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Tuesday, 15 January 2019

More Myelin? Or just Better Myelination - Intelligence, PDE4 and Clemastine again




Myelination in the Central Nervous System (CNS)                  Oligodendrocyte myelinating multiple axons

The previous post on myelin was this one.


In that post we saw that you can activate P2X7 receptors with an antihistamine called Clemastine and you can block P2X7 with another cheap antihistamine called Oxatomide. The P2X7 receptor plays a role in both inflammation and myelination and this receptor appears to be linked to neurological disorders including schizophrenia and even depression.
In that post I also compared experimental MS therapies with experimental autism therapies.




The yellow box means, we know it works, at least for some people, based on trial results.

The widely available PDE4 inhibitor, Roflumilast, has been patented as a cognitive enhancer, but even at that lower dose it can make people vomit.  Ibudilast seems to have fewer side effects and is under investigation in the US to treat MS, but is currently only approved in Japan and as an asthma therapy.
The logical next step is to investigate the two P2X7 modifying antihistamines, which should have opposing effects.
Oxatomide is widely used in Italy. Clemastine is OTC in the US and the UK.
I did some more investigation of Clemastine and came across some encouraging reports of off-label use in psychiatry at modest doses. Off label use to treat MS at high doses was associated with quite negative reports, due to the sedating effect, which is inevitable with antihistamines that can cross the blood brain barrier.
Today’s post goes into more detail about myelination and concludes with the open question of who might actually benefit from a half dose of clemastine, (Dayhist in the US, Tavegil in the UK); clearly some people do already benefit. 
At least one US child psychiatrist is a fan and the research suggests many conditions might benefit, ranging from severe to more trivial.  At 15-20 times higher dosage, clemastine is proposed as a therapy for Multiple Sclerosis (MS), but at that dosage clemastine is highly sedating. High dose clemastine might be a potential immediate response to the onset of regression in autism and CDD (Childhood Disintegrative Disorder).
Clemastine and Ibudilast have different modes of action. Clemastine works by activating P2X7 receptors in oligodendrocytes (in the CNS) and schwann cells (in the PNS) to make more myelin.
PDE4 inhibitors cause enhanced differentiation of OPCs (oligodendrocyte progenitor cells). OPC are precursors to oligodendrocytes.
So Roflumilast and Ibudilast should make more oligodendrocytes, while clemastine just kicks the ones you already have to work harder.  So in any one person the effect of these two types of drug may very well differ. 
Also, note that myelin needs to be constantly repaired in a process naturally called remyelination. So really we are just trying to benefit from improving this already existing repair service.

Some relevant background information:



“Myelination is only prevalent in a few brain regions at birth and continues into adulthood. The entire process is not complete until about 25–30 years of age. Myelination is an important component of intelligence. Neuroscientist Vincent J. Schmithorst proposes that there is a correlation with white matter and intelligence. People with greater white matter had higher IQs. A study done with rats by Janice M. Juraska showed that rats that were raised in an enriched environment had more myelination in their corpus callosum. 
In cerebral palsy, spinal cord injury, stroke and possibly multiple sclerosis, oligodendrocytes are thought to be damaged by excessive release of the neurotransmitter, glutamate. Damage has also been shown to be mediated by N-methyl-D-aspartate receptors. Oligodendrocyte dysfunction may also be implicated in the pathophysiology of schizophrenia and bipolar disorder.”

The role of myelin
Myelin has been compared to the insulation on electrical cables.  If only it was that simple, there would not be so many genes involved in the process.

Nodes of Ranvier do matter
If you look at the above graphic of a neuron you will see gaps in the myelin, that are called Nodes of Ranvier.
The electrical signal does not pass along the axon like a piece of copper wire, rather it jumps from one Node of Ranvier to the next, in a process called saltatory conduction.
Also each subsequent piece of myelin along the length of an axon is connected to a different oligodendrocyte. Otherwise there would be no electrical conduction possible; there has to be a “potential difference” for a current to flow.
Each oligodendrocyte can be connected to 50 different pieces of myelin, many on different axons. Just imagine what that looks like; forget the spaghetti of cables connected to your TV, this is something really jumbled up.
If the electrical signal jumps to an adjacent axon rather than jumping along the same axon, there will be a problem.
If there is too much myelin produced you might squeeze out the node of Ranvier and then the signal cannot pass along to the next neuron.



Myelination Defects in Autism
We have already seen in previous posts that myelination is often found to be abnormal in autism.
A very thorough recent study looked at myelination in a number of single gene autisms. The conclusion was that in these very different types of autism there was a common theme of defective myelination.
This adds further weight to the idea of considering impaired myelination a key feature of much autism.
Loss of myelination has been suggested to be a core feature of regressive autism and I propose a very likely driver of Childhood Disintegrative Disorder (CDD).
“Improving myelination” rather than simply “more myelination” might well be very helpful to many types of severe autism. It seems that even in much milder neurological conditions improving myelination can be therapeutic.
The usual target of experimental myelination therapies is Multiple Sclerosis (MS), it may also be the hardest to treat.
Some researchers and clinicians are repurposing MS therapies for other neurological disorders, either in mouse models or in humans.  This seems like a very good idea to me. 

One Sentence Summary: RNA sequencing of seven syndromic autism mouse models identify myelination genes disrupted in human ASD.

Autism Spectrum Disorder (ASD) is genetically heterogeneous in nature with convergent symptomatology, suggesting dysregulation of common molecular pathways. We analyzed transcriptional changes in the brains of five independent mouse models of Pitt-Hopkins Syndrome (PTHS), a syndromic ASD caused by autosomal dominant mutation in TCF4, and identified considerable overlap in differentially expressed genes (DEGs). Gene and cell-type enrichment analyses of these DEGs identified oligodendrocyte dysregulation that was subsequently validated by decreased protein levels. We further showed significant enrichment of myelination genes was prevalent in two additional mouse models of ASD (Ptenm3m4/m3m4, Mecp2KO). Moreover, we integrated syndromic ASD mouse model DEGs with ASD risk-gene sets (SFARI) and human idiopathic ASD postmortem brain RNA-seq and found significant enrichment of overlapping DEGs and common biological pathways associated with myelination and oligodendrocyte differentiation. These results from seven independent mouse models are validated in human brain, implicating disruptions in myelination is a common ASD pathophysiology.

To address these questions, we performed integrative transcriptomic analyses of seven independent mouse models of three syndromic forms of ASD generated across five laboratories, and assessed dysregulated genes and their pathways in human postmortem brain from patients with ASD and unaffected controls. These cross-species analyses converged on shared disruptions in myelination and axon development across both syndromic and idiopathic ASD, highlighting both the face validity of mouse models for these disorders and identifying novel convergent molecular phenotypes amendable to rescue with therapeutics. 

Shared myelination gene regulation between mouse models of syndromic ASD. Venn diagram of DEGs (differentially expressed genes) in each mouse model of ASD




Top GO (Gene ontology) terms of the CAGs (convergent ASD genes) enrich for myelination processes



P2X purinoceptor 7 is a protein that in humans is encoded by the P2RX7 gene.

The product of this gene belongs to the family of purinoceptors for ATP. Multiple alternatively spliced variants which would encode different isoforms have been identified although some fit nonsense-mediated decay criteria.
The receptor is found in the central and peripheral nervous systems, in microglia, in macrophages, in uterine endometrium, and in the retina. The P2X7 receptor also serves as a pattern recognition receptor for extracellular ATP-mediated apoptotic cell death, regulation of receptor trafficking, mast cell degranulation, and inflammation.


Our findings point to P2X7R as a potential therapeutic target in schizophrenia.


The P2X7 purinergic receptor: An emerging therapeutic target in cardiovascular diseases

The P2X7 purinergic receptor, a calcium permeable cationic channel, is activated by extracellular ATP. Most studies show that P2X7 receptor plays an important role in the nervous system diseases, immune response, osteoporosis and cancer. Mounting evidence indicates that P2X7 receptor is also associated with cardiovascular disease. For example, the P2X7 receptor activated by ATP can attenuate myocardial ischemia-reperfusion injury. By contrast, inhibition of P2X7 receptor decreases arrhythmia after myocardial infarction, prolongs cardiac survival after a long term heart transplant, alleviates the dilated cardiomyopathy and the autoimmune myocarditis process. The P2X7 receptor also mitigates vascular diseases including atherosclerosis, hypertension, thrombosis and diabetic retinopathy. This review focuses on the latest research on the role and therapeutic potential of P2X7 receptor in cardiovascular diseases.

Clemastine is an extracellularly binding allosteric P2X7 receptor modulator.
Clemastine can potentiate the sensitivity of P2X7 to lower ATP concentrations. Additionally, clemastine increases the release of IL-1β from macrophages. Thus, clemastine may be a potential P2X7 activator.

Brain ischemia leading to stroke is a major cause of disability in developed countries. Therapeutic strategies have most commonly focused on protecting neurons from ischemic damage. However, ischemic damage to white matter causes oligodendrocyte death, myelin disruption, and axon dysfunction, and it is partially mediated by glutamate excitotoxicity. We have previously demonstrated that oligodendrocytes express ionotropic purinergic receptors. The objective of this study was to investigate the role of purinergic signaling in white matter ischemia. We show that, in addition to glutamate, enhanced ATP signaling during ischemia is also deleterious to oligodendrocytes and myelin, and impairs white matter function. Thus, ischemic oligodendrocytes in culture display an inward current and cytosolic Ca(2+) overload, which is partially mediated by P2X7 receptors. Indeed, oligodendrocytes release ATP after oxygen and glucose deprivation through the opening of pannexin hemichannels. Consistently, ischemia-induced mitochondrial depolarization as well as oxidative stress culminating in cell death are partially reversed by P2X7 receptor antagonists, by the ATP degrading enzyme apyrase and by blockers of pannexin hemichannels. In turn, ischemic damage in isolated optic nerves, which share the properties of brain white matter, is greatly attenuated by all these drugs. Ultrastructural analysis and electrophysiological recordings demonstrated that P2X7 antagonists prevent ischemic damage to oligodendrocytes and myelin, and improved action potential recovery after ischemia. These data indicate that ATP released during ischemia and the subsequent activation of P2X7 receptor is critical to white matter demise during stroke and point to this receptor type as a therapeutic target to limit tissue damage in cerebrovascular diseases.

Clemastine as a practical intervention
I came across a discussion among MS sufferers and a specific comment from a US child psychiatrist that drew my attention.


Daniel Kerlinsky says:   september 1 1, 2018 at 123 AM

Clemastine is a highly effective medication for re-myelination of white matter fiber bundles that connect neurons everywhere in the brain.
High doses aren't needed. One quarter of a 2.68 mg tablet is enough to start recruiting new oligodendrocytes to start making and applying myelin.
It does not have to be taken every day; it can be taken twice a week and still have a positive effect by recruiting the worker cells that repair the brain.
Remember normal myelination starts at the top of the brain and works downward during childhood development. At first the baby can't hold its head up, then it can sit up, then crawl, then stand.
Many MS lesions are located further down inside the brain and spinal cord so it takes time to get there.
The anti-inflammatory Minocycline taken once or twice a week is needed to stop the inflammatory part of the disease.                                                                            
And it takes cranio-sacral therapy to take full advantage of the new myelin which plumps the brain and even lubricates stiff joints like the sphenoid-occipital junction.
Don't give up on clemastine.

Its first and most obvious effect is improved emotional self regulation. Because myelination increases the speed of information processing ten-fold you will notice that thinking better comes next.
I can't tell you how long it will take to notice a difference. But the MS patient who told me about Clemastine got up out of her electric wheel chair and walked down the hall and back without a walker or her canes for the first time in two years.
It works great for kids with tantrums and developmental problems in about a month. It helps people with chronic depression and PTSD in about three months.
Back your dose down to 1.34 mg or 0.67 mg and give it two years. It takes a toddler that long.„



Increasing evidence suggests that white matter disorders based on myelin sheath impairment may underlie the neuropathological changes in schizophrenia. But it is unknown whether enhancing remyelination is a beneficial approach to schizophrenia. To investigate this hypothesis, we used clemastine, an FDA-approved drug with high potency in promoting oligodendroglial differentiation and myelination, on a cuprizone-induced mouse model of demyelination. The mice exposed to cuprizone (0.2% in chow) for 6 weeks displayed schizophrenia-like behavioral changes, including decreased exploration of the center in the open field test and increased entries into the arms of the Y-maze, as well as evident demyelination in the cortex and corpus callosum. Clemastine treatment was initiated upon cuprizone withdrawal at 10 mg/kg per day for 3 weeks. As expected, myelin repair was greatly enhanced in the demyelinated regions with increased mature oligodendrocytes (APC-positive) and myelin basic protein. More importantly, the clemastine treatment rescued the schizophrenia-like behavioral changes in the open field test and the Y-maze compared to vehicle, suggesting a beneficial effect via promoting myelin repair. Our findings indicate that enhancing remyelination may be a potential therapy for schizophrenia.

Altered myelin structure and oligodendrocyte function have been shown to correlate with cognitive and motor dysfunction and deficits in social behavior. We and others have previously demonstrated that social isolation in mice induced behavioral, transcriptional, and ultrastructural changes in oligodendrocytes of the prefrontal cortex (PFC). However, whether enhancing myelination and oligodendrocyte differentiation could be beneficial in reversing such changes remains unexplored. To test this hypothesis, we orally administered clemastine, an antimuscarinic compound that has been shown to enhance oligodendrocyte differentiation and myelination in vitro, for 2 weeks in adult mice following social isolation. Clemastine successfully reversed social avoidance behavior in mice undergoing prolonged social isolation. Impaired myelination was rescued by oral clemastine treatment, and was associated with enhanced oligodendrocyte progenitor differentiation and epigenetic changes. Clemastine induced higher levels of repressive histone methylation (H3K9me3), a marker for heterochromatin, in oligodendrocytes, but not neurons, of the PFC. This was consistent with the capability of clemastine in elevating H3K9 histone methyltransferases activity in cultured primary mouse oligodendrocytes, an effect that could be antagonized by cotreatment with muscarine. Our data suggest that promoting adult myelination is a potential strategy for reversing depressive-like social behavior.

SIGNIFICANCE STATEMENT Oligodendrocyte development and myelination are highly dynamic processes influenced by experience and neuronal activity. However, whether enhancing myelination and oligodendrocyte differentiation is beneficial to treat depressive-like behavior has been unexplored. Mice undergoing prolonged social isolation display impaired myelination in the prefrontal cortex. Clemastine, a Food and Drug Administration-approved antimuscarinic compound that has been shown to enhance myelination under demyelinating conditions, successfully reversed social avoidance behavior in adult socially isolated mice. This was associated with enhanced myelination and oligodendrocyte differentiation in the prefrontal cortex through epigenetic regulation. Thus, enhancing myelination may be a potential means of reversing depressive-like social behavior.



BACKGROUND:

Multiple sclerosis is a degenerative inflammatory disease of the CNS characterised by immune-mediated destruction of myelin and progressive neuroaxonal loss. Myelin in the CNS is a specialised extension of the oligodendrocyte plasma membrane and clemastine fumarate can stimulate differentiation of oligodendrocyte precursor cells in vitro, in animal models, and in human cells. We aimed to analyse the efficacy and safety of clemastine fumarate as a treatment for patients with multiple sclerosis.

METHODS:


We did this single-centre, 150-day, double-blind, randomised, placebo-controlled, crossover trial (ReBUILD) in patients with relapsing multiple sclerosis with chronic demyelinating optic neuropathy on stable immunomodulatory therapy. Patients who fulfilled international panel criteria for diagnosis with disease duration of less than 15 years were eligible. Patients were randomly assigned (1:1) via block randomisation using a random number generator to receive either clemastine fumarate (5·36 mg orally twice daily) for 90 days followed by placebo for 60 days (group 1), or placebo for 90 days followed by clemastine fumarate (5·36 mg orally twice daily) for 60 days (group 2). The primary outcome was shortening of P100 latency delay on full-field, pattern-reversal, visual-evoked potentials. We analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT02040298.

FINDINGS:


Between Jan 1, 2014, and April 11, 2015, we randomly assigned 50 patients to group 1 (n=25) or group 2 (n=25). All patients completed the study. The primary efficacy endpoint was met with clemastine fumarate treatment, which reduced the latency delay by 1·7 ms/eye (95% CI 0·5-2·9; p=0·0048) when analysing the trial as a crossover. Clemastine fumarate treatment was associated with fatigue, but no serious adverse events were reported.

INTERPRETATION:


To our knowledge, this is the first randomised controlled trial to document efficacy of a remyelinating drug for the treatment of chronic demyelinating injury in multiple sclerosis. Our findings suggest that myelin repair can be achieved even following prolonged damage.



Drug: Clemastine

12mg (4mg 3x/day) clemastine for 7 days followed by 8mg clemastine (4mg 2x/day) until 3 months. Patients will be off treatment from 3-9 months and will be reevaluated at 9 months.



Conclusion
Hopefully this post takes us one step closer to finding safe, side effect free, inexpensive ways to improve myelination in those with impaired myelination.

In the case of treating Multiple Sclerosis (MS), side effects clearly remain an issue. The suggestion of the psychiatrist in today’s post is to just lower the clemastine dosage and give it some time (2 years).  That sounds like smart advice to me.
Fortunately, it appears that in less severe cases of impaired myelination you may not need to wait 2 years.

Who exactly is going to benefit remains an open question, but for people already using H1 antihistamines to treat allergy, or other mast cell activation, switching to a different OTC antihistamine drug does not look like such a big step to take.
People with schizophrenia and allergy also might want to consider switching their antihistamine.

Undoubtedly some people will have the opposite issue with P2X7 receptors and for them there is another old antihistamine drug called Oxatomide.




61 comments:

  1. Peter,your blog posts have gotten increasingly dense over time.They have become harder and harder to follow,even for someone with a fairly good grounding in medical science.However,you may have published something that might help me a lot.

    You know nearly ten years ago,I started on high dose leucovorin,and in about 3 1/2 years,mostly reversed regressive autism,that was verbal but otherwise low functioning,with severe cognitive impairment and learning disabilities,in the American sense of the term.I have had multiple regressions triggered by acute infection.A couple of years later,I became one of the early patients diagnosed with high levels of folate receptor alpha autoantibodies,but as I explained in a comment on this blog a while back,unlike most with FRAAs,I do not have mitochondrial dysfunction.I do have double strand DNA breaks,and rearrangements on both copies of chromosome 11.As well as a pair of pathogenic mutations,in the MRN complex.

    While I was able to mostly reverse my autism,and stop my regressions,I still have two very disabling medical disorders,I have lived with all of my life,GI disease,that is likely a mix of Crohn's,and refractory coeliac,and a type of Chronic Inflammatory Demyelating Polyneuropathy,I lived with undiagnosed for decades.This causes me unbearable pain,in all four limbs,and may be a contributing factor to the severe muscle wasting I have in my limbs.During a very bad flare,I am unable to move my arms or legs.I take very high dose gabapentin,which helps mask the pain,but that is all.

    I don't have MS,but I do likely have another genetic autoimmune disorder.The closest we can figure out is a rare form of childhood onset systemic lupus,that involves both the brain/CNS,the GI tract.With what we know about the gut-brain connection,this makes a lot of sense.

    As you know,FRAAs are also found in some forms of schizophrenia,especially where there is autoimmune disease.

    So my question is,could Clemastine rebuild myelin elsewhere in the body?Has this been proven in MS?Would you suggest a higher dose for someone who has had the condition much longer than fifteen years?

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    1. Roger, the research shows that clemastine works in both the central nervous system and the peripheral nervous system (outside the brain and spinal cord).

      Clemastine might indeed help you.

      Dr Kerlinsky's very valid point is that "things take time", so better a low dose taken for years than a high dose that gives you side effects and then you quit taking it.

      Kerlinsky's dose is less than half the allergy dose.

      Fortunately this is a cheap OTC drug in the US.

      If I had MS I would already be taking it.

      My posts are indeed complicated, but all anyone really needs to do is to read the beginning and the end. The middle is just there to show there is indeed a scientific basis for what I am writing about. All my posts have an easy to read conclusion.

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  2. Peter, will reread these 2 posts to understand it more thoroughly (as I am a little lost) -- you mention "that post we saw that you can activate P2X7 receptors with an antihistamine called Clemastine and you can block P2X7 with another cheap antihistamine called Oxatomide." They would do opposite things? Are there clinical signs of needing one vs. the other and if so, what are they? Thanks, KM

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    1. KM, if you want to stimulate myelination you would want to activate P2X7 and so Clemastine might well help.

      Someone with MS would want to trial Clemastine and not Oxatomide.

      But in autism we nearly always have both extremes of any biological dysfunction, so many big heads but some tiny heads. Normally too many synapses, but sometimes the opposite i.e. too few.

      My guess is most people with autism are more likely to benefit from clemastine, but I am confident there will be those who benefit from Oxatomide. The one I am trying is Clemastine.

      If the myelination abnormalities in autism are due to P2X7, you can be almost certain that a small group will have the opposite defect.

      P2X7 is also involved in inflammation and mast cell degranulation. So perhaps there is a link between people with mast cell degranulation and people with a particular myelin issue.

      The problem is that you do not know the status of your child's myelin, you just know that in most "autism" it is not normal and that it tends to be thinner than normal.

      Because this is a cheap safe OTC product, I do not think you need to wait 20 years for a series of clinical trials, you can just try it yourself and follow Dr Kerlinsky.

      Delete
    2. Thanks Peter. My son has a large head and was more regressive type. He has had various autoimmune issues. It sounds like Clemastine would be the one to trial?

      Delete
    3. For most people Clemastine is the only one they will be able to get. I also think it is the right one to try. If you try it, let us know after a month or two what your verdict is.

      Delete
  3. Fwiw, I did not find clemastine fumarate otc (no longer carried at Amazon, cvs, etc), but in an international online shipping company located item from UK. If someone has found it in the US can you please let us know. Thanks.

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    Replies
    1. It was available very recently (mid 2018), perhaps because of its potential use in MS they want a large price increase. This happens frequently in the US. You can ask the FDA if it is still an OTC drug, then you can buy online from elsewhere.

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    2. It is sold OTC in the UK as Tavegil. 60 tablets for £7.95, about $10. Find a regular pharmacy that will ship to the US.

      The FDA site says it has been discontinued in the US.

      Probably later to reappear as an expensive prescription only drug for MS.

      Delete
  4. Hi Peter, the result of prednisone was spectacular,vocal tics are gone, he is more engaged and calmer and the hysterical laughter disappeared from the first dose. It would be awasome to be able to use it longer but I know it is not safe. What could I use that replaces it? Regarding myelin, there is a mushroom called Lion's Mane that is used in MS, may be could be of help.
    Valentina

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    1. Valentina, I expect it was just a short term auto-immune response that then caused a problem with the receptors associated with PANS, hence the vocal tics. By damping down his immune system the receptors go back to their previous functioning and the problem is solved. If you did not treat the problem rapidly, it could then become difficult to get these receptors to revert back to normal function.

      I do not think you need to replace prednisone, just keep it at home so if the same sudden onset behaviours occur in 3 years time you are able to respond quickly.

      Lion's Mane is interesting and was covered in this blog. It stimulates the production of NGF (nerve growth factor), NGF could well be a helpful therapy to prevent some types of dementia. The problem with such supplements is that they may not be pure; I suggested Lion's Mane capsules to my own mother, but it caused a fungus to grow in the back of her throat. I think that NGF eye drops are the best method of delivery.

      Delete
    2. Valentina, since you do have MS in your family, you might look into the anti-inflammatory therapies used in MS, separately from the pro-myelinating therapies. There are many therapies, and clearly there is no perfect therapy yet.

      In the above post the psychiatrist says "Minocycline taken once or twice a week is needed to stop the inflammatory part of the disease". This is just his idea/opinion, there are many others.

      Delete
    3. Peter, I can get here Tetracycline, is cheap, would it be ok?
      Valentina

      Delete
    4. Valentina

      Minocycline is an antibiotic of the tetracycline class. As we saw this class of antibiotic is immunomodulatory. Mostly research uses minocycline because it is the one that crosses best into the brain (more lipid soluble).

      So minocycline is clearly the one with the most potential. But at least one reader did report a benefit from other tetracycline drugs.

      Here is a related post.

      https://epiphanyasd.blogspot.com/2015/03/antibiotics-and-autisms-pass.html

      Delete
    5. Peter, minocycline comes in 100mg tablets and tetracycline comes in 500mg.Should I use a 500 mg tablet of tetracycline or less once a week?
      Valentina

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    6. Valentina, I think you would need at least the standard dose of tetracyline to try and achieve the effect of 100mg of minocycline. So 500mg make sense.

      Delete
    7. Peter, what do you think about drug induced lupus with mynocicline? Could tetracyclines cause autoimmunity in low doses?
      Valentina

      Delete
    8. Valentina, I think you have to ask a doctor these questions. All drugs and indeed supplements can cause side effects, and so care has to be taken.

      Delete
  5. Hi Peter,

    Hope all is well.

    Peter, I would really appreciate your advice on something. For background, as you know, we have been using C8 + BHB with better results than anything else we had tried and this is our main treatment protocol (along with P5P, Riboflavin, Vitamins C+D, and Pterostilbene)

    Recently, we have been getting some messages from our daughter's school that she is very "energetic" (i.e. runs around too much, jumps all the time very hyperactive, etc.) and that she isn't very focused (we know this too). Getting her to calm down a bit and focus more at school would be great, and even at home as homework time can be challenging (she'll sit for a few minutes but can't focus longer than that on homework, then runs / jumps around a lot)

    I suspect that based on our reports and school's observations, she could be viewed as having "ADHD" on top of the ASD diagnosis. We will be seeing our family doc soon and I would really appreciate any advice you may have on med options that would both address the focus / hyperactivity issues and would potentially be beneficial in her ASD diagnosis. As you may recall, my daughter has cognitive issues (although extremely bright in some areas, has issues with complex ideas), as well as speech / socialization issues.

    I know you had posted about a year ago about ADHD, including about guanfacine, but wondered if you had any new / updated thoughts before we see the family doc.

    Thanks very much in advance Peter!

    AJ

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    1. AJ, I am not very knowledgeable about ADHD treatment. I think there must be some good resources out there.

      It looks like stimulant drugs have some big issues.

      I think you tried high dose EPA, which some people find to be very helpful in ADHD.

      It looks like some people with ADHD have a diet that makes the condition worse. They have too much sugar, bad fats etc.

      You might want to double check that the BHB+C8 is not causing the ADHD.

      Delete
  6. AJ, I am definitely not an expert on ADHD. But you might want to know that Bacopa have had effect in ADHD trials.
    https://www.ncbi.nlm.nih.gov/pubmed/24682000
    I think also sulforaphane and phosphatidylserine have been trialled with some success. Other interventions would be the combo of Mg+Zn+P5P, or EPA as Peter mentions above.
    Not sure this helps, but at least you have something to look up.

    /Ling

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  7. This clemastine treatment seems to be promising even for my son. Unfortunatelly here in Slovakia clemastine is on prescription and moreover seems like it is not imported here by any drugstore. Does enybody here know if it is possible order it online in EU without prescription?

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    1. It can be ordered in the UK online without prescription. They should be happy to mail it within the EU. Just google "buy Tagevil UK".

      Delete
    2. Well it doesn't seems to be that straight forward. Here is an answer from one online shop:
      "Dear P. S.
      Please be advised that we have now cancelled your order 1247459
      due to the prohibited restricted supply to the destination country of the following items:

      Tavegil 1mg Tablets 60 x 1"

      This one was from ExpressChemist.co.uk
      For now I'm not sure if I have to keep trying with next eshops.

      Delete
    3. I wonder if they will ship to people in the US, where it is now unavailable, but still classed as OTC. For now it seems only straightforward for people present in the UK.

      Delete
  8. Here is some interesting research on Nicotanimide Riboside (NR) that may be of use to older mothers (age 30+) who may face problems with nursing after birthing their child:

    Press Release:

    https://www.sciencedaily.com/releases/2019/01/190122114958.htm

    Paper (Open Access PDF):

    https://www.cell.com/cell-reports/pdf/S2211-1247(19)30015-4.pdf

    First off, it should also be noted this research was funded by Chromadex which is the maker of Niagen and the primary seller of Nicotanimide Riboside. Nevertheless, if you accept the researchers as working in good faith, this research is very interesting for several reasons:

    (1) Previous research had concluded that postpartum women lose a lot of NAD+ in the liver which is shunted to the mammary glands and helps promote lactaction.

    (2) In the mice that were tested, NAD+ supplementation via NR effectively eliminated the loss of NAD+ in the liver and induced strong lactation in the postpartum mice.

    (3) The offspring of NR supplemented postpartum mother mice were superior in many desirable qualities than the offspring of control mice including being hypoglycemia resistant as well as having major improvements in motor learning relative to control offspring (missing motor milestones is a hallmark of low-functioning autism).

    (4) The offspring mice of NR supplemented postpartum mice had higher levels of BDNF in their brains.

    (5) The postpartum mice (mothers) also lost their postpartum fat much faster. To add to that, in my experience very few of the mothers I have met with a child with autism do not have a body type indicative of metabolic syndrome. In other words, pregnancy takes a hard toll on their body, many of whom never seem to recover from metabolically. This may be somewhat due to the country I live in (USA) where 70% of adult women are overweight and 40% or more are clinically obese, but in spite of these stark statistics, it seems like mothers of autistic children by and large have greater problems post-pregnancy with regards to losing fat gained during pregnancy, as well as not significantly and permanently increasing their weight after each successive pregnancy.

    ReplyDelete
  9. So perhaps this research may suggest that NAD+ depletion which may be exacerbated by:

    (1) Postpartum stress (American women typically only get 3 months of maternity leave and men get two weeks at the most which means more unnecessary stress on the mother since the father is unable to pick up the slack).

    (2) The mother is often forced to pump milk at work or only do feedings after work. This limits milk production and forces the mother to rely on formula to nourish her infant.

    (3) In spite of many public service campaigns promoting nursing as being good for the baby, it is still unfashionable among many socioeconomic groups for the mother to nurse their child.

    (4) First-time American mothers are on average pretty old relative to the rest of the world and previous generations and getting older which means more problems with nursing, especially in the mid to late thirties and thereafter. Older men and women produce less NAD+ as this just seems to be part of the aging process.

    (5) Though diets of higher income American mothers tend to have more salad relative to soda, still very few women overall eat a healthy diet, especially one with enough fiber, especially after the baby is born which critically impacts the quality of the milk produced. Nutritional ignorance and even advice given by doctors (if they give any advice at all) can often be quite extreme and this inevitably has a negative impact on children both prenatally and postnatally. Poor diets will mean less NAD+ produced in the body, especially if the diet is deficient in tryptophan and vitamin B6 (B6 is a cofactor in producing NAD+ via the kynurenine pathway).

    So really this begs the question of whether postpartum NR supplementation could reduce the risks of neurodevelopmental disorders in western women who may have reduced NAD+ production for any combination of the aforementioned reasons. I assume the next step for this research group (and Chromadex as well) may be to do research in human mothers to see of NR supplementation causes superlactation in at-risk mothers for breastfeeding challenges, as well as what impact such an intervention may have on the developmental milestones of children fed milk from NR supplemented mothers.

    And with respect to autism, I have a gut feeling if you could get a large enough sample size in the study, you would find less intense autism symptoms in the children of the NR supplemented mothers. It seems clear by the current research that most autism development seems to start in the third-trimester, but in terms of the intensity of the symptoms, those can be attenuated or exacerbated by factors happening after they are born and it seems that the research is clear that breastfeeding is neuroprotective relative to bottle-feeding in all children, so any intervention that increases the success rate of breastfeeding may reduce the severity of autism symptoms for those already on a trajectory for an autism diagnosis via professional observation a few years later.

    ReplyDelete
  10. Interesting how different I would be for my pregnancies (including trying earlier with my husband as we thought we had forever back then). Thank you for this post and introducing us to Niagen. Also, did want people to know that I ordered from two pharmacies from UK (just googled it) and got Clemastine received today. My son is at university so not going to have him try it until spring break.

    ReplyDelete
  11. Peter,
    It`s a wonderful post, you've made great connections among different things, thank you.
    Started with small dose of Tavegyl few days ago, quarter of 1,34 mg, once , before sleep.
    My daughter (aged 14, ASD) has chronic rhinosinusitis, and it will be beneficial in many ways.
    I was sure that I am imagining, but the others in family conferred that she is in the best mood ever since she has been using it (maybe the good night sleep is the reason, who knows...).
    Anyway, I shall inform you about possible desired effects few months later,
    Maja

    ReplyDelete
    Replies
    1. Maja, I was surprised but in my 15 year old son a whole tablet causes no sedation. He can have it in the morning as if it was Cetirizine. In fact the allergy dose is twice a day.

      I think the people with MS are taking a dose of at least 4 tablets and I suppose that is going to make you sleepy.

      Delete
    2. Peter,
      I suppose it is individual reaction, as I've seen in MS blog. Maybe she wouldn't feel sleepy if I gave her a tablet in the morning, when she is not suppose to go to bed?

      My daughter do reacts very strong in "sleeping pills". From 0,25mg mg of melatonin she use to sleep so tight that it scares me.
      The same think happens now, so, that's the reason for such a small dose.
      I added a pinch of inulin with a Tavegyl too. It doesn't let her to sleep so tight. It isn't a fact, it is just result of my observation.

      However, she is feeling good with Tavegyl, cheerful and present.
      Unfortunately, she got sick last night (virus).
      By the way, she gets sick each time her autism symptoms attenuate.

      Delete
  12. Incidentally, while looking for ideas related to the neglected topic of coping with stress in severe autism, this paper emerged on my list:

    "Clemastine Alleviates Depressive-Like Behavior Through Reversing the Imbalance of Microglia-Related Pro-inflammatory State in Mouse Hippocampus"

    https://www.frontiersin.org/articles/10.3389/fncel.2018.00412/full

    It's about mice experiencing chronic unpredictable mild stress and treated with a huge dose of clemastine.

    They found that "clemastine administration for 4 weeks remarkably decreased IL-1β and TNF-α protein levels in hippocampus and serum", which is contradictory to the previous findings on clemastine and IL-1β. The authors also point to P2X7 receptor mechanism.

    How to interpret this?

    ReplyDelete
    Replies
    1. Agnieszka, this fits in with Dr Kerlinsky's suggested use to treat depression and PTSD.

      I think in my previous post on P2X7 there were contradictory findings in the research. I that think this take us back to the what, when and were of neuroscience. Opposite things can be happening at the same time in the same brain, but in different places. This was true with NMDA hyperfunction occurring in one region while there is hypofunction elsewhere.

      That it is why both Oxatomide and Clemastine are worth trying, to see which one helps (perhaps neither will).

      Delete
    2. To complicate more, from Peters link, there is a IL-1 receptor antagonist too:

      “…although we demonstrated release of the proinflammatory cytokine IL-1β from hMDM, P2X7 activation also gives rise to production and secretion of IL-1 receptor antagonist (IL-1Ra), which is in turn expected to exert anti-inflammatory activity …”

      I would like to add one more good thing that clemastine does –shifting M1 microglia cells back to an M2 anti-inflammatory phenotype. In that state it can do their job in pruning synapses.

      From Agnieszkas link:

      “…potential function of clemastine in modulating the expression of P2X7 receptor possibly independent of HRH1, therefore suppressing the microglial M1-like activation and pro-inflammatory cytokines release in brain regions…”

      Delete
    3. Maja, as I wrote in the main post, many people with autism are already taking an H1 antihistamine on a regular basis and so to switch to Clemastine is an easy and safe step to take. Whether people without allergy/mast cell problems want to add clemastine is up to them.

      Since it may take months for any potential benefit to become evident, it becomes harder to know for sure that any changes are due to Clemastine. The good thing is that half or a quarter pill a day is very safe and not expensive.

      There are very good reasons to expect a benefit from Clemastine.

      Delete
    4. I am already satisfied with its antihistamine H1 affect.
      The possible expecting effect three or more months later I am looking forward to see.
      I shall be glad to inform about that, thank you, Peter.

      Delete
    5. Thanks Maja and Peter. It seems like you need a trial an error as usual.

      Oxatomide short trial resulted in irritability in my son and perhaps this had nothing to do with P2X7 receptor as most anithistamines have several mechanisms of action and it happened in the past with some others as well. In case of Clemastine the jury is still out on its effect here.

      Delete
  13. This comment has been removed by the author.

    ReplyDelete
  14. Hi Peter,

    Slightly off topic but I was just on a flight and saw this on the Ted Talks section of their entertainment system.

    https://www.ted.com/talks/jocelyne_bloch_the_brain_may_be_able_to_repair_itself_with_help/up-next

    It’s aimed at being a potential treatment for traumatic brain injury and Parkinson’s but I’m wondering if you like me see the possibilities in treating some forms of ASD especially those mentioned in the above blog post?

    ReplyDelete
    Replies
    1. Kei, for the benefit of other readers, this talk was about:

      Through treating everything from strokes to car accident traumas, neurosurgeon Jocelyne Bloch knows the brain's inability to repair itself all too well. But now, she suggests, she and her colleagues may have found the key to neural repair: Doublecortin-positive cells. Similar to stem cells, they are extremely adaptable and, when extracted from a brain, cultured and then re-injected in a lesioned area of the same brain, they can help repair and rebuild it. "With a little help," Bloch says, "the brain may be able to help itself."

      It is very interesting and clearly the big step is to try this in humans. It certainly worked well for the monkey.

      I am not sure what would happen to someone with autism. Perhaps those people lacking a complete corpus callosum (which joins the two sides of the brain) might re-grow one.

      In someone just a bit quirky, I doubt it would help.

      I think we will find out only after a few decades.

      It looks like a perfect therapy for traumatic brain injury or neurological disorders in younger people, who have decades of healthy life potentially ahead of them. I doubt it would be developed for dementia, except perhaps for very rich people.

      Delete
  15. I have an interesting clue that I need some intelligent people (or maybe a geneticist) look at. I am comparing two complicated quotes:

    "Clemastine induced higher levels of repressive histone methylation (H3K9me3), a marker for heterochromatin, in oligodendrocytes, but not neurons, of the PFC. () Therefore, clemastine induces OPC differentiation possibly by enhancing the activity of histone methyltransferases and favoring chromatin compaction."
    http://www.jneurosci.org/content/36/3/957

    and:

    "Mitochondrial stress response activation requires the di-methylation of histone H3K9 through the activity of the histone methyltransferase met-2 and the nuclear co-factor lin-65. While globally the chromatin becomes silenced by these marks, remaining portions of the chromatin open up, at which point the binding of canonical stress responsive factors such as DVE-1 occurs"

    Now, in the second quote I happen to note that DVE-1 is the homolog of my daughters mutated gene.
    If I just for a while assume that both genes/homologs are placed similarily in the genetic material an important but maybe naïve question arises:
    Could clemastine open up the chromatin on a part where my daughter's gene is located, so that it gets transcribed a little bit more?

    We know that clemastine has some effect on osteoporosis and myelin, and one study mentioned it was less suitable for breast cancer patients.
    My daughter is at risk of osteoporosis and eventually at low myelinisation, but probably at less risk of breast cancer due to her insufficient gene. Sounds straightforward, but if there was a major effect on her gene it wouldn't be an allergy drug for kids...

    On a side note, it looks like Clemastine often makes children hyper, but adults lethargic.

    /Ling

    ReplyDelete
  16. Maybe I'm overinterpreting, but it looks like those P2X7 receptors are involved in GLUT1 / ATP / energy metabolism:

    "P2X7R expression allows better adaptability to unfavorable ambient conditions via upregulation of glycolytic enzymes and by increasing intracellular glycogen stores"

    "P2X7R-expressing cells upregulate (a) the glucose transporter Glut1"

    The P2X7 receptor is a key modulator of aerobic glycolysis
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3434661/

    /Ling

    ReplyDelete
    Replies
    1. Ling, GLUT1 reductions exacerbate Alzheimer's disease. So if you can upregulate GLUT1 at the blood brain barrier with Clemastine, you have a new add-on therapy for Alzheimer. And a cheap one!

      Delete
  17. I don't get this P2X7-topic.
    Almost all articles I can find on the subject tells us that it is antagonists we want, and not agonists.

    It doesn't matter if we are talking about brain inflammation, IBD, Crohns, asthma, neurogenic bladder dysfunction, mood disorders, schizophrenia or something else. It is antagonists that are mentioned almost everywhere.
    Still, Clemastine use seems to have a beneficial effect on myelin.

    Surely there has to be an explanation?

    /Ling

    ReplyDelete
    Replies
    1. Ling, this is an excerpt from another post:

      When an Antagonist behaves like an Agonist –

      P2X7 Receptor Antagonists Display Agonist-like Effects on Cell Signaling Proteins
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3087820/

      Conclusions

      Several agents used as P2X7R blockers promote the activation of various signaling proteins and thereby act more like receptor agonists than antagonists.

      This means your P2X7 blocking natural supplement may actually be having the opposite effect to the one you believe.
      As I keep repeating in this blog, for all kinds of reasons, it is very easy to get things the wrong way around. So instead of forwards, try reverse – just like if you get your car stuck in snow.

      If Clemastine has a bad effect, try Oxatomide, and vica versa. This of course just applies to their effect on P2X7, both of these allergy drugs affect numerous other receptors as well. In both cases we are talking about a fraction of the allergy dose, so not exactly a risky exercise.

      ======

      The other thing to note is that two different mechanisms are proposed for Clemastines effect in myelin, P2X7 and being a muscarinic receptor antagonist.

      There will be a correct explanation, but there are multiple possibilities. I also thought Oxatomide might be helpful for some people.

      Delete
    2. Thanks for the link, it was exactly the puzzlepiece I was looking for!
      You are right about getting things the wrong way, it is very easy. The typical example is when a study shows something is upregulated in the body because of an added substance and you don't know if it is a bad thing happening or something the body does to counteract the effect of the substance.
      Anyway, this makes me more sure on starting a trial. :-)

      /Ling

      Delete
  18. This reminds me of the Suramin trial. Anti-purinergic therapy which had a remarkable effect albeit with a small sample size. Clemastine appears to work contrary to this. On the plus side - finally a drug that is easy to buy otc in the UK!

    Btw...would caffeine complement or antagonise the effect of Clemastine as an adenosine receptor antagonist?

    What are your thoughts about the following paper:

    Adenosine Actions on Oligodendroglia and Myelination in Autism Spectrum Disorder

    Front. Cell. Neurosci., 07 December 2018 | https://doi.org/10.3389/fncel.2018.00482

    Best wishes
    Mashhood

    ReplyDelete
    Replies
    1. Mashhood, nice to meet you at the conference. You have been busy making comments, so my response is rather extended, so non-medical people can understand.

      Nothing is simple and even Clemastine's up-regulation of myelin has multiple possible modes of action. Also we have agonists acting like antagonists, so it is easy to get bewildered by apparent contradictions.

      I think only fool would claim to understand it all.

      I am really only interested in the practical application and note that sometimes you can get the exact opposite effect to the one expected.

      For many reasons I think some people will benefit from caffeine (and indeed nicotine). I am not surprised people with Schizophrenia are smokers and coffee drinkers.

      Caffeine, and the drugs theobromine/phylline, are so-called methylated xanthine derivatives. They are found in coffee (no surprise), tea and cocoa.

      As methylated xanthines, they have two different functions:-

      1. competitive nonselective phosphodiesterase inhibitor which raises intracellular cAMP, activates PKA, inhibits TNF-alpha and inhibits leukotriene synthesis, and reduces inflammation and innate immunity

      2. nonselective adenosine receptor antagonist

      The first function would be beneficial to many people with ASD, regardless of their myelination status.

      α2 agonists, like the Guanfacine taken by our reader SB’s son and Luis’ son can be used to treat high blood pressure and ADHD.

      Your caffeine is the opposite. It is an antagonist of α1, α2A, α2B and α3

      If you think of caffeine as coffee then you add in all the coffee flavanols, that have been discussed in this blog like Chlorogenic acid and Caffeic Acid.

      I did write at length about caffeic acid phenethyl ester (CAPE), which has remarkable properties including being a PAK1 inhibitor. This would seem to be a very cheap and possibly very effective therapy for Neurofibramatosis and some autism, like those that responds to FRAX486. CAPE is a cheap research chemical, FRAX486 is an expensive research chemical.

      Your paper on adenosine's actions in ASD is interesting.

      I think trying an agonist and then an antagonist is the only way you will know whether this is relevant to your case of autism.

      This was the case with Clemastine. You could write 10 pages on why it would not help and another 10 pages on why it might. Or you could pop down the high street and buy some for ten pounds ($8), and of those 60 tablets you need just 5 to find your answer. The rest you can put aside to treat someone's pollen allergy.

      Delete
    2. Thank you Peter.

      I agree - it's a lot of information and interactions to keep track of. I can't say I understand it. Best way as you say is to be methodical and trial and error.

      I have sourced some clemastine.

      Hopefully will see some benefit!

      Delete
  19. Hi Peter,
    I would like to do a trial with Clemastine.However,it is not available in usa.Could you recommend something equivalent in USA?
    Thanks
    SB

    ReplyDelete
  20. Hi Peter,
    I found something on ebay
    https://www.ebay.com/i/173873959168?chn=ps
    Is it the same as Clemastine?
    Thanks
    SB

    ReplyDelete
    Replies
    1. SB, yes that is the same thing.

      Clemastine 2mg by Teva is available in the US, but you may need a prescription. Ask in your local pharmacy.

      Delete
  21. I'm having a funny feeling that our (baby) teething periods start with ameliorated apraxia (we hear syllables), and after a few days instead there is excessive oxidative stress leading to irritability/aggressiveness.

    It would be so nice to keep the positive language gains, but I have no idea why it is happening at all, and why it happens before the negative effects.
    Slightly more signaling of some type?

    Peter, do you have any suggestion or clue on what might be going on?

    /Ling

    ReplyDelete
    Replies
    1. Ling, I think you might experience something similar to the fever effect. In some people the numerous biological changes during fever shifts homeostasis briefly to a place where "autism" symptoms fade.

      Pain will cause irritability in all of us. But before the pain there are changes in inflammatory cytokines that in your daughter are helpful. In the ideal world you would take a blood sample and measure what has changed.

      This is another reminder that immunomodulatory therapy is a an avenue to pursue in autism. The problem is there will be no one size fits all therapy. Without a blood sample you cannot know what is going on.

      Delete
    2. Very interesting. Do you mean that measuring blood inflammatory cytokines levels during such a period of positive gains would be a good idea? Perhaps with the baseline values to compare?

      It is not impossible in practicie. Where I live you can easily get a panel of 6 main inflammatory cytokines serum levels for 70 EUR. Including IL-10 which I would suspect, if any, for the good effect. But would you expect that the supposed changes of their blood concentration affect central nervous system without any visible systemic symptoms during teething?

      Delete
    3. Agnieszka, if autism was ever treated methodically you would for each child establish the baseline for inflammatory/anti-inflammatory markers and then if something unusually good or bad occurred, that was related to inflammation, you would immediately take the child to give a blood sample. Wait a week/month thinking about it and you would lose the opportunity.

      That is part of the reason why motivated parents would benefit from long term monitoring by a well informed doctor. So that doctor could tell the local GP, please take a blood sample ASAP.

      For example it might be that in most children IL-6 makes autism worse, but in a small group it is beneficial.

      Teething is the visible symptom of cytokine changes.

      It may be only a small change in cytokines is needed to affect behavior. Since there is no data, we do not know.

      When the Gdansk Autism Clinic opens, a profile of inflammatory cytokines could be included on the "menu". You could even have Paul Ashwood at UC Davis review which cytokines should be measured.

      Parents would complain about the need for a blood draw.

      Delete
  22. For clemastine in the USA I would go with Teva
    https://www.tevagenerics.com/product/clemastine-fumarate-tablets-usp
    Just a heads up though that Teva (and other companies) are in trouble for price-fixing and some might not survive.
    https://www.bloomberg.com/news/articles/2019-05-13/collusion-allegations-send-generic-drug-company-shares-spiraling

    LG

    ReplyDelete
  23. So, here is my report on Clemastine – the jury is still out…
    Subject was 4 y, 18 kg

    A. Trialled for 3 weeks at 2*0.25mg daily.
    More “talking” but lots of repetition. Dryer skin.

    B. After a pause, retrialled for another 4 weeks on 2*0.25 mg daily…
    10 days in I notice that she stands her ground more now, she doesn’t give up as easy. She has started to pull my clothes as she wants a lot of things. Also, she has started to use pointing a lot, either with her own finger or mine. I’m not sure this is a good sign of a more urgent wish to communicate or if it is a bad thing caused by loss of signing skills.
    C. ..directly followed by 5 weeks on 2*0.5 mg daily.
    After 4 weeks we suddenly notice stimming – both hand flapping and some kind of leg flapping. There is a tooth upcoming which could be related, but we have not seen stimming for 2½ years and now we see it several times daily when she becomes excited or upset. Good or bad?

    /Ling

    ReplyDelete
    Replies
    1. Ling, an increased desire to communicate and have opinions must be good signs. Since your daughter is non-verbal I think you would expect this to come with some frustration which will accompany it.

      There clearly is an effect, which I think is encouraging. You will have to decide if you think there is an overall benefit.

      I think other interventions also have their pluses and minuses. Increasing awareness and cognitive function is a good thing, but may make some people with autism harder to handle.

      Delete
    2. I almost forgot, but I've also seen a notable mouthing activity in the last weeks. While some might think that is bad, I still believe it is an improvement compared to the previous 'no interest of the mouth at all'.
      I'll stick with this intervention for a while and let time tell.
      /Ling

      Delete
  24. Three articles on myelination/oligodendrocyte differentiation.

    The first one hypothesizes that despite previous dogma myelin formation is not dependent on the estrogen receptors at all but on cholesterol pathways. The drug that was studied, Basedoxifene, is an osteoporosis drug for prevention of postmenopausal osteoporosis (so not for kids, but we’ll learn a lot anyway):

    “our results demonstrate that certain SERMs [selective estrogen receptor modulators] promote [oligodendrocyte precursor cell, OPC] differentiation, whereas others, as well as estrogens, do not. [..] We therefore sought to determine the mechanism of action for BZA [basedoxifene]. BZA acts as an agonist and antagonist on both nuclear ERs. Therefore, we isolated OPCs from total ERβ and ERα KO mice and assessed OPC differentiation after treatment with BZA for 48 h. We were surprised to see significantly enhanced OPC differentiation across all treatment groups to the same magnitude as WT cells, indicating that BZA does not induce OPC differentiation through ERα or ERβ. [..]
    To ensure there was no compensation from the complementary receptor, we generated ERα and ERβ double-KO animals. After treatment with BZA or tamoxifen, we again saw significant enhancement of OPC differentiation [..] This led us to conclude that BZA and other SERMs exert potent effects on OPC differentiation independently of their intended nuclear ER targets.
    [..]
    In light of the surprising lack of requirement for either ER for BZA to mediate its effect on OPC differentiation, we took steps to gain greater clarity into the mechanism of action and to isolate SERMs' veritable target. [..] Of these possible targets, EBP was of particular interest. EBP (encoding 3β-hydroxysteroid-▵8-▵7-sterol isomerase) is an important enzyme in the biosynthesis of cholesterol.
    [..]
    Here, we demonstrate that, in combination with clemastine (at maximal dose), a compound previously shown to promote OPC differentiation by antagonizing the muscarinic acetylcholine receptor 1 subtype, BZA (at maximal dose) exerts an additive effect on OPC differentiation

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433770/

    -----------------------------------------------------
    "High-throughput chemical screening approaches have been used to identify small molecules that stimulate the formation of oligodendrocytes from oligodendrocyte progenitor cells and functionally enhance remyelination in vivo. Here we show that a wide range of these pro-myelinating small molecules function not through their canonical targets but by directly inhibiting CYP51, TM7SF2, or EBP, a narrow range of enzymes within the cholesterol biosynthesis pathway. Subsequent accumulation of the 8,9-unsaturated sterol substrates of these enzymes is a key mechanistic node that promotes oligodendrocyte formation"

    https://www.ncbi.nlm.nih.gov/pubmed/30046109/

    -----------------------------------------------------
    "We have been investigating pharmacological approaches to enhance OPC differentiation, and have identified that the combination of two agents, triiodothyronine (T3) and quetiapine [schizophrenia drug], leads to an additive effect on OPC differentiation and consequent myelin production via both overlapping and distinct signaling pathways. While the ultimate production of myelin requires cholesterol biosynthesis, we identified that quetiapine enhances gene expression in this pathway more potently than T3. Two blockers of cholesterol production, betulin and simvastatin, reduced OPC differentiation into myelin producing oligodendrocytes."

    https://www.ncbi.nlm.nih.gov/pubmed/31490950


    Anyone up for the challenge to find a child-friendly solution?
    /Ling

    ReplyDelete

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