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Wednesday 22 February 2023

Treating Rett syndrome, some autism and some dementia via TrkA, TrkB, BDNF, IGF-1, NGF and NDPIH. And logically why Bumetanide really should work in Rett

Source: Rett Syndrome: Crossing the Threshold to Clinical Translation

 

Today’s post is on the one hand very specific to Rett syndrome, but much is applicable to broader autism and other single gene autisms.

Today’s post did start out with the research showing Bumetanide effective in the mouse model of Rett syndrome. This ended up with figuring out why this should have been obvious based on what we already know about growth factors that are disturbed in autism and very much so in Rett.

We even know from a published human case studies that Bumetanide can benefit those with Fragile X and indeed Down syndrome, but the world takes little notice.

If Bumetanide benefits human Rett syndrome would anyone take any notice?  They really should.

To readers of this blog who have a child with Rett, the results really are important.  You can even potentially link the problem symptoms found in Rett to the biology and see how you can potentially treat multiple symptoms with the same drug.

One feature of Rett is breathing disturbances, which typically consist of alternating periods of hyperventilation and hypoventilation.

Our reader Daniel sent me a link to paper that suggest an old OTC cough medicine could be used to treat the breathing issues.

The antitussive cloperastine improves breathing abnormalities in a Rett Syndrome mouse model by blocking presynaptic GIRK channels and enhancing GABA release


Rett Syndrome (RTT) is an X-linked neurodevelopmental disorder caused mainly by mutations in the MECP2 gene. One of the major RTT features is breathing dysfunction characterized by periodic hypo- and hyperventilation. The breathing disorders are associated with increased brainstem neuronal excitability, which can be alleviated with antagonistic agents.

Since neuronal hypoexcitability occurs in the forebrain of RTT models, it is necessary to find pharmacological agents with a relative preference to brainstem neurons. Here we show evidence for the improvement of breathing disorders of Mecp2-null mice with the brainstem-acting drug cloperastine (CPS) and its likely neuronal targets. CPS is an over-the-counter cough medicine that has an inhibitory effect on brainstem neuronal networks. In Mecp2-null mice, CPS (30 mg/kg, i.p.) decreased the occurrence of apneas/h and breath frequency variation. GIRK currents expressed in HEK cells were inhibited by CPS with IC50 1 μM. Whole-cell patch clamp recordings in locus coeruleus (LC) and dorsal tegmental nucleus (DTN) neurons revealed an overall inhibitory effect of CPS (10 μM) on neuronal firing activity. Such an effect was reversed by the GABAA receptor antagonist bicuculline (20 μM). Voltage clamp studies showed that CPS increased GABAergic sIPSCs in LC cells, which was blocked by the GABAB receptor antagonist phaclofen. Functional GABAergic connections of DTN neurons with LC cells were shown.

These results suggest that CPS improves breathing dysfunction in Mecp2-null mice by blocking GIRK channels in synaptic terminals and enhancing GABA release.

  

Cloperastine (CPS) is a central-acting antitussive working on brainstem neuronal networks The drug has several characteristics. 1) It affects the brainstem integration of multiple sensory inputs via multiple sites including K+ channels, histamine and sigma receptors. 2) Its overall effect is inhibitory, suppressing cough and reactive airway signals. 3) With a large safety margin, it has been approved as an over-the-counter medicine in several Asian and European countries.  

With the evidence that DTN cells receive GABAergic recurrent inhibition, we tested whether the inhibitory effect of CPS was caused by enhanced GABAergic transmission. Thus, we recorded the evoked firing activity of DTN cells before and during bath application of CPS in the presence of 20 μM bicuculline. Under this condition, CPS failed to decrease the excitability of DTN neurons (F(1,9) = 0.41, P > 0.05; two‐way repeated measures ANOVA) (n=9) (Fig. 8), indicating that the inhibitory effect relies on GABAA synaptic input 

 

It appeared to me that the breathing issues might be considered as another consequence of the excitatory/inhibitory (E/I) imbalance that is a core feature of much severe autism.

In the case of Rett the lack of BDNF will make any E/I imbalance worse and that by treating the E/I imbalance we will produce the inhibitory effect from GABAa receptors that is needed to ensure correct breathing.  Note that in bumetanide responsive autism there is no inhibitory effect from GABAa receptors, the effect is excitatory.

I did wonder if arrhythmia (irregular heartbeat) is present in Rett, since the breathing problems in Rett are also seen as being caused by a dysfunction in the autonomic nervous system. Arrhythmia is actually a big problem for girls with Rett syndrome.  Regular readers of this blog might then ask about Propranolol, does that help?  It turns out to have been tried and it is not so helpful.  What is effective is another drug we have come across for autism, the sodium channel blocker Phenytoin.  Phenytoin is antiepileptic drug (AED) and it works by blocking voltage gated sodium channels.

Low dose phenytoin was proposed as an autism therapy and a case study was published from Australia. In a separate case study, phenytoin was used to treat self-injury that was triggered by frontal lobe seizures.

When you treat arrhythmia in Rett girls with Phenytoin does it have an impact on their breathing problems?

If you treat the girls with Phenytoin do they still go on to develop epilepsy?

What about if you add treatment with Bumetanide to reduce symptoms of autism? 

Lots of questions looking for answers.

 

What is Rett Syndrome?

Rett syndrome was first identified in the 1950s by Dr Andreas Rett as a disorder that develops in young girls.  Only as recently as 1999 was it determined that the syndrome is caused by a mutation in the MECP2 gene on the X chromosome.  The X chromosome is very important because girls have two copies, but boys have just one.  Rett was an Austrian like many other early researchers in autism like Kanner and Asperger. Even Freud was educated in Vienna. Eugen Bleuler lived pretty close by in Switzerland and he coined the terms schizophrenia, schizoid and autism. 

Rett syndrome is a rare genetic disorder that affects brain development, resulting in severe mental and physical disability.

It is estimated to affect about 1 in 12,000 girls born each year.

Rett is a rare condition, but among these rare conditions it is quite common and so there is a lot of research going on to find treatments.  The obvious one is gene therapy to get the brain to make the missing MeCP2 protein.

Rett syndrome is thankfully rare in absolute terms, but it is one of the best known development conditions that is associated with autism symptoms.

While Rett syndrome may not officially be an ASD in the DSM-5, the link to autism remains. Many children are diagnosed as autistic before the MECP2 mutation is identified and then the diagnosis is revised to RTT/Rett. 

Fragile X  syndrome (FXS), on the other hand, is the most common inherited cause of intellectual disability (ID), as well as the most frequent single gene type of autism.

In the meantime, the logical strategy is to treat the downstream consequences of the mutated gene. Much is known about these downstream effects and there overlaps with some broader autism and indeed dementia.

One area known to be disturbed in Rett, some other autisms and dementia is growth factors inside the brain. The best known growth factors are IGF-1 (Insulin-like Growth Factor 1), BDNF (brain-derived neurotrophic factor) and my favorite NGF (Nerve growth factor).

Without wanting to get too complicated we need to note that BDNF acts via a receptor called TrkB.  You can either increase BDNF or just find something else to activate TrkB, as pointed out to me by Daniel.

For readers whose children respond to Bumetanide they are benefiting from correcting elevated levels of chloride in neurons. Too much had been entering by the transporter NKCC1 and too little exiting via KCC2.

One of the effects of having too little BDNF and hence not enough activation of TrkB is that chloride becomes elevated in neurons.  If you do not activate TrkB you do not get enough KCC2, which is what allows chloride to exit neurons.

To what extent would TrkB activation be an alternative/complement to bumetanide in broader autism?

To what extent would TrkB activation be success in treating some types of chronic pain (where KCC2 is known to be down regulated)?

Low levels of BDNF are a feature of Rett and much dementia.

So you would want to:

·        Increase BDNF

·        Activate TRKB with something else

·        Block NKCC2 to compensate for the lack of KCC2

Note that BDNF is not reduced in all types of autism, just in a sub-group.

I note that there already is solid evidence in the research:-

Restoration of motor learning in a mouse model of Rett syndrome following long-term treatment with a novel small-molecule activator of TrkB

Reduced expression of brain-derived neurotrophic factor (BDNF) and impaired activation of the BDNF receptor, tropomyosin receptor kinase B (TrkB; also known as Ntrk2), are thought to contribute significantly to the pathophysiology of Rett syndrome (RTT), a severe neurodevelopmental disorder caused by loss-of-function mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). Previous studies from this and other laboratories have shown that enhancing BDNF expression and/or TrkB activation in Mecp2-deficient mouse models of RTT can ameliorate or reverse abnormal neurological phenotypes that mimic human RTT symptoms. The present study reports on the preclinical efficacy of a novel, small-molecule, non-peptide TrkB partial agonist, PTX-BD4-3, in heterozygous female Mecp2 mutant mice, a well-established RTT model that recapitulates the genetic mosaicism of the human disease. PTX-BD4-3 exhibited specificity for TrkB in cell-based assays of neurotrophin receptor activation and neuronal cell survival and in in vitro receptor binding assays. PTX-BD4-3 also activated TrkB following systemic administration to wild-type and Mecp2 mutant mice and was rapidly cleared from the brain and plasma with a half-life of 2 h. Chronic intermittent treatment of Mecp2 mutants with a low dose of PTX-BD4-3 (5 mg/kg, intraperitoneally, once every 3 days for 8 weeks) reversed deficits in two core RTT symptom domains – respiration and motor control – and symptom rescue was maintained for at least 24 h after the last dose. Together, these data indicate that significant clinically relevant benefit can be achieved in a mouse model of RTT with a chronic intermittent, low-dose treatment paradigm targeting the neurotrophin receptor TrkB. 

Early alterations in a mouse model of Rett syndrome: the GABA developmental shift is abolished at birth

Genetic mutations of the Methyl-CpG-binding protein-2 (MECP2) gene underlie Rett syndrome (RTT). Developmental processes are often considered to be irrelevant in RTT pathogenesis but neuronal activity at birth has not been recorded. We report that the GABA developmental shift at birth is abolished in CA3 pyramidal neurons of Mecp2−/y mice and the glutamatergic/GABAergic postsynaptic currents (PSCs) ratio is increased. Two weeks later, GABA exerts strong excitatory actions, the glutamatergic/GABAergic PSCs ratio is enhanced, hyper-synchronized activity is present and metabotropic long-term depression (LTD) is impacted. One day before delivery, maternal administration of the NKCC1 chloride importer antagonist bumetanide restored these parameters but not respiratory or weight deficits, nor the onset of mortality. Results suggest that birth is a critical period in RTT with important alterations that can be attenuated by bumetanide raising the possibility of early treatment of the disorder.

    

The GABA Polarity Shift and Bumetanide Treatment: Making Sense Requires Unbiased and Undogmatic Analysis

 

GABA depolarizes and often excites immature neurons in all animal species and brain structures investigated due to a developmentally regulated reduction in intracellular chloride concentration ([Cl]i) levels. The control of [Cl]i levels is mediated by the chloride cotransporters NKCC1 and KCC2, the former usually importing chloride and the latter exporting it. The GABA polarity shift has been extensively validated in several experimental conditions using often the NKCC1 chloride importer antagonist bumetanide. In spite of an intrinsic heterogeneity, this shift is abolished in many experimental conditions associated with developmental disorders including autism, Rett syndrome, fragile X syndrome, or maternal immune activation. Using bumetanide, an EMA- and FDA-approved agent, many clinical trials have shown promising results with the expected side effects. Kaila et al. have repeatedly challenged these experimental and clinical observations. Here, we reply to the recent reviews by Kaila et al. stressing that the GABA polarity shift is solidly accepted by the scientific community as a major discovery to understand brain development and that bumetanide has shown promising effects in clinical trials.

 

Back in 2013 a case study was published showing Bumetanide worked for a boy with Fragile X syndrome. A decade later and still nobody has looked to see if it works in all Fragile X. 

Treating Fragile X syndrome with the diuretic bumetanide: a case report

https://pubmed.ncbi.nlm.nih.gov/23647528/

We report that daily administration of the diuretic NKCC1 chloride co-transporter, bumetanide, reduces the severity of autism in a 10-year-old Fragile X boy using CARS, ADOS, ABC, RDEG and RRB before and after treatment. In keeping with extensive clinical use of this diuretic, the only side effect was a small hypokalaemia. A double-blind clinical trial is warranted to test the efficacy of bumetanide in FRX.

 

What do Rett syndrome and Fragile X have in common? 

In a healthy mature neuron the level of chloride needs to be low for it to function correctly (the neurotransmitter GABA to be inhibitory).

 


Rett and Fragile X are part of a large group of conditions that feature elevated levels of chloride in neurons.

 


Elevated chloride in neurons is treatable.

 

Is Bumetanide a cure for Rett syndrome, or Fragile X?

No it is not, but it is a step in that direction because it reverses a key defect present in at least some Rett and some Fragile X.

In the mouse model of Rett, bumetanide corrected some, but not all the problems caused by the loss of function of the MECP2 gene.

 

Moving on to IGF-1

IGF-1 is a growth hormone with multiple functions throughout aging. Production of IGF-1 is stimulated by GH (growth hormone).

The lowest levels occur in infancy and old age and highest levels occur around the growth spurt before puberty.

Girls with Turner syndrome, lack their second X chromosome and this causes a lack of growth hormones and female hormones. They end up with short stature and with features of autism. Treatment is possible with GH or indeed IGF-1.

In dementia one strategy is to increase IGF-1.  This same strategy is also being applied to single gene autisms like Rett and Pitt Hopkins.

Trofinetide and NNZ-2591 are improved synthetic analogues of peptides that occur naturally in the brain and are related to IGF-1. Trofinetide is being developed to treat Rett and Fragile X syndromes, NNZ-2591 is being developed to treat Angelman, Phelan-McDermid, Pitt Hopkins and Prader-Willi syndromes.

 

NGF (nerve growth factor)

Nerve growth factor does what it says (boosting nerve growth), plus much more. NGF plays a key role in the immune system, it is produced in mast cells, and it plays a role in how pain in perceived.

NGF acts via NGF receptors, not surprisingly, but also via TrkA receptors. We saw earlier in this post that BDNF acts via TrkB receptors.

Once NGF binds to the TrkA receptor it triggers a cascade of signalling via  the Ras/MAPK pathway and the PI3K/Akt pathway.  Both pathways relate to autism and Ras itself can play a role in intellectual disability. 

These are also cancer pathways and indeed NGF seems to play a role.  Beta cells in the pancreas produce insulin and these beta cells have TrkA receptors. In type 1 diabetes these beta cells die.  Beta cells need NGF to activate their TrkA receptors to survive.

Clearly for multiple reasons you need plenty of NGF.

Lack of NGF would be one cause of dementia and that is why Rita Levi-Montalcini choose to self-treat with NGF eye drops for 30 years. Rita won a Nobel prize for discovering NGF.

In Rett syndrome we know that the level of NGF is very low in the brain.

Logical therapies for Rett would seem to include:

·        NGF itself, perhaps taken as eye drops, but tricky to administer

·        A TrkA agonist, that would mimic the effect of NGF

·        The traditional medicinal mushroom  Lion’s Mane (Hericium erinaceus) 

We should note that effect of NGF acting via TrkA is mainly in the peripheral nervous system, not the brain.

It has long been known that Lions’ Mane (Hericium erinaceus) increases NGF but it was not clear why.  This has very recently been answered.

The active chemical has been identified to be N-de phenylethyl isohericerin (NDPIH).

The opens the door to synthesizing NDPIH as drug to treat a wide range of conditions from Alzheimer’s to Rett. 


Mushrooms Magnify Memory by Boosting Nerve Growth  

Active compounds in the edible Lion’s Mane mushroom can help promote neurogenesis and enhance memory, a new study reports. Preclinical trials report the compound had a significant impact on neural growth and improved memory formation. Researchers say the compound could have clinical applications in treating and preventing neurodegenerative disorders such as Alzheimer’s disease.

Professor Frederic Meunier from the Queensland Brain Institute said the team had identified new active compounds from the mushroom, Hericium erinaceus.

“Extracts from these so-called ‘lion’s mane’ mushrooms have been used in traditional medicine in Asian countries for centuries, but we wanted to scientifically determine their potential effect on brain cells,” Professor Meunier said.

“Pre-clinical testing found the lion’s mane mushroom had a significant impact on the growth of brain cells and improving memory.

“Laboratory tests measured the neurotrophic effects of compounds isolated from Hericium erinaceus on cultured brain cells, and surprisingly we found that the active compounds promote neuron projections, extending and connecting to other neurons.

“Using super-resolution microscopy, we found the mushroom extract and its active components largely increase the size of growth cones, which are particularly important for brain cells to sense their environment and establish new connections with other neurons in the brain.” 

 

Hericerin derivatives activates a pan‐neurotrophic pathway in central hippocampal neurons converging to ERK1/2 signaling enhancing spatial memory

The traditional medicinal mushroom Hericium erinaceus is known for enhancing peripheral nerve regeneration through targeting nerve growth factor (NGF) neurotrophic activity. Here, we purified and identified biologically new active compounds from H. erinaceus, based on their ability to promote neurite outgrowth in hippocampal neurons. N-de phenylethyl isohericerin (NDPIH), an isoindoline compound from this mushroom, together with its hydrophobic derivative hericene A, were highly potent in promoting extensive axon outgrowth and neurite branching in cultured hippocampal neurons even in the absence of serum, demonstrating potent neurotrophic activity. Pharmacological inhibition of tropomyosin receptor kinase B (TrkB) by ANA-12 only partly prevented the NDPIH-induced neurotrophic activity, suggesting a potential link with BDNF signaling. However, we found that NDPIH activated ERK1/2 signaling in the absence of TrkB in HEK-293T cells, an effect that was not sensitive to ANA-12 in the presence of TrkB. Our results demonstrate that NDPIH acts via a complementary neurotrophic pathway independent of TrkB with converging downstream ERK1/2 activation. Mice fed with H. erinaceus crude extract and hericene A also exhibited increased neurotrophin expression and downstream signaling, resulting in significantly enhanced hippocampal memory. Hericene A therefore acts through a novel pan-neurotrophic signaling pathway, leading to improved cognitive performance.

 

Since the discovery of the first neurotrophin, NGF, more than 70 years ago, countless studies have demonstrated their ability to promote neurite regeneration, prevent or reverse neuronal degeneration and enhance synaptic plasticity. Neurotrophins have attracted the attention of the scientific community in the view to implement therapeutic strategies for the treatment of a number of neurological disorders. Unfortunately, their actual therapeutic applications have been limited and the potential use of their beneficial effects remain to be exploited. Neurotrophins, for example, have poor oral bioavailability, and very low stability in serum, with half-lives in the order of minutes  as well as minimal BBB permeability and restricted diffusion within brain parenchyma. In addition, their receptor signaling networks can confer undesired off-target effects such as pain, spasticity and even neurodegeneration. As a consequence, alternative strategies to increase neurotrophin levels, improve their pharmacokinetic limitations or target specific receptors have been developed. Identification of bioactive compounds derived from natural products with neurotrophic activities also provide new hope in the development of sustainable therapeutical interventions. Hericerin derivative are therefore attractive compounds for their ability to promote a pan-neurotrophic effect with converging ERK1/2 downstream signaling pathway and for their ability to promote the expression of neurotrophins. Further work will be needed to find the direct target of Hericerin capable of mediating such a potent pan-neurotrophic activity and establish whether this novel pathway can be harnessed to improve memory performance and for slowing down the cognitive decline associated with ageing and neurodegenerative diseases.



 

What this means is that there are 2 good reasons why Lion’s Mane should be helpful in Rett syndrome, both increasing BDNF and NGF.

  

Conclusion

Interestingly, one of the above papers is co-authored by a researcher from the European Brain Research Institute, founded by Rita Levi-Montalcini, the Nobel laureate who discovered NGF (Nerve growth factor). My top pick to test next in Rett syndrome would be NGF. Administration would have to follow Rita’s own example and be in the form of eye drops or follow the Lion’s Mane option, that has recently been further validated.

Rett syndrome is very well documented and many researchers are engaged in studying it.

As with broader autism, the problem is translating all the research into practical therapy today.

Clearly polytherapy will be required.

More than one type of neuronal hyperexcitability seems to be in play.

It looks like one E/I imbalance is the bumetanide responsive kind, that can be treated and will reduce autism symptoms and improve learning skills.  Then we have the hypoventilation/apnea for which Cloperastine looks a fair bet.  For the arrhythmia we have Phenytoin.  If there are still seizures after all that therapy it looks like sodium valproate is the standard treatment for Rett.

Sodium valproate is also an HDAC inhibitor and so has possibly beneficial epigenetic effects as a bonus.

I have always liked the idea of the Lion’s Mane mushrooms as a means to increase NGF (Nerve growth factor).  In today’s post we saw that it is the NDPIH from the mushrooms that acts to increase both BDNF and NGF.  You would struggle to buy NDPIH but you can buy these mushrooms. I did once buy the supplement version of these mushrooms and it was contaminated, so I think the best bet is the actual chemical or the actual mushroom.  One reader did write in once who is a big consumer of these mushrooms.

 


Lion's Mane Mushroom

Source: Igelstachelbart Nov 06

 

A Trk-B agonist that can penetrate the blood brain barrier would look a good idea.  There are some sold by the nootropic people.

7,8-dihydroxyflavone is such an agonist that showed a benefit in the mouse model.

 

7,8-dihydroxyflavone exhibits therapeutic efficacy in a mouse model of Rett syndrome

Following weaning, 7,8-DHF was administered in drinking water throughout life. Treated mutant mice lived significantly longer compared with untreated mutant littermates (80 ± 4 and 66 ± 2 days, respectively). 7,8-DHF delayed body weight loss, increased neuronal nuclei size and enhanced voluntary locomotor (running wheel) distance in Mecp2 mutant mice. In addition, administration of 7,8-DHF partially improved breathing pattern irregularities and returned tidal volumes to near wild-type levels. Thus although the specific mechanisms are not completely known, 7,8-DHF appears to reduce disease symptoms in Mecp2 mutant mice and may have potential as a therapeutic treatment for RTT patients.

Rett syndrome also features mitochondrial dysfunction and a variant of metabolic syndrome.  We have quite a resource available from broader autism, not much of it seems to have been applied in Rett.

You can see that in Rett less oxygen is available due to breathing issues and yet more oxygen is required due to “faulty” mitochondria. 

“Intensified mitochondrial O2 consumption, increased mitochondrial ROS generation and disturbed redox balance in mitochondria and cytosol may represent a causal chain, which provokes dysregulated proteins, oxidative tissue damage, and contributes to neuronal network dysfunction in RTT.”

https://www.frontiersin.org/articles/10.3389/fphys.2019.00479/full#:~:text=Rett%20syndrome%20(RTT)%2C%20an,inner%20membrane%20is%20leaking%20protons.

 

We have seen in this blog that 2 old drugs exist to increase oxygen levels in blood.  The Western world has Diamox (Acetazolamide) and the former soviet world has Mildronate/Meldonium. Mildronate also was suggested to have some wider potential benefit to mitochondria.

Rett is proposed as a neurological disorder with metabolic components, so based on what we have seen in this blog, you would think along the lines of Metformin, Pioglitazone and a lipophilic statin (Atorvastatin, Simvastatin or Lovastatin). 

The Anti-Diabetic Drug Metformin Rescues Aberrant Mitochondrial Activity and Restrains Oxidative Stress in a Female Mouse Model of Rett Syndrome


Statins improve symptoms of Rett syndrome in mice


The ultimate Rett cure will be one of the new gene therapies given to a baby before any significant progression of the disorder has occurred.

For everyone else, it looks like there is scope to develop a pretty potent individualized polytherapy, just by applying the very substantial knowledge that already exists in the research.

Good luck to Daniel and all the others seeking answers.



 


48 comments:

  1. Peter, my kid 4y 20kg. how much the dose of bumex you recommend. 0,5 mg or1 mg and once or twice per day?

    ReplyDelete
    Replies
    1. It depends how much urgent urination is produced and how the child deals with it. In some kids this is the limiting factor. If the child is not toilet trained it can be a big problem

      For some people once a day is the only practical option. For others diuresis is minimal and twice a day works fine.

      I think 0.5mg once a day should be enough. If after a month there is no effect, you could increase the dosage just to be sure.

      Delete
  2. guy, what you think about cerebrolysin have BDNF. more BDNF increase KCC2

    ReplyDelete
    Replies
    1. In blood samples BDNF is usually elevated in those with autism plus low IQ.

      A low level of BDNF would not be helpful, but I expect there is a point at which increasing BDNF provides no benefit or has negative effects.

      Many things influence KCC2, not just low levels of BDNF.

      Delete
  3. I'd be a bit cautious regarding phenytoin, mainly because it is one of the few drugs I know of that actually represses the expression of the gene of my interest (=bad). Long-term phenytoin can have detrimental effects on bone and cognitive processes. It's probably a medication that is good for some disorders (breast cancer!) and detrimental to others (schizophrenia).

    Rett's is more complicated as it affects both sides of E/I balance. It may sound a bit contradictory, but enhancing the excitatory side of things can enhance the inhibitory side too. This is because excitatory circuits drive inhibitory ones. Too little E causes too little I and correcting only one of them may not turn out well.
    Usually with disorders with a disturbed excitation also suffer from unbalances in the excitatory pathways. For example if one NMDA receptor subtype is weakened, other NMDAr subtypes are elevated. Hypofunction can thus result in hyperfunction due to compensatory processes.
    This explains a lot of contradicting symptoms and also similarities between opposite conditions.

    /Ling

    ReplyDelete
    Replies
    1. Hi Ling, I've read a lot of your insightful comments on this blog. You must have come a long way. Would you mind sharing with us, what helped the most and what did not work for your child?

      Delete
    2. Thanks Janu,
      I'm happy to hear you found my comments useful. What helped most for my child is:
      a) That I dared enter science, thanks to Peter's blog.
      b) That I dared to do something, instead of doing nothing.
      c) Having a genetic diagnosis.
      I have shared some of my insights in earlier comments, what is relevant depends highly on how your child's autism corresponds to my child's syndrome...
      (I know, it was not the answer you hoped for.)

      On the topic of the post, curcumin is perfect - in theory - for TrKB agonism, but bioavailability is a limiting factor. I still has an effect, but it is not huge. Peter has a post somewhere on how to raise bioavailability of curcumin - I recall heat, fat and piperine as part of that.

      /Ling

      Delete
  4. Peter, is there any clinical presentation of kids who have E/I imbalance due to excess chloride accumulation and therefore are probable Bumetanide responders? Do they have symptoms like hyperactivity, Insomnia, aggression etc because of excessive excitatory signaling?

    PQQ also increases NGF.

    Anonymous, Taurine and Lutein also increase BDNF in case you don't know.

    ReplyDelete
    Replies
    1. Bumetanide responders will likely show a severe negative reaction to a benzodiazepine drug. Instead of getting calmed they will show the opposite.

      The super responders will have previously had severe learning difficulties, which will then fade away.

      Delete
  5. Going to see Dr Boles tomorrow. Wish us luck. Hope he'll prescribe Bumetanide or something like. Son has ANK3 mutations so hoping genetic investigation might turn up something
    -Name

    ReplyDelete
  6. Peter, you said Azosemid and Torsemid maybe better than bumex cross bbb but in real Azosemid and Torsemid binds to serum albumin more than bumex, so It's actually the opposite. what you think? maybe its reason Dr Ben Ari use Bumex not Torsemid

    ReplyDelete
  7. Good morning does anyone know of this information?http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572136

    ReplyDelete
    Replies
    1. Sporanox brand name is very difficult to get in the United States and extremely expensive. I live next to Canada so I could go over the border and pick some up. I've tried a short dose and noticed very small gains. But doing weekly blood test/biweekly liver test is really annoying.

      https://patentscope.wipo.int/search/en/result.jsf?_vid=P21-LESLTP-63271

      Try looking into nitroimidazoles (Flagy). Sporanox/Itraconazole has an azole group on it an might work that way.

      -Stephen

      Delete
  8. Hello, so has no one tried disulfiram in a small dose? I think it is very interesting, it has a strong activity on lyme, candida, parasites and other organisms. I am not a doctor, but autism is only an infection that if treated is cured. Disulfiram seems to have unexpected properties and I think it has the ability to stop the response to cellular danger, it is the next test for Denis my son. Peter, we are waiting for your research and your opinion regarding disulfiram.https://pubmed.ncbi.nlm.nih.gov/33358402/

    ReplyDelete
    Replies
    1. Buga Dragos, I too think it's the infections. But I also think there is a possibility for OP like compound induced neurodegeneration through AChE or NTE inhibition.

      Looks like PAK1 inhibitors also are effective for infections as pathogens use PAK1 pathway to cause damage. Have you tried Ivermectin before with any success?

      Delete
    2. Hello, Janu, I didn't use invermectin daily, I gave 6 mg once every 10 days, I don't know if it's toxic, in fact, on the day it was given, he had better cognition and was much more present vocally and in the landscape, as a secondary reaction I saw that in the evening the eyes were red from the injections, and it seems that the appetite also decreased after the administration........I know that he has bartonella from the skin stripes he has on his back and hips and an aggressive candida, an intestinal dysbiosis .I will administer invermectin for a few days and see what happens.....I hope we don't damage the liver

      Delete
    3. Buga Dragos, check the discussion about this spanish study of Ivermectin on epilepsy. Looks like they've used Ivermectin long term but pulsed on and off. I think pulsing is the key for safe use. https://www.epiphanyasd.com/2017/09/making-sense-of-abnormal-eegs-in-autism.html?showComment=1506998307268#c4257569714852987295

      Also a mom reported in a private chat group that Ivermectin got her 3 year old child to talk, however it didn't help her older child. It was prescribed to her, to treat parasites.

      Delete
    4. guy, did you have any test for your kid. IgE, CRP maybe. how you sure your kid have problem with parasites?

      Delete
    5. God Ianu, what an important discovery for all of us, in fact now I sit and realize that since I administered 4 doses of invermectin 6 mg every 10 days, Denis has not had any fits of anger, we have had 14 good days since Denis has no more no fits of anger. The crazy appetite has calmed down, the food is not diversified, but he no longer eats crazy.........god, what a discovery........

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    6. So, the medicines for those with autism with digestive problems (sibo, candida, parasites, clostridium, lyme or the devil's bacteria) are: invermectin, pamoate de pyrantel, metylen blue, biocidin, rifaximin. It is possible to be a big game changer and great help Lamictal (lamotrigine seems to block the sodium channels that produce excess electrical power in neurons) and Disulfiram (antabuse) which I have not tested yet, but which has unexpected properties (antiparasitic giardia, lyme, candida, etc.) although it is not an antibiotic, although maybe it is no longer needed if invermectin has already fixed these convulsive attacks. Thanks to Peter, he opened the way for us to get to know each other and gave us all hope....so a great discovery , invermectin stops aggression.....

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    7. Anonymous, I've read somewhere that the mere presence of eosinophils is an indicator of parasites. I don't know about the efficacy of the other tests. Infectious agents are hard to get tested I think. Also the medical system has deviated so much that they don't tend to believe infectious agents play a role in neurological issues any more. Don't know if this is some kind of politics. For instance we know that roughly 50 years back children could get handicapped by polio virus. But in the current times that we live, if a child loses it's ability to walk (has happened with mine), even in the alternative medicine they only think it could be because of mitochondrial dysfunction or idiopathic.

      Delete
    8. Buga Dragos, I have not tried Ivermectin, as I don't have it. But I had bought Bio 30 propolis (which is also PAK1 inhibitor), about 3 months back. Finally I got the courage to stop the current interventions (Leucovorin, Mito support and iBuprofen -pulsed) and give the propolis a try. It definitely seems to be more effective than my previous interventions. But it's too soon to tell. I don't wanna go gaga about it yet, before I know for sure.

      Delete
    9. IVM increases Bifidobacterium and decreases reactive cytokines (cytokine storm). Thats why it was beneficial in Covid-19. The key is to take it with a fatty meal.

      https://www.frontiersin.org/articles/10.3389/fmicb.2022.952321/full

      -Stephen

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    10. https://patentimages.storage.googleapis.com/1b/62/4d/f1d1383ddf5d0d/WO2019033142A1.pdf

      Interesting patent

      Thomas Borody is the mentor to Sabine Hazan and James Adams.

      -Stephen

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    11. More patent documents for the microbiome crowd.

      https://patentscope.wipo.int/search/en/detail.jsf?docId=AU362975817&_cid=P21-LESKSP-48443-1

      -Stephen

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    12. I usually refrain from pointing a finger at other parents trying to help their children, because I'm not in their shoes and I don't know the circumstances or health issues or anything.
      But I do get concerned over people telling they give their kid an unusual drug, and directly thereafter write "I don't know if it's toxic" and "I hope we don't damage the liver".
      _Please_ be careful with your little ones!
      Do your homework and read up on safety, dosages, interactions and side effects before using anything on the most precious you have!

      Also, try to back up statements like "autism is only an infection that if treated is cured" with some kind of reference or at least explanation why you think so. Let's stay scientific (in line with the blog itself) or, alternatively, personal by sharing no=1 experiences.

      /Ling

      Delete
  9. hi, synaptic purning maybe a cause of many kid. so what drug you think have effect. verapamil, statin....

    ReplyDelete
    Replies
    1. If microglia are constantly activated this will disrupt synaptic pruning. There is 2 way communication with the immune system outside the brain. You would need to reduce inflammation in the brain and the rest of the body.

      You would need to customize therapy to your specific case.

      Delete
    2. so if test ige and crp normal mean only have problem in brain and statin or pea is the key ?

      Delete
  10. Hi Peter,
    Just saw this on twitter. Letting you know in case you hadn't seen it and it is of interest.
    Aspie2

    ReplyDelete
  11. Hi Peter Congratulations on game changer.I have just finished reading mine and shared with other parents too.Hopefully they will take your advice and do something.Its so interesting and a must have for every parent with a child with autism .I will also advise my other two children too about looking for a beta female that also loves animals .
    I started low dose clonazepam again after a very long time.What dose would you think for a 34kg old boy.Hes still on the old dose you recommended.I crushed 0.5 in 100mls of water and give 3mls daily.
    He has been very calm and regulated as hes been home for 3 weeks and I have been able to keep and eye closely and monitor him.He's quiet and vocal tics have reduced and he's been generally good compared to where he was about 6 to 7 weeks ago when he was constantly agitated and wetting himself up to 6 times a day at school.I also introduced 5mg of Donepzeil to see if it would help with speech but will discontinue after a month if there is no improvement.I read on your blog that at times LDC may be too much and that was why I wanted to find out if this dose he's on is okay.
    Thank you
    Apinke

    ReplyDelete
  12. Thanks Apinke. I found that the best dose was 0.0006 mg/kg. That would be 0.02 mg for your son. That would equal 4ml of your solution.

    It does need to be well mixed, because it does not dissolve fully. A hand held coffee frappe mixer works well.

    If the dose is too high it will cause agitation. Then you just reduce by say 20% and try again.

    ReplyDelete
  13. Thank you Peter I usually shake the bottle before giving but will order a coffee frappe mixer now

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  14. Hi Peter, thank you for this information, it’s very helpful. My son is 8, severe asd/intellectual disability, verbal but not conversational. I want him to try Bumetanide, so I recently sent the developmental pediatrician some of the articles you have posted. Unfortunately she wouldn’t prescribe it, and neither would the director of the autism clinic that we go to. I will take your advice and look for a MAPS doctor (we are in the US). In the meantime, my son is taking leucovorin 75 mg/day; we think this has helped his speech. We have tried NAC effervescent tablets in the past when he was vocally stimming a lot, but I can’t say if it worked or didn’t work. We would like to try a statin, maybe—do you think that would improve cognition? I should mention that my husband has Type 1 Diabetes. My husband has 5 siblings and only he and his sister have Type 1 Diabetes; the diabetic sister also has a son with severe autism. The other 4 siblings do not have diabetes and all of their children are typical. Not sure if there’s a connection between intellectual disability/asd and the type 1 diabetes lineage or “genes”, but maybe there’s something to it

    ReplyDelete
    Replies
    1. I do think that the right statin can improve cognition in some autism. In our case Atorvastatin does this. The other common statins that are interesting include Simvastatin and Lovastatin, their cognitive effects are slightly different.

      I do think there is a connection to T1 diabetes in the family.

      Interestingly the common T2 diabetes drug metformin improves cognition in some autism, specifically fragile X.

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    2. Peter, please tell me the dosage of atorvastatin for a 12 year old with severe autism. We also started Ponstan and she seemed to be calmer. Can these two drugs be taken at the same time?
      ~Yuliya

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    3. Yuliya, the pediatric dose for high cholesterol is normally 10mg, rising to 20mg.

      For autism it looks like 5 to 10mg is what works. Low doses of atorvastatin are well tolerated. If you can get the 5mg tablets, that would be the best. If 5mg has no effect then try 10mg. If 10mg has no effect, I would assume she is not a responder.

      The issue with Ponstan is possible GI side effects in some people. At a low dose it seems most people have no side effects.

      Delete
    4. Another reason why statins work.
      Rho GTPase inhibitors, such as fasudil and simvastatin, have been studied for their potential to treat inflammatory diseases by inhibiting the migration and activation of immune cells. These inhibitors can target downstream signaling pathways activated by FROUNT.

      -Stephen

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    5. Peter, thanks a lot for the info.. Please tell me, in the case of Ponstan, what side effects of the gastrointestinal tract can occur? My daughter is not verbal, what should I look out for? Diarrhea, stomach pain? And in your opinion, how long does it take to understand whether atorvastatin works or not? it seemed to me that children with severe autism had a longer response time to therapy than children with milder autism.
      ~Yuliya

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    6. hi. you can buy online bumetanid from mexico. i bought one month ago, paid by paypal. its ok. https://mexmeds4you.com.mx/product/product?product_id=4258
      mail or call this guy

      Delete
    7. Yuliya, just Google COX 1 side effects.

      Typically people might get reflux, heart burn sensation, indigestion, stomach pain. If you ignored that for a long time you might get an ulcer.

      People taking high dose NSAIDs long term might take s drug to lower stomach acidity. Like Zantac.

      Taking a low dose once a day means you are not blocking the protective effect of COX 1 on the GI tract.

      In my son when he was not able to communicate, I noticed reflux because he had a dry cough, put his hand on his upper chest and went to lie down in his bed. This was many years ago and unrelated to Ponstan.

      One adult reader of this blog takes Ponstan and looked into the side effects. In one cancer study 1000mg was taken daily for 6 months and nobody had side effects.

      Delete
    8. Thank you so much for your blog and for help in finding the way. Yuliya

      Delete
  15. Hi Peter,
    I tried Bumetanide on my 5 year old autistic child for more than 3 weeks with increasing dose, and it turned to be ineffective. Actually, it increased the negative stimming behavior and worsen the brain fog. My question is: do you know any drug or supplement that do the opposite to Bumetanide?
    This may hopefully works!

    ReplyDelete
    Replies
    1. how much the dose of bumetanid you used? i think maybe antioxydant maybe help, ALA or NAC or Astaxanthin

      Delete
    2. Maas, we assume that the beneficial effect in some people with severe autism is caused by lowering the level of chloride inside neurons. To increase the level of chloride in neurons you would either open NKCC1 or close KCC2. I do not suggest you try and do this.

      Many people are not bumetanide-responders, some people do not tolerate sulfonamide drugs, some people are affected by low potassium or dehydration. At least you tried and can cross one potential therapy off your list.

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  16. Hi Peter,

    I've been reading about NKCC1 and came across this study, I thought it might be interesting to you since potassium and sound sensitivity crop regularly in ASD: (Apologies if you've seen it already)

    https://www.nature.com/articles/s41467-022-30407-3
    "This side effect is consistent with the genetic studies that NKCC1−/− animals are profoundly deaf because NKCC1 contributes to maintenance of unusually high extracellular [K+] of endolymph in inner ear10,11"

    Refs:
    10. Delpire, E., Lu, J., England, R., Dull, C. & Thorne, T. Deafness and imbalance associated with inactivation of the secretory Na-K-2Cl co-transporter. Nat. Genet 22, 192–195 (1999).
    https://pubmed.ncbi.nlm.nih.gov/10369265/

    11. Flagella, M. et al. Mice lacking the basolateral Na-K-2Cl cotransporter have impaired epithelial chloride secretion and are profoundly deaf. J. Biol. Chem. 274, 26946–26955 (1999).
    https://pubmed.ncbi.nlm.nih.gov/10480906/

    Perhaps there is a correlation between sound sensitivity and response to bumetanide?

    Also, I looked for non-prescription inhibitors for NKCC1 and came across these as candidates so far:
    hawthorn (vitexin)? caffeine? geranium (geraniin)? Astaxanthin?

    Aspie2

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    Replies
    1. It does get complicated.

      NKCC1 in the ear has the job of ensuring the cochlear is bathed in potassium (K+) rich endolymph in the inner ear.
      Inhibiting NKCC1 with Furosemide or Bumetanide at high doses stops the ear functioning. It is called ototoxicity and leads to deafness. This requires huge doses of for Furosemide/Bumetanide.

      In neurons in the brain NKCC1 has the job of maintaining the level of chloride (Cl-) which determines the effect of GABA.

      The problem with sound sensitivity does not seem to have anything to do hearing, but rather the processing of the input by the brain. This sensory processing also seems to be influenced by potassium, but this is more of a coincidence.

      The expression of NKCC1 in the human brain is supposed to drop very substantially shortly after birth. I do not believe its expression in the ear changes, otherwise we would go deaf.

      To some extent at least you would think that inhibiting NKCC1 to treat autism must affect sodium (Na) and potassium (K) inside neurons. This is why it is called the sodium potassium chloride co-transporter (NKCC).

      At the autism dosage Bumetanide does not seem to affect hearing or its processing. My son was moderately sound sensitive before starting bumetanide, much less than most people with autism (the ones with noise cancelling headphones). Ten years after taking bumetanide he suddenly became much more sound-sensitive and ended up like the autistic people wearing headphones. A few days later I then gave him Ponstan and he went 80% back to his old normal for sound sensitivity.

      The use of low dose mefenamic acid (the OTC product Ponstan) appears to improve not only sound sensitivity but also some visual processing dysfunctions. I was contacted by someone who suffers from “visual snow syndrome”, which causes you to see static/snow and also comes with tinnitus. It is supposed to be untreatable. The guy had read research suggesting that GABAa receptors might be implicated and hence he was asking me about bumetanide. He cannot access bumetanide, so I said try Ponstan. From the first pill, he has seen a dramatic improvement. ("it's wonderful stuff", he says)

      Ponstan has numerous effects and they include on various Kir channels (inward rectifying potassium channels). There is extremely little written in the literature about it.

      I do not think the OTC bumetanide alternatives are potent enough to act inside the brain. Many people have looked into this.

      Delete

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