present. NAWM stains with Luxol Fast Blue (LFB) and contains sparse LN3(HLA-DR)-positive inflammatory cells, organized SMI-31 axon fibers, and no Tcf4-positive cells. Chronic plaques have sparse LFB staining and LN3-positive cells, intact axons, but no Tcf4-positive cells. In contrast, Tcf4-positive cells are present in active areas of plaques with abundant LN3-positive cells and intact demyelinated axons. Tcf4 expression in active lesions colocalizes (open arrowheads) with a subset of Olig2 cells.

Don’t worry if you don't follow everything. There is nothing wrong with your white matter.
We come back to Wnt signalling that we covered in depth in older posts. This is a complex signalling pathway implicated in autism, some cancers and other conditions. You can both increase and reduce Wnt signalling, which will affect the transcription of numerous genes.
TCF4 is the Pitt Hopkins gene. We have across this syndrome several times, while it is rare, a milder miss-expression of the gene is actually quite common.  Reduced expression of TCF4 is a common feature of MR/ID very broadly. TCF4 has been found to be over-expressed in schizophrenia.
People with Multiple Sclerosis (MS) have been found to have oligodendrocytes “stuck” as non-myelinating (premyelinated oligodendrocytes, pre-OL). Inhibiting the Wnt pathway might play a role in treatment during periods of acute demyelination, when there is a lack of newly minted myelin-producing oligodendrocytes. The study below does refer to Wnt inhibitors in the pipeline as potential cancer therapies.  It looks to me that safe Wnt inhibitors like the cheap drugs widely used to treat children with parasites (Mebendazole/ Niclosamide) could be repurposed to treat the acute phase of multiple sclerosis.
Mebendazole/ Niclosamide are safe and dirt cheap, whereas the (slightly) disease changing MS drugs currently cost $50,000+ a year.

TCF4 links everything together
Wnt signalling needs to be active to block premyelinated oligodendrocytes into transforming into oligodendrocytes (OL). So by inhibiting Wnt signalling you may remove one of the problems in MS; you probably only need to do this during relapses of MS.  
There actually is a finally stage to getting the oligodendrocytes (OL) to myelinate many axons and not be lazy.
In the jargon “dysregulation of Wnt–β-catenin signaling in OLPs results in profound delay of both developmental myelination and remyelination”.
A miss-expression of TCF4 is clearly also going to affect myelination and its does in both Pitt Hopkins and MS.
One feature of Pitt Hopkins (caused by haploinsufficiency of the transcription factor 4) is indeed delayed myelination measured via MRI at the age of 1. By the age of 9 white matter (the myelin-coated part of your brain) appears normal. This fits with what I highlighted in red under figure 6 above.
Nothing is simple. Activating Wnt signalling is known to increase expression of TCF4.  

The progressive loss of CNS myelin in patients with multiple sclerosis (MS) has been proposed to result from the combined effects of damage to oligodendrocytes and failure of remyelination. A common feature of demyelinated lesions is the presence of oligodendrocyte precursors (OLPs) blocked at a premyelinating stage. However, the mechanistic basis for inhibition of myelin repair is incompletely understood. To identify novel regulators of OLP differentiation, potentially dysregulated during repair, we performed a genome-wide screen of 1040 transcription factor-encoding genes expressed in remyelinating rodent lesions. We report that 50 transcription factor-encoding genes show dynamic expression during repair and that expression of the Wnt pathway mediator Tcf4 (aka Tcf7l2) within OLPs is specific to lesioned—but not normal—adult white matter. We report that β-catenin signaling is active during oligodendrocyte development and remyelination in vivo. Moreover, we observed similar regulation of Tcf4 in the developing human CNS and lesions of MS. Data mining revealed elevated levels of Wnt pathway mRNA transcripts and proteins within MS lesions, indicating activation of the pathway in this pathological context. We show that dysregulation of Wnt–β-catenin signaling in OLPs results in profound delay of both developmental myelination and remyelination, based on (1) conditional activation of β-catenin in the oligodendrocyte lineage in vivo and (2) findings from APCMin mice, which lack one functional copy of the endogenous Wnt pathway inhibitor APC. Together, our findings indicate that dysregulated Wnt–β-catenin signaling inhibits myelination/remyelination in the mammalian CNS. Evidence of Wnt pathway activity in human MS lesions suggests that its dysregulation might contribute to inefficient myelin repair in human neurological disorders 
Potential Tcf4-catenin activities in oligodendrocyte development
The pattern of Tcf4 protein expression, from P1 to P30 and during remyelination after injury, defines the window of potential canonical Wnt pathway functions. Within this context, we observed that Tcf4 expression marked 15%–20% of OLPs at any given stage assessed. These findings were consistent with two possibilities. First, Tcf4 expression could demarcate a subset of OLPs. Second, it was possible that Tcf4 expression transiently marks all (or the vast majority) of OLPs during development. Our functional evidence strongly supports the latter conclusion, based on the fact that activity of activated β-catenin is Tcf-dependent (van de Wetering et al. 2002), coupled with the robust phenotype in DA-Cat and APCMin animals, in which we observe pervasive effects of Wnt pathway dysregulation on myelin production throughout the CNS. Interestingly, although Tcf4 proteins are coexpressed with nuclear Olig1 proteins, Tcf4 segregated from cells expressing Olig1 mRNA transcripts, consistent with the possibility that Tcf4 is expressed at a transition stage when nuclear Olig1 proteins become down-regulated during remyelination.

Previous work has suggested inhibitory functions of Tcf4 on myelin basic protein gene expression in vitro (He et al. 2007), and our studies indicate that Tcf4 interactions with β-catenin inhibit myelination in vivo. Additional studies are warranted to rule out possible β-catenin-independent roles for Tcf4 in oligodendrocyte development. Although Wnt pathway activation has conventionally been thought of as activating gene targets, recent work has identified novel Tcf–β-catenin DNA regulatory binding sites that repress targets (Blauwwkamp et al. 2008). In this regard, one intriguing candidate target is HYCCIN (DRCTNNB1A), a Wnt-repressed target (Kawasoe et al. 2000) with essential roles in human myelination (Zara et al. 2006), which is expressed in rodent oligodendrocytes and down-regulated in Olig2cre/DA-Cat mice (Supplemental Fig. 8). Further studies are needed to better understand Tcf4–catenin function and its direct gene targets during oligodendrocyte lineage progression.

Wnt pathway dysregulation in OLPs as a mechanism leading to chronic demyelination in human white matter diseases
Therapeutic opportunities might arise from an enhanced understanding of the process regulating normal kinetics of remyelination. How might the negative regulatory role of the canonical Wnt pathway help to explain the pathology of demyelinating disease? Delayed remyelination due to Wnt pathway dysregulation in OLPs could lead to chronic demyelination by OLPs then missing a “critical window” for differentiation (Miller and Mi 2007; Franklin and Ffrench-Constant 2008). This “dysregulation model” of remyelination failure requires the Wnt pathway to be active during acute demyelination, as suggested by data from our animal systems and human MS tissue.
Canonical WNT signaling has been implicated in a variety of human diseases (Nelson and Nusse 2004), and gain-of-function mutations in β-catenin are etiologic in several cancers including the majority of colon adenocarcinomas. Approaches for treating Wnt-dependent cancers by promoting differentiation (and hence cell cycle arrest or apoptosis) using pharmacological inhibitors of the pathway are under development (Barker and Clevers 2005). It is possible that such antagonists might play a role in the therapeutic enhancement of remyelination by normalizing the kinetics of myelin repair. If so, the animal models described here (e.g., APC+/−) should be useful in preclinical testing. However, it is important to note that while dysregulation of a pathway might delay remyelination, it is overly simplistic to expect that inhibition of the same pathway would accelerate repair in the complex milieu of an MS lesion in which several inhibitory pathways might be active, compounded by the presence of myelin debris (Kotter et al. 2006). Indeed, because of the need to synergize with other processes (e.g., those associated with inflammation), accelerated differentiation might negatively affect repair (Franklin and Ffrench-Constant 2008). Further work is needed to comprehensively understand interactions of regulatory networks required for optimal remyelination and how these may be dysregulated in human demyelinating diseases.

Neurologic and ocular phenotype in Pitt-Hopkins syndrome and a zebrafish model.


In this study, we performed an in-depth analysis of the neurologic and ophthalmologic phenotype in a patient with Pitt-Hopkins syndrome (PTHS), a disorder characterized by severe mental and motor retardation, carrying a uniallelic TCF4 deletion, and studied a zebrafish model. The PTHS-patient was characterized by high-resolution magnetic resonance imaging (MRI) with diffusion tensor imaging to analyze the brain structurally, spectral-domain optical coherence tomography to visualize the retinal layers, and electroretinography to evaluate retinal function. A zebrafish model was generated by knockdown of tcf4-function by injection of morpholino antisense oligos into zebrafish embryos and the morphant phenotype was characterized for expression of neural differentiation genes neurog1, ascl1b, pax6a, zic1, atoh1a, atoh2b. Data from PTHS-patient and zebrafish morphants were compared. While a cerebral MRI-scan showed markedly delayed myelination and ventriculomegaly in the 1-year-old PTHS-patient, no structural cerebral anomalies including no white matter tract alterations were detected at 9 years of age. Structural ocular examinations showed highly myopic eyes and an increase in ocular length, while retinal layers were normal. Knockdown of tcf4-function in zebrafish embryos resulted in a developmental delay or defects in terminal differentiation of brain and eyes, small eyes with a relative increase in ocular length and an enlargement of the hindbrain ventricle. In summary, tcf4-knockdown in zebrafish embryos does not seem to affect early neural patterning and regionalization of the forebrain, but may be involved in later aspects of neurogenesis and differentiation. We provide evidence for a role of TCF4/E2-2 in ocular growth control in PTHS-patients and the zebrafish model. 


If you have a myelinating disease, you might want to read up on TCF4 and Wnt signalling. Probably not what the Minions take to read on the beach in the Maldives.

We also should recall the importance of what I am calling the "what, when and where" in neurological disorders. This is important for late onset disorders like schizophrenia, since the symptoms often develops in late teenage years and so it is potentially preventable, if identified early enough.

Today we see that TCF4 is expressed in white matter only in early childhood. If you knew what changes take place in the brains of children who go on to develop schizophrenia, you might well be able to prevent its onset.

Preventing some autism is already possible, as has been shown in mouse models, but in humans it is more complicated because of the "when" and quite literally the "where". There will be a post showing how the brain overgrowth typical of autism can be prevented using bumetanide, before it occurs, at least in mice.



  1. Hi Peter, do you think that using mebendazole once per month would be of any benefit taking in consideration my son's possible relation with MS, or is it only effective in acute demyelination?

    1. Valentina, Wnt signalling is known to be disturbed in autism. You could use a trial and error approach to see if modifying it gave a benefit. Most drugs have multiple effects, so a Wnt activator/inhibitor will also do other things as well. So this is a very personalized kind of therapy to find what gives a benefit, with no negative effects. Using substances already widely used in small children would seems a smart place to start.

  2. Coincidentally, today some scientists are claiming a "breakthrough" molecule in repairing myelin in MS:

    Press Release:


    The drug is a derivative of another drug that is an thyroid hormone agonist which the researchers claim can also effectively penetrate the blood brain barrier, thereby making it useful in the central nervous system.

    With everything I know about MS and myelination now just as a side-effect of trying to understand the concept as it relates to autism, I never knew that thyroid hormone naturally repairs myelin. In a way it makes sense as a disproportionate number of people with MS also suffer from obesity, and obesity in many cases is linked with thyroid dysfunction.

    1. Tyler, one of my ideas elsewhere in this blog is that there is central hypothyroidism is some types of autism, because although enough prohormone T4 is present it does not get converted to T3. Giving T3 orally briefly can identify who this applies to, but is not possible as a therapy. Some DAN type doctors do prescribe T3 long term even though blood tests do not warrant it, by mainstream standards. This will cause a problem in the long term as the thyroid begins to shut down.

      One suggestion was that oxidative stress in the brain is reducing the level of the D2 enzyme that is needed to convert T4 to T3. That suggests that all you might need is NAC or ALA, which many people already take.

      Based on your paper, this would then improve myelination as well.

    2. "To thyroid or not to thyroid" has been a question that I keep asking myself with respect to autism. Plenty of studies have been done on endocrine hormones and autism, though the relationship between TSH/TRH and Prolactin is rather puzzling even though many of these studies were done in the past when a great number of those people on antipsychotics like risperidone which block D2 receptors, leading to a rise in prolactin levels via disinhibition of the TIDA neurons in the hypothalamus.

      TRH stimulates prolactin release and from there things can get quite complicated as prolactin has many indirect effects on many other hormones. With respect to risperidone, one could ask if some of its acute effects in severely autistic people when used for the purposes of chemical lobotomization is via prolactin.

      Also, as I am sure you well know Prolactin stimulates myelination as well (my understanding previously was that Prolactin was the primary cause of myelination but this research above suggests thyroid hormone itself stimulates myelination too). Prolactin inhibits pretty much all of the sex hormones, especially gonadotropin releasing hormone, which of course gets back to whether or not TSH/TRH inhibition from exogenous thyroid hormones is good/bad for autism since their release is dependent on circulating levels of T3 I believe (autoregulation).

      I tried to better understand prolactin in a non-superfical way a while back and pretty much gave up on it being a rabbit hole leading to many other rabbit holes. I recall you did a couple blog posts on the thyroid/prolactin relationship so maybe you can elucidate further what you think about all of this as it relates to autism.

  3. Also, as per the recent discussions on autophagy inducing drugs, new research suggests repurposing another blood pressure drug for neurodegenerative diseases, may help clean up protein aggregates that help contribute to diseases like Parkinson's and Huntington's:

    Press Release:


    Also, interestingly if you read the paper the research was inspired by Verapamil as it was shown to induce autophagy in an mTOR dependent manner, though they were looking for related L-Type Calcium Channel blockers that more readily cross the BBB as Verapamil apparently does not do so all that well (according to these researchers).

    1. There are different sub-types of L-type calcium channels and different ones are expressed in different parts of the body.

      So some clever research is needed to consider which one is optimal for which neurological disorder and so minimize unwanted side-effects. The odd one that recurs is changes to some people's gums. This affects both Verapamil and Felodipine and was reported by our reader Maja.

      "Different calcium channels are present in vascular tissue and cardiac tissue; an in vitro study on human vascular and cardiac tissues comparing how selective various calcium channel blockers are for vascular compared to cardiac tissue found the following vascular/cardiac tissue ratios: mibefradil 41, felodipine 12; nifedipine 7, amlodipine 5, and verapamil 0.2"

  4. Hi Peter,
    We got the PET scan done for my son.The dictor said that the learning and memory side is very affected much more than the autism side.Do you know of anything that might help the hippocampus region of the brain?

    1. In autism the standard imaging tool is an MRI. This detects structural anomalies.

      A PET is a special type of CT scan that uses biomarkers to record the metabolic function at the cellular level. It can be used to measure hyper/hypometabolism of a particular area of the brain.

      In theory you may be able to modify metabolic function via a therapy, so you would then repeat the PET scan to measure the change.

      The PET scan would commonly produce its output in terms of SUV numbers.

      The standard uptake value (SUV), also known as standardized uptake value, is a simple way of determining activity in PET imaging, most commonly used in fluorodeoxyglucose (FDG) imaging.

      If the tracer molecule chosen for PET is indeed fludeoxyglucose, an analogue of glucose, the concentrations of tracer imaged will indicate tissue metabolic activity as it corresponds to the regional glucose uptake.

      So you measure the SUV in various parts of the brain, then you apply your therapy and then respeat and measure SUV again.
      A good example is in this case study below.

      Case Report Open Access
      Intrathecal Autologous Bone Marrow Mononuclear Cell Transplantation in a Case of Adult Autism

      You have a hippocampus in each side of your brain. If one does not work well the other can often take over, so to speak.
      The hippocampus is one part of the brain known to be able to regenerate, with exercise suggested.

      The question is whether the MRI shows that the hippocampus is structurally “normal”. Dementia is thought to start in the hippocampus, but that will be visible on an MRI.

      I presume you have a normal MRI, but “abnormal” PET scan based on reduced glucose uptake to certain areas. How is the glucose uptake to the rest of the brain?

      Some Alzheimer’s therapies are based on improving glucose uptake.

      You need to ask your doctor to be more specific about his findings.

    2. The left hippocampus tends to be more involved in left hemisphere dominant functions such as speech, while the right hippocampus tends to be involved in right hemisphere functions such as spatial awareness.

      Also, the anterior (frontal) part of each hippocampus tends to be more involved in new memories, while the posterior (rear) part of the hippocampus tends to be more involved in long-term memories.

      Also, the dominant but by means consensus view of the hippocampus is that it's primary role is not to store memories long-term, but rather to index them and activate them later under the appropriate context. So when you learn a new word, the brain makes a memory trace called an engram in the anterior left hippocampus and the cortex at the same time and then if the memory is reactivated and strengthened over the next couple of weeks, the left anterior hippocampus will replay the memory in the cortex at high speed over and over which is thought to strengthen it and induce more permanent plasticity changes to the synapses that comprise that engram. If this does not happen, then the memory will eventually fade in the left anterior hippocampus and be less accessible over time.

  5. HI Peter,
    This was in Bipolar News Network. How do you see this relative to your posts about Wnt Signaling. New research on mice clarifies lithium’s effects on neurons and suggests how it can lead to improved symptoms. Dendrites are the long projections on neurons that seem to reach out to form synapses with other neurons. The surface of these dendrites is covered in mushroom-shaped spines that help create these synaptic connections. A 2016 article by research Ben Cheyette and colleagues in the journal Molecular Psychiatry reports that in mice with a genetic mutation common to people with autism, schizophrenia, and bipolar disorder, lithium restored healthy numbers of the mushroom-shaped spines. The lithium treatment also reversed symptoms such as lack of interest in social interactions, lack of motivation, and anxiety in the mice.

    Cheyette and colleagues first identified a genetic mutation that affects signaling in what is known as the brain’s Wnt pathway. The mutation, while rare, is 80% more common in people with bipolar disorder, autism, and schizophrenia than in people without these disorders.

    When the mice were given a similar mutation, they exhibited symptoms such as anxiety, decreased sociability, and lack of motivation. They also had reduced numbers of dendritic spines and impaired Wnt signaling.

    Lithium can improve Wnt signaling by blocking an enzyme called GSK-3 beta that impairs the signaling.

    Treating the mice with lithium restored their dendritic spines and improved their behavior.

    Wnt signaling and dendritic spines may offer the key to lithium’s success in treating a variety of psychiatric disorders in people.

    1. If you look at this presentation I wrote

      about half way through you see a some nice slides about dendritic spines, lithium and 7-Up.

      The 7-Up drink used to contain lithium.

    2. Those charts are highly relevant! Glad to have a wide range of your thinking in once presentation.
      How do you know if your child needs more/less WNT signaling? Looks like lots of types of dysfunction on the spines. Or does Lithium moulate it too?

    3. Unless you have a single gene autism you cannot be 100% sure if you need more or less. Wnt signalling affects both the number and shape of dendritic spines. It may be important when you modify Wnt signalling, not just in which direction and by how much. There is more than one Wnt pathway.

      In some people a "simple" intervention like lithium can have a big impact. It may end up being a case of trial and error.

    4. Hi Peter,

      First of all, that is a fantastic presentation!

      I have been thinking about trialing Lithium for autophagy alone, and in looking at the info you've provided, it may also be very helpful with dendritic spines (assuming our single gene mutation is affecting this).

      When looking at lithium supplements, based on your knowledge, is there anything we should consider in terms of type (e.g. Lithium orotate versus other lithium aspartate) and dosage (e.g. microdosing, or a particular mgs/kg)?

      The one I was looking at was Lithium orotate, at 125 mgs of LO resulting in 5mgs of Lithium. As this is the adult dose, I would cut this in half just to compensate for a child dose, and then cut this in half in again to about 30mgs of LO (1.25mgs of L) as an initial dose and then titrate up to 62.5mgs of LO depending on what I see.

      Also, anything to look for as far as you know (i.e. side effects)?

      Thanks very much in advance Peter!


    5. Hi AJ, hope all is well, my son takes lithium orotate 5 mg since 3 years, I think less than half a pill is too little,5 mg is not much, it is ok for our children.

    6. Hi Valentina,

      Hope all is well with you and your family.

      Thank you so much for providing your experience! I hadn't ever considered Lithium before it came up recently as a potential autophagy inducer, and as I look into it, it seems to have other potential benefits as well.

      I really appreciate your input on this Valentina,


    7. So, reading your presentation --would one not take Lithium for schizophrenia because you would want a wnt inhibitor (for gsk activation). it is confusing.

    8. AJ, many people with autism are taking OTC lithium, some are definitely taking it as orotate. I have not looked into side effects etc, but being OTC there will be reports from users on the web.

      People with characteristics of bipolar would seem particularly likely to be responders. Some people with autism do end up also with a bipolar diagnosis.

      Some people with schizophrenia do take lithium. This blog is mainly about autism and it shows that both extremes are present in many biological features of autism. This may well also be possible with schizophrenia, so there may be most schizophrenia (80%) that we generalize as schizophrenia and the other 20% that may indeed be the opposite.

      I doubt an OTC lithium supplement will do any harm and a quick trial is the only way to establish whether there is a benefit.

    9. A few comments on that excellent Translating Science presentation.

      First and foremost I am clueless about biology and would really welcome learning advice such as resources that anyone has found useful to quickly get up to speed.

      On the dendritic spine graph (p22 & p24) I am guessing that AD is Alzheimers.

      I was surprised to see the ketone BHB mentioned on p29 as harmful in SZ. Confused since of keto diet is supposed to be helpful in SZ (just anecdotally I guess).
      Once again I really appreciate all the helpful sharing of info here.


    10. LG, the ketone BHB is an inhibitor of HDAC, but has numerous other effects.

      Some are listed here.

      In someone with schizophrenia who follows the ketogenic diet, all of these effects will take place. Some will be positive, some negative and some negligible. The overall effect will be what it is.

      So I am not saying BHB is harmful in schizophrenia. I am saying that BHB will increase TCF4, which itself would be expected to be over-expressed. That would not be helpful, but the effect might be a small negative that is outweighed by a large positive from the other effects of BHB.

      The best way to learn biology is looking up words you do not understand on wikipedia and to stat by (trying to) read research papers that are autism clinical trials written by psychiatrists. They tend not to be so complicated, are directly relevant and you will not have so many words to look up. Antonio Hardan is a Stanford psychiatrist will several autism trials published.

  6. Hi Peter,

    Thank you very much!

    I'm going to add LO to my regimen shortly and will keep everyone posted. I did order the GS15-4, so will trial that first, and then once I know if that provides any benefit or not, will trial LO.

    Have a great day Peter!


  7. Peter - Is Super Sprout still the company you recommend for Sulforaphane? We tried the powder several years ago, but my daughter refused it due to taste. She is swallowing pills now so we would like to try again in capsule form. Thanks!

    1. Many people now seem to use Brocccomax, which is easier for most people to obtain. It does seem that after a time you may need to increase the dose to maintain the effect

  8. Ascorbyl palmitate is a faily low
    risk addition to any remylinating strategy imo

  9. So should I try Lithium? Just found this:
    "SATB2 is also involved in the wingless/integrated (WNT) signaling pathway, serving as an upstream activator" (paywalled)

    Too little SATB2 would mean too little WNT activation would mean...?


  10. Ling, Wnt signaling affects the expression of many genes, including these ones:

    1. Thank you Peter, it is an interesting list with some old acquaintances of mine!
      Unfortunately it looks like lithium is an NMDAr antagonist, which is the opposite of what I am looking for. Too bad.


  11. On the topic of pollen allergies, I realized that pycnogenol was mentioned as one of those remedies that can alleviate symtoms besides quercetin. It's a little too late to start with it here since it takes 5-7 weeks to have an effect and the season is peaking now. Looking very briefly into this substance, it does have a long list of nice properties including longevity (which basically means it is beneficial for a lot of things). Since I have heard very little about it, and it has only been mentioned once I think on this blog, I wonder if anyone has tried it for some reason or other?


    1. Tried pycnogenol a long time ago with no effect at all. Maybe the dose was wrong, I don't know.
      Antioxidants have "lifting effect" on my child (14y, ASD). She becomes excited, "anxiously happy", scripting more.
      From the other side, she learns school lectures better with them (or, should I say - she is even worse without them? :) )
      Anyway, I've noticed that antioxidant has to be given with CLO. In the opposite, CLO with time makes her irritable (in the beginning not, she is better, cuddlier; but, after the month of use, she becomes irritable, nervous, even aggressive - don't know the reason or for the similar experience of others).
      Still on trial for fisetin. Doesn't have that miracle cognitive effect like strawberries themselves, but she is stronger, cheerful (in a good way). And, she has a few normal bowel movements per day - that is quite unexpected and good.
      Tried bacopa - it was a disaster even with the smallest dose - she used to be stupid, foggy, complained that her stomach hurts (she pointed on gastric region).
      Taurine is very interesting. A few years ago, when I tried it, it gave her bad reflux (with bad breath and burping) - similar experience, as I can recall, you had, Peter, hadn't you? Now she tolerates a small dose of 250mg/day. It has "a sobering effect" and it is clearly noticeable. With higher doses the effect is the same, so I stick with the lowest dose that gives effect.
      Magnesium citrate was the real discovery to me (glycinate hasn't got that power). Within half an hour, her divergent eye returns to the normal position after citrate. Magnesium threonate is now on trial - it seems to me that its effect last longer.
      With Tavegyl she starts to spin (never did that before), even tries to dance (that was impossible mission). I expect much of Tavegyl - it is good for her overall...

    2. Maja, I have not used taurine, but many people do use it. It was Acetazolamide that caused reflux.

      In our case clemastine/Tavegyl seems to have produced "opinions" in my son. It is not defiance, he just now expresses what he wants, rather than just accepting what you want him to do. I take it as a positive, but some people might not.

    3. Thank you, Peter, I've mixed it up.
      Oh, it is definitely positive - sign of selfawereness.
      Good luck,

    4. Maja, I think Bacopa can be hard on the stomach for some people, but I don't know why. I remember vaguely that some Bacopa substituents have to be metabolized in the gut before becoming active. It could also be a bad Bacopa supplement, they are not all the same according to many reviews I went through before choosing. Anyway, if it didn't work it just didn't.
      Happy to hear that Fisetin has some positive effect for her - what dose are you trying? When I tried it myself, it gave me a better mood.


    5. Thank you, Ling, for interesting, and for informing about fisetin.
      At working days, I give her half capsule of 100mg, during the weekend whole (she is 1,68m/53kg)
      She is better on fisetin than on others antioxidants - not so lift on, willing to talk. The mood is better, less resistance.
      A friend of mine has even greater results (10 yo, ASD) - her daughter started to use full sentences in conversation (she was capable of doing that before only on speech therapy lessons).
      Best wishes,

    6. My daughter, 17 kg, also does 50mg daily (same all days). Optimal for a 53 kg could be at between 100-200 mg daily.
      I've reordered sulforaphane to see if it stacks with Fisetin, it should theoretically but I need to confirm it practically.
      I'll keep you updated.


  12. Oh, and I forgot to mention that I liked that you used Monty's illustration for this post very much. Expectations - some action - and then relief. You should do it more often, me thinks. :)


  13. Really hated to be the parent who observed this happen but since we are on the topic of myelination and how that process works


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