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Monday, 11 December 2017

Cognitive Loss/Impaired Sensory Gating from HCN Channels - Recovered by PDE4 Inhibition or an α2A Receptor Agonist

Today we have a complex dysfunction, but we have a plausible understanding of the detailed biological underpinnings and several therapeutic options. It is relevant to people with autism who have impaired sensory gating (they find noises like a clock ticking annoying), and perhaps those who struggle with complex thought. It is very likely to be disturbed in some people with ADHD and many with schizophrenia.

Trouble in the Pre-Frontal Cortex


For a recap on sensory gating, here is an earlier post:-

Sensory Gating in Autism, Particularly Asperger's


Today’s dysfunction relates to HCN channels located on those tiny dendritic spines in a part of the brain called the pre-frontal cortex. These are a type of voltage gated potassium channel found in your brain and heart, there are 4 types, it looks to me that HCN2 is the key one today.
The pre-frontal cortex (PFC) is seen as the part of the brain most affected by mental illness (schizophrenia, bipolar, ADHD etc.), although medicine’s current understanding looks rather medieval to me.
These HCN channels can open when they are exposed to cAMP (cyclic adenosine monophosphate). When open, the information can no longer flow into the cell, and thus the network (created by numerous interacting neurons) is effectively disconnected.
By keeping these channels closed, it is thought that you can improve working memory and reducing distractibility. Now you might think distractibility is an odd word, and it is not a word I expected to encounter, what it really means is impaired sensory gating. This is a core feature of Asperger’s, ADHD and schizophrenia.
One of the key risk genes for schizophrenia, DISC1, also affects HCN channels and this may account for some of the cognitive deficit found in schizophrenia. High level thinking is particularly affected.  It is thought that loss of DISC1 function in the PFC would likely prevent proper PDE4 function, leading to a dysregulated build-up of cAMP in dendritic spines resulting in excessive opening of HCN channels


I did wonder how nicotine fits in, since in earlier post we saw that α7 nAChR agonists, like nicotine, improve sensory gating and indeed that people with schizophrenia tend to be smokers. It turns out that nicotine is also an HCN channel blocker. For a change, everything seems to fit nicely together. There are different ways to block HCN channels, some of which are indirect. One common ADHD drug, Guanfacine, keeps these channels closed, but in a surprising way.
Alpha-2A adrenergic receptors near the HCN channels, on those dendritic spines, inhibit the production of cAMP and the HCN channels stay closed, allowing the information to pass through into the cell, connecting the network. These Alpha-2A adrenergic  receptors are stimulated by a natural brain chemical norepinephrine, or by drugs like Guanfacine.
Stress appears to flood PFC neurons with cAMP, which opens HCN channels, temporarily disconnects networks, and impairs higher cognitive abilities.
This would explain why stress makes people’s sensory gating problems get worse. So someone with Asperger’s would get more distracted/disturbed at exam time at school for example, or when he goes for a job interview. Reducing stress is another method to improve sensory gating and indeed cognition. In Monty, aged 14 with ASD, the only time he exhibits significantly impaired sensory gating, is when he has stopped all his Polypill therapies for several days. I think stress/anxiety is what has changed and this opens those HCN channels. Then even the sound of someone eating food next to him makes him angry.
Excessive opening of HCN channels might underlie many lapses in higher cognitive function.
While the researchers at Yale patented the idea of HCN blockers to improve cognition, we can see how other existing ideas to improve cognition may indeed have the same mechanism, most notably PDE4 inhibitors.
The University of Maastricht holds patents on the use of Roflumilast, a PDE4 inhibitor, to improve cognition; most interestingly, this takes effect at one fifth of the COPD dosage, for which it is an approved drug. At high doses PDE4 inhibitors have annoying side effects, but at low doses they tend to be trouble-free.
One effect of a PDE4 inhibitor is that it reduces cAMP. So a PDE4 inhibitor acts indirectly like an HCN blocker.
Not surprisingly recent research showed that low doses of Roflumilast improves sensory gating in those affected by this issue.
So rather than waiting for a brain selective HCN blocker, the potential exists to use a one fifth dose of Roflumilast today. This is something that should indeed be investigated across different types of cognitive dysfunction.
There are numerous dysfunctions that can impair cognition and they can occur in different diagnosis. For example impaired autophagy is a key feature of Huntington’s, impaired remyelination defines multiple sclerosis, low levels of nerve growth factor are a key feature of Rett syndrome. Less severe dysfunctions of these processes occur in entirely different conditions.
It is thought that people with Alzheimer’s might benefit from PDE4 inhibition. If it was me, I would try it in all types of dementia or cognitive loss of any kind.

PDE4 Inhibitors
There have been many mentions of PDE4 inhibitors elsewhere in this blog. They are broadly anti-inflammatory and anti-oxidant, but currently only widely used to treat asthma in Japan and COPD in Western countries. COPD is a kind of very severe asthma.
Traditionally a PDE4 inhibitor is thought of as drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). That all sound complicated, just think of it as increasing cAMP.
Now cAMP is a messenger in many biological processes, one of which relates to PKA (Protein Kinase A). In autism we know that PKA, PKB and PKC are often disturbed. These PKs are very important because they have the ability to literally change the function of thousands of proteins in your body. This is similar to how epigenetic tags can switch on or switch off a particular gene. PKs, via a different mechanism we will look at in another post, change the function of proteins, so it is very important that you have the correct level of PKA, PKB and PKC.
We saw in a recent post that the Pitt Hopkins gene TCF4 is regulated by PKA and that under-expression of TCF4 is also a feature of some ID and schizophrenia. So more PKA, please.

You can use a PDE4 inhibitor to increase cAMP, which then increases PKA.

Other effects of PDE4 inhibitors
Today’s post is about sensory gating and the effect here of PDE4 inhibitors is via the effect of cAMP on those HCN channels in your tiny dendritic spines.
There are numerous other effects of PDE4 that may also be therapeutic. One interesting effect is that inhibition of PDE4 can mimic calorie restriction by activating AMPK/SIRT1 pathway.
Calorie restriction has just been shown in a large trial to be able to reverse type 2 diabetes, if initiated with a few years of the disease developing.
Humans have evolved based to periods of feast and famine. Periods of fasting may be therapeutic for many modern conditions.
Not surprisingly one side effect of PDE4 inhibitors is weight loss. Many psychiatric drugs cause troubling weight gain.

Acute administration of Roflumilast enhances sensory gating in healthy young humans in a randomized trial. 

Abstract

 

INTRODUCTION:

Sensory gating is a process involved in early information processing which prevents overstimulation of higher cortical areas by filtering sensory information. Research has shown that the process of sensory gating is disrupted in patients suffering from clinical disorders including attention deficit hyper activity disorder, schizophrenia, and Alzheimer's disease. Phosphodiesterase (PDE) inhibitors have received an increased interest as a tool to improve cognitive performance in both animals and man, including sensory gating.

METHODS:

The current study investigated the effects of the PDE4 inhibitor Roflumilast in a sensory gating paradigm in 20 healthy young human volunteers (age range 18-30 years). We applied a placebo-controlled randomized cross-over design and tested three doses (100, 300, 1000 μg).

RESULTS:

Results show that Roflumilast improves sensory gating in healthy young human volunteers only at the 100-μg dose. The effective dose of 100 μg is five times lower than the clinically approved dose for the treatment of acute exacerbations in chronic obstructive pulmonary disease (COPD). No side-effects, such as nausea and emesis, were observed at this dose. This means Roflumilast shows a beneficial effect on gating at a dose that had no adverse effects reported following single-dose administration in the present study.

CONCLUSION:

The PDE4 inhibitor Roflumilast has a favourable side-effect profile at a cognitively effective dose and could be considered as a treatment in disorders affected by disrupted sensory gating.


Background Information
Selective phosphodiesterase (PDE) inhibition has been considered as a very promising target for cognition enhancement.
Roflumilast is a PDE4 inhibitor that has been developed by Takeda for Chronic Obstructive Pulmonary Disease (COPD). In recent year, Maastricht University has been collaborating with Takeda to develop Roflumilast for cognitive impairments
In 2015 Takeda sold COPD indication of Roflumilast to AstraZeneca, and ownership of IP for treatment of cognitive impairment returned to Maastricht University.
Compelling clinical results
A single administration of Roflumilast improves episodic memory in mice, and in young and elderly healthy subjects at a non-emetic dose
As shown in the figure, healthy (A) and memory impaired (B) elderly subjects showed better performances in the delayed recall of the Verbal Learning Task after roflumilast

Key Features and Advantages
Opportunities to reposition a clinically-proven safe compound with a well-established pharmacology.
Compelling preclinical and clinical evidences showing that Roflumilast effectively deliver to the brain to produce robust cognitive enhancement.
Pro-cognitive effects at low dose (5 times lower than COPD indication), which allows to circumvent the emetic effects commonly observed with other PDE4 inhibitors
Maastricht University has a strong IP protection extending to at least 2033.

PDE inhibitors in psychiatry--future options for dementia, depression and schizophrenia?

Author information

Abstract

Phosphodiesterases are key enzymes in cellular signalling pathways. They degrade cyclic nucleotides and their inhibition via specific inhibitors offers unique 'receptor-independent' opportunities to modify cellular function. An increasing number of in vitro and animal model studies point to innovative treatment options in neurology and psychiatry. This review critiques a selection of recent studies and developments with a focus on dementia/neuroprotection, depression and schizophrenia. Despite increased interest among the clinical neurosciences, there are still no approved PDE inhibitors for clinical use in neurology or psychiatry. Adverse effects are a major impediment for clinical approval. It is therefore necessary to search for more specific inhibitors at the level of different PDE sub-families and isoforms.


The current study found that brain cells in PFC contain ion channels called hyperpolarization-activated cyclic nucleotide-gated channels (HCN) that reside on dendritic spines, the tiny protrusions on neurons that are specialized for receiving information. These channels can open when they are exposed to cAMP (cyclic adenosine monophosphate). When open, the information can no longer flow into the cell, and thus the network is effectively disconnected. Arnsten said inhibiting cAMP closes the channels and allows the network to reconnect.
Guanfacine can strengthen the connectivity of these networks by keeping these channels closed, thus improving working memory and reducing distractibility," she said. "This is the first time we have observed the mechanism of action of a psychotropic medication in such depth, at the level of ion channels."
Arnsten said the excessive opening of HCN channels might underlie many lapses in higher cognitive function. Stress, for example, appears to flood PFC neurons with cAMP, which opens HCN channels, temporarily disconnects networks, and impairs higher cognitive abilities.
The study also found alpha-2A adrenergic receptors near the channels that inhibit the production of cAMP and allow the information to pass through into the cell, connecting the network. These receptors are stimulated by a natural brain chemical  norepinephrine or by medications like guanfacine.
 “Guanfacine can strengthen the connectivity of these networks by keeping these channels closed, thus improving working memory and reducing distractibility,” she said. “This is the first time we have observed the mechanism of action of a psychotropic medication in such depth, at the level of ion channels.”
Yale has submitted a patent application on the use of HCN blockers for the treatment of PFC cognitive deficits based on the data reported in the Cell paper.

The full Yale paper:

The prefrontal cortex (PFC) is among the most evolved brain regions, contributing to our highest order cognitive abilities. It regulates behavior, thought, and emotion using working memory. Many cognitive disorders involve impairments of the PFC. A century of discoveries at Yale Medical School has revealed the neurobiology of PFC cognitive functions, as well as the molecular needs of these circuits. This work has led to the identification of therapeutic targets to treat cognitive disorders. Recent research has found that the noradrenergic α2A agonist guanfacine can improve PFC function by strengthening PFC network connections via inhibition of cAMP-potassium channel signaling in postsynaptic spines. Guanfacine is now being used to treat a variety of PFC cognitive disorders, including Tourette’s Syndrome and Attention Deficit Hyperactivity Disorder (ADHD). This article reviews the history of Yale discoveries on the neurobiology of PFC working memory function and the identification of guanfacine for treating cognitive disorders.

Molecular modeling suggests that, similarly to ZD 7288, nicotine and epibatidine directly bind to the inner pore of the HCN channels. It is therefore likely that nicotine severely influences rhythmogenesis and high cognitive functions in smokers.

Modulation of HCN channels in lateral septum by nicotine


Conclusion
I think many people stand to benefit from the drugs mentioned in today’s post, but for different biological reasons. A person with Pitt Hopkins may benefit from Roflumilast because it will upregulate PKA and then increase expression of their remaining TCF4 gene.
In a person with schizophrenia there are multiple reasons these drugs might help them and it will depend on which genes they have that are misexpressed (TCF4, DISC1 etc.).
In a person with idiopathic Asperger’s and impaired sensory gating it looks like the effect on HCN channels is what is important.
I think low dose Roflumilast has great potential for many. The Japanese drug Ibudilast very likely will provide similar benefits, but at what dosage?
PDE4 inhibitors do have side effects at higher doses in part because there are several different types of PDE4 (PDE4A, PDE4B, PDE4C etc) and different drugs effect different subtypes differently.
Ibudilast is used as a daily drug therapy for asthma in Japan and is being studied as a therapy for Multiple Sclerosis (MS) in the US.
Roflumilast is sold by Astra Zeneca as Daxas/Daliresp but at a high dose of 500mcg to treat flare ups of COPD (Chronic Obstructive Pulmonary Disease) it does cause troubling side effects, but it reduces your chance of dying from COPD.
The cognitive dose used in research is 100mcg. Higher doses had no cognitive/sensory gating benefit.
Further investigation of the ADHD drug Guanfacine should be made, because some of the people who benefit from a PDE4 inhibitor might get a similar effect from Guanfacine. People with Pitt Hopkins would not be in this category. A person with Asperger’s and impaired sensory dating should respond to Guanfacine, a cheap drug.
At the end of the day, choice of therapy will come down to side effects and cost. In the US, Roflumilast is expensive ($330), seven times more expensive than in some other countries; in the UK the price of the same 30 tablets is $50. One pack would be enough for 5 months at the suggested dose.




46 comments:

  1. For this purpose, Is Clonidine an effective substitute? I read that it is "an α2 adrenergic agonist and imidazoline receptor agonist that’s been in use for over 40 years. Guanfacine by comparison, is a selective α2a adrenergic agonist. "

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    1. I assume the researchers had a good reason to use Guanfacine, but Clonidine does agonize a2a adrenergic receptors and Agmatine does as well. Interestingly, before Agmatine was called "Agmatine" it was called "Clonidine Displacing Substance".

      I assume they used Guanfacine because it is very selective for a2a adrenergic receptors, while Clonidine as well as Agmatine bind to many other receptors and are much more complex.

      Clonidine has side effects, but long-term use of Guanfacine can as well.

      I think Peter's main point is there are not many clean PDE4 inhibitors in the sense that it is its only mechanism of action (Resveratrol inhibits PDE4 but does many other things as well), so going upstream with A2A adrenergic agonists as they inhibit the production of cyclic AMP which is ultimately what keeps these HCN channels closed. So ultimately these researchers recommend the development of a useful and safe for humans drug that blocks HCN channels directly, as opposed to inhibiting cAMP itself (which has side effects) via a2a adrenergic agonism or else otherwise via PDE4 inhibition.

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    2. What are the side effects of long term use of Guanfacine? I thought it was safe as it is an approved treatment for children with ADHD. I’m sorry to ask about it, Im just laic....

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    3. All drugs can have side effects. Drugs approved for psychiatric use are particularly known for having side effects; weight gain is very common, which leads to other problems (metabolic disorders). The worst drugs are antipsychotics like Risperidone, which can cause big problems.

      Guanfacine is actually a heart drug so some side effects relate to your heart.

      https://www.mayoclinic.org/drugs-supplements/guanfacine-oral-route/side-effects/drg-20064131

      Always inform yourself about the side effects, it is well documented. In some drugs the bad side effects only appear after extended use, like high dose benzodiazepines.

      In many cases you can use a drug long term with no side effects, but it pays to do your homework.

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  2. Here is an interesting paper linking RAS to circadian functions as they pertain to cancer. What is interesting is RAS's implications with autism and the circadian issues just about every parent of a child with autism has to deal with at some point.

    Press Release:

    https://www.sciencedaily.com/releases/2017/12/171207141751.htm

    Paper:

    http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2002940

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  3. Also, here is a very strange mechanism of action of how the infamous paraside Toxoplasmosis Gondii so readily infects the brain which involves it directly manipulating immune cells (dendritic cells) via GABA signaling (i.e. it produces GABA to manipulate the dendritic cell activity).

    Press Release:

    https://www.sciencedaily.com/releases/2017/12/171208095923.htm

    Paper:

    http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006739

    In effect the extra GABA via manipulation of Voltage Dependent Calcium Channels (VDCC's) would cause the dendritic cells to be pushed into a hypermotile state causing them to more readily migrate to the brain where Toxoplasmosis Gondii continues to replicate and directly infect brain cells.

    Now Toxoplasmosis Gondii obviously has been linked with schizophrenia (as well as autism by some fringe autism doctors), but what is interesting here is that in autism invasion of peripheral immune cells into the brain seems to happen as well and even though Toxoplasmosis may not be the culprit with respect to autism, it is plausible that this GABA hijack mechanism could be involved with immune cells going to the wrong places at the wrong time in the brain and causing all sorts of inflammatory problems.

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  4. Very interesting Peter,

    If my memantine trial (planning to use it 6-8weeks to see if it helps me) ends up not benefiting me enough im definatly interested in trialing Roflumilast. It turns out it is also a prolyl endopeptidase inhibitor:

    A Randomized, Placebo-controlled Trial of Roflumilast. Effect on Proline-Glycine-Proline and Neutrophilic Inflammation in Chronic Obstructive Pulmonary Disease.
    https://www.ncbi.nlm.nih.gov/pubmed/26151090

    " Roflumilast treatment decreased sputum AcPGP by more than 50% (P < 0.01) and prolyl endopeptidase by 46% (P = 0.02), without significant improvement in leukotriene A4 hydrolase activity compared with placebo."

    Not sure to what extend this would affect the brain, but im sure there is potential.
    As I said before baicalin (present in chinese skullcap) is also a PREP-inhibitor, basically lets peptides including oxytocin stay longer in the body.

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  5. Turns out that CDP-Choline, which till recently was a part of my stack also improves sensory gating.

    CDP-choline: effects of the procholine supplement on sensory gating and executive function in healthy volunteers stratified for low, medium and high P50 suppression.
    https://www.ncbi.nlm.nih.gov/pubmed/25315828

    __

    Caffeine modulates P50 auditory sensory gating in healthy subjects.
    https://www.ncbi.nlm.nih.gov/pubmed/16278075

    "These results reinforce the participation of adenosine (cordyceps contains adenosine and cordycepin) in the modulation of P50 sensory gating and suggest that caffeine ingestion should be controlled for in the P50 sensory gating paradigm."

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  6. Hi Peter, today may son came and asked me:Do you remember about my classes about the ancient civilizations? He started to talk me about the Incas,about his main gods and kinship and his occupations.He gave me a mini history class.Do you think that I should keep the 1 mg dose or go up to 2mg? I don´t have many miccil packs. Valentina

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    1. Valentina, I would stay at 1mg so you do not run out of miccil (bumetanide) try and get your cousin to send more.

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  7. Peter, much of what is dicussed here obviously concerns my son's disorder. These HCN channels are not "funny" at all. It was due to extreme pain when my son started on nicotine, although he has an aversion to it. This pain would come with some kind of hypotension, hypoglycemia, muscle spasms, like a seizure after spinal cord injury.
    I have some reasons to believe that norepinephrine is the key word here for him. It may be that locus coeruleus, where brain's norepinephrine is synthesized, during extreme stress not being able to produce enough or something wrong with dopamine-b-hydroxylase being inhibited and depletes brain's norepinephrine as we sometimes have lowering of body temperature and a different kind of sensory gating which I call it "cold feet" impairment.
    I think Tanya mentioned propranolol for PTSD ( blocks the action of norepinephrine) and I have to say that I had a mini trial with it in the past (just took 5 pills) and didn't seem to work at all. Increasing the three monoamines (serotonin, dopamine, norepinephrine) simultaneously is even a better idea.
    Thank you Peter, very helpful, indeed, I'm really looking forward to novel HCN inhibitors and their mechanism of action.

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    1. Petra,

      Though my son is much younger than yours, I have observed identical symptoms which you describe....some kind of hypoglycemia, hypotension, cold hands and discomfort which could be pain, somatic or psychosomatic I cant say, lasting for a short while and which happens only on days he goes to his therapy center and also usually within a few hours after being picked up. Is it some kind of stressful memory leading to these episodes...stress experienced at the center? Are even a few hours where he loses his independence and has to follow diections so traumatic to him?

      Interestingly, chocolates and spicy food...salt and sugar seem to work well for him and I would try to ensure his blood pressure, blood circulation and sugar levels is not on the lower side.

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    2. Certain spicy foods (ginger, chilli pepper) activates TPVR receptors and this results in an increase in endorphins and adrenalin (this is the rush alot of people seek from ingesting a large amount of chilli).

      I also suffer from cold hands (mainly tips) and seems to be a mild form of raynauds.

      Has anyone tried nicergoline?

      Delete
    3. Hi Petra,

      In response to your comment above ... "Increasing the three monoamines (serotonin, dopamine, norepinephrine) simultaneously is even a better idea'.

      On the chance that you weren't aware of the key effect of 'Tranylcypromine (Parnate)' being that it increases the availability of serotonin, norepinephrine and dopamine. It is an MAOi though and as such requires dietary restriction.

      A very close family member takes it as treatment for an anxiety and mood disorder. On a n=1 case, its effectiveness is superior. After exhausting the usual suspects, multiple SSRI's, Mirtazapine, Olanzapine and a couple of Benzos, there can be no comparison to the clinical effectiveness of this medication.

      It's a very old medication that does not induce weight gain or tolerance but will cause insomnia if taken too late in the day. The so-called dietary restrictions are over-blown but discipline must be exercised.

      I recommended her trial this after it's virtues were extolled by retired Dr K. Gillman (website) who prescribed it extensively in his practice but also published extensive research to substantiate its use.

      It's seen as more a last-line medication today due to its ill-effects when dietary restrictions aren't observed or known classes of medications known to interact are also taken. Dr Gillman's site comprehensively breaks down the dangers and separates fact from fiction.

      Again, when taken responsibly, it's proven superior in our n=1 case and is a long-term option. This may come-across as a sales pitch, but the results have been that pronounced for alleviating anxiety and elevating mood where all else failed and actually exacerbated the condition.

      I believe there is a restriction on prescribing for under 18 but a controlled trial on ASD population for this age-group would be interesting to see what effects there are on alleviating anxiety related symptoms.

      Regards,
      D&G

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    4. Thank you very much, keep this in mind and look further into.
      Petra

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    5. D&G, would you mind elaborating more on your family member's history - did she have PTSD?

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    6. D&G, one more question - hope you see this - and any other readers with experience with mood disorders in ASD, please comment:
      Does your relative who uses parnate use it with lithium? Even lower doses of non prescription form of lithium?

      Delete
    7. Hi Tanya,

      Sorry for not replying sooner.

      Yes she does use Parnate with low dose Lithium but it is prescribed 'Lithium Carbonate'. She still hasn't reached therapeutic dose. It has helped but nowhere to the degree of Parnate.

      I don't wish to elaborate too much on someone else's behalf but yes certainly PTSD was disproportionately over represented in her condition.

      Thanks for asking and I can't overstate how effective it has been in her case.

      Regards,
      D&G

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    8. D&G, thanks for the reply. I was just reading this combination is very helpful esp. when in crisis mode.

      Delete
  8. Yes, Kritika, something like that, seems minor in the beginning, could be somehow under control for several years and then regression is triggered, one starts excluding places, people, activities to such an extent that he ends up not even being able to go to the toilet anymore and utterly loses independance.
    During such episodes, fortunately we don't have them anymore, I used intranasal insulin and what I found striking is the fact that he could describe what was happening in detail at those very moments. I searched on pubmed and found out articles claiming that people after spinal cord injury when administrated insulin were able to describe their symptoms clearly on their way to the emergency, as weird as it may seem.

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  9. Aspie, I've done all the rheumatological tests for any kind of arthritis, including raynauds, and doctor told me to forget about arthritis, no gout, nothing. Angiologist, endocrinologist and neurologist found him perfectly healthy, even the psychiatrist said it's ok, he could have some fluoxetine when he needs it. Tardive dyskinesia is excluded because he was on a very small dose of olanzapine and mostly worked as an antidepressant. Electrophoresis protein for kidney or liver disease was a little low in proteins and a little higher in albumin (he was taking fluoxetine and it binds to albumin), no clinical significance, uric acid reached normal means, only low in vitamin D.
    Depending on food my son adds, lots of black pepper, oregano, lemon, vinegar, mustard, mayonnaise on top and makes him feel good.

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  10. Petra, I also was never diagnosed with raynauds, but blood flow enhancers definatly have a very positive effect on my brain function.

    Oddly enough coffee (which is often considered a vasoconstrictor due to caffeine, but also increases basal metabolic rate) often seems to get rid of my cold hands for a few hours, so Im puzzled.
    I have found citrulline to be the best supplement to help with the cold fingers (I have minor scartissue from the poor bloodflow through my fingertips throughout the years).

    Also since I have been on memantine and my stress leves are only 5% of what Im normally like, which is amazing considering this has only been day 8 on memantine!.

    So in my case atleast it is DEFINATLY NOT stress induced vasoconstriction.
    Raynauds has to do with norepiphedrine receptors in the hands, I wonder if prazosin (or other alpha blockers) could help me with this issue.

    My TSH levels came in at 2.30, which is quite normal (allthough I have upped my levothyroxine a bit with winter incoming), T4 levels seem fine too.

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  11. Acute administration of roflumilast enhances immediate recall of verbal word memory in healthy young adults.
    Neuropharmacology. 2017 Dec 11;131:31-38. doi: 10.1016/j.neuropharm.2017.12.019.
    https://www.ncbi.nlm.nih.gov/pubmed/29241652

    "No side effects typical for PDE4-Is were reported for the lowest and effective dose of 100 μg roflumilast. The current proof-of-concept study shows for the first time the potential of low-dose roflumilast administration as a memory enhancer in humans."

    Once again showing the efficiacy of this drug and once again the 100mcg dose.

    Side note: still doing incredibly well on memantine (best thing I have ever tried so far and closest I have come to feeling normal besides a hangover).

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    1. Aspie1983, the low dose of roflumilast really does look interesting. This should be trialled in large group with Asperger's.

      Delete
    2. Peter and others, you might want to have a look at this quick blog collection I made regarding sigma 1 receptors.

      To me it is allready clear that the main reason memantine is working for me is sigma 1 activation, it also highlights why alcohol hangover benefits and why I have normally have an aversion for alcohol intake (It was during the a hangover that I realized that I have capability of being 100% human). After a long puzzle (3years+) I have finally pinned it down to sigma 1 activation.

      https://aspie1983.wordpress.com/2017/12/17/sigma-receptors-the-volume-control-button-for-learning-hedonic-tone-and-seizure-control/

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  12. I agree, however Im also sure im onto something with regards to sigma 1 agonism for aspergers, I have looked into over 20 different papers and it seems that sigma 1 agonism is in direct control of nmda manipulation, it can both potentiate nmda receptors and at the same type protect from the same excitotoxicity that comes along with enhancing nmda signalling.

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  13. Peter, I think your idea of using adrenergic receptors agonists works. After a sinus and mild throat infection, which made everything to go worse, I used vicks inhaler/rub and sinus nasal spray and my son responded very well.
    Vicks sinex (oxymethazoline) is a selective a1 adrenergic receptor agonist and a2 receptor partial agonist....wikipedia says that it may produce profound central nervous system depression due to stimulation of central a2 receptors and imidazoline receptors, much like clonidine. I saw my son being very active and sociable with clarity of mind. Just hope this lasts for a few days. I know this cannot be used for more than a week, but by then I should know what happens.

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    1. Petra, very interesting. What about trying Guanfacine, if it is used in Greece? This can be used long term.

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  14. Guanfacine is not available in Greece. If you know places I could find it, please let me know. Meanwhile I'll have to check if what I am saying is in effect with the means I have.

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    1. Petra, if you have a friend in Spain, ask about Guanfacine there. Ask about Roflumilast (trade names Daxas) in Greece, here it will be a case of splitting one tablet into 5 daily doses. It looks to me that like Daxas is available in Greece.

      https://www.galinos.gr/web/drugs/main/packages/16802

      I think I will try the 1/5 of a pill on myself and see if it does anything.

      Delete
  15. Unveiling the secrets of my daughters genetic condition feels like investigating the damage after a dirty bomb in the CNS.
    The haploinsufficient gene in question is unfortunately deeply involved in the transcription of other genes, many implicated in brain functionality.
    I could try to address some of the downstream mess, but since it is so extensive it is probably best to start at the source.
    So... This is the time for some heroic deeds. I do need help putting pieces together.

    These are my first puzzle pieces, mostly gathered quotes from different PubMed articles:
    ---
    In the adult brain Satb2 is almost exclusively expressed in pyramidal neurons in the cerebral cortex and the CA1-hippocampal field.
    Satb2 contributes to long term potentiation (LTP) maintenance and memory consolidation
    We found that the spatial memory and working memory were significantly damaged in the haploinsufficient mice.
    Functionally, late phase long-term potentiation (L-LTP) in these mice was greatly impaired.

    In primary hippocampal neurons we show that calcium influx through L-type voltage-gated calcium channels as well as BDNF up-regulate Satb2 in the nucleus.
    Satb2 induction after synaptic stimulation depends on calcium influx through L-type voltage-gated calcium channels and not through NMDA receptors
    Synaptic activity-triggered Satb2 induction is mediated via BDNF/TrkB signaling.
    In hippocampal neurons BDNF up-regulates Satb2 through a pathway that requires ERK1/2 and MSK1

    ---
    So, PolyPill team, what conclusions can I draw from this?
    It looks like I am dealing with glutamate signaling. But, it's not about NMDA receptors but more likely AMPA receptors.
    Calcium influx through VGCCs... This sounds like Verapamil would be a really bad idea(?)
    But then, what calcium influx are we talking about here? AMPA receptors are not permeable to calcium in most cases (at least not if they contain the GLuA2 subunit).
    Obviously I should look into upregulation of BDNF. Can there be too much BDNF and what happens then?

    Positive allosteric modulators of AMPA? Activate cAMP with PD4 inhibitors (Arc protein was low)? Enhance Wnt signaling too(?) CILTEP(?) Upregulate Akt?

    Jeesh, I hope Santa brings me a new head this year, because mine is soon about to explode...

    Is there anything I can do for you meanwhile?

    /Ling

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    1. Ling, I will make a post early next year about Glass Syndrome /Satb2 and then all the comments can be in one place.

      Delete
    2. Peter... I don't know what to say. You continue to amaze me, time after time.
      Thank you.

      /Ling

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    3. Ling,

      If you have read my previous posts about cordyceps is that one of its MOA (mechanisms of action) is enhancement of AMPA signalling.

      3’-Deoxyadenosine (Cordycepin) Produces a Rapid and Robust Antidepressant Effect via Enhancing Prefrontal AMPA Receptor Signaling Pathway
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851261/

      "This study identified 3’-dA as a novel rapid antidepressant with clinical potential and multiple beneficial mechanisms, particularly in regulating the prefrontal AMPA receptor signaling pathway."

      Now, there might be more drugs that target this system, but considering the very good safety profile of this mushroom extract its worth a shot to see if it atleast fits your bill.

      Luteolin is also a PDE4-inhibitor (also present in the ciltep stack often as artichoke extract together with forskolin and tyrosine/phenylalanine).

      Delete
    4. Thank you Aspie, I did not know about that!

      And for anyone else who wants to look into SATB2 this is the best paper so far that I've found:
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207769/

      /Ling

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    5. No problem Ling,

      One thing I did found annoying with cordyceps was that you have to keep dosing it a few times throughout the day.

      Where as with memamtine (which im currently on) it has a half life of 60-100hours, so there is more a stable effect throughout the entire day.

      Delete
  16. And yes, it would be very nice to know at what dosage Ibudilast works... To my big surprise, the package actually made its way all from Japan. And now I am looking at it, expensive as it was, wondering what hidden mysteries lie within those foreign signs on the leaflet and if it's safe enough for a trial. Hmm...

    /Ling

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    Replies
    1. Ling, people do use Ibudilast on kids with autism. I would first check a small dose in case your daughter has any kind of unusual allergy to it. It is used in Japan as a daily treatment for asthma and not severe asthma/COPD. I think the asthma dose of Ibudilast is going to be much weaker than the standard dose of Roflumilast/Daxas since this is used for severe COPD.

      You would have to experiment, but if you use a dose less than or equal to the asthma dose you are being prudent. I think it was only ever used in over 12 year olds (as with many drugs). Look how the asthma dose is determined.

      When I used a Japanese drug, I found google translate very useful.

      Delete
    2. Hi Ling,

      Good to know some people are not giving up, I really hope you have success with it and let us know how it goes!

      Delete
    3. Thank you Aspie for encouraging words! :)

      /Ling

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  17. Peter I have just found that there actually might exists certain subtypes of autism (possibly me myself also being affected) that benefits from lowering lactate in the brain (I suspect this indeed due to mito dyfunction).

    _____

    Brain imaging EVIDENCE that mitochondrial dysfunction is a neurobiological subtype of Autism Spectrum Disorder
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239991/


    Results:
    Lactate doublets were present at a significantly higher rate in participants with ASD (13%) than controls (1%) --->> (p=.001). <<--- In the ASD group, the presence of lactate doublets correlated significantly with age (p=.004) and was detected more often in adults (20%) than in children (6%), though it did not correlate with sex, ASD subtype, intellectual ability, or ADOS total score or subscores. In those with ASD, lactate was detected most frequently within the cingulate gyrus, but it was also present in the subcortical gray matter nuclei, corpus callosum, superior temporal gyrus, and pre- and post-central gyri.

    Conclusions and Relevance
    --->> THESE IN VIVO BRAIN FINDINGS PROVIDE EVIDENCE FOR A POSSIBLE NEUROBIOLOGICAL SUBTYPE OF MITOCHONDRIAL DYSFUNCTION IN ASD. <<---

    ____

    Brain lactate as a potential biomarker for comorbid anxiety disorder in autism spectrum disorder. [JAMA Psychiatry. 2015]
    https://www.ncbi.nlm.nih.gov/pubmed/25650814

    ____

    I have reading up on this website about lactic acidosis and the symptoms seem to have a very strong overlap with mine.
    As I have mentioned before my emotional capacity gets WORSE exercise on average (well known to raise lactate), however I do try to do some exercise 2-3 times a week (mildly and I do not go overboard).

    https://www.theguthealthprotocol.com/wp/d-lactic-acidosis/


    As you know I have had huge success with cordyceps (proven over increase the lactic acid threshold and lower BUN), so today I once again tried GPLC (glycine propionyl l carnitine) and there is an immediate moodlift that lasts half of the day and it even seems to change my perspection on things.

    Once again back to cordyceps, as I have said before the effects are very fast (within 5minutes after taking it on the empty stomach I feel relieve) I suspect it also has to do with the polysaccharides modulating gut microbes.

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  18. Peter and all, what do you think about inulin and its effects on feeding good an bad bacteria, what dr. Nemechek says is confusing.
    Valentina

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  19. And here is my report on Pterostilbene.

    The brand was Life Extension PteroPure 50 mg and my daughter is 2½ year and weighs around 15 kg.

    We started out with a dose of 2 * 5 mg daily, morning and evening. It was not very easy to get out one tenth of a small capsule, so the dosing was probably a bit uneven. After 2 weeks use we noticed that she was doing "speech sounds" like "mmm" and "mmmaa". At 3 weeks her daycarers surprisingly announced that she had said both "ma-ma" and "pa". This was the same day I decided to change dosing to around 1 mg/kg/day (= 16 mg and easier to dose). After this, she was still using her new sounds occasionally, but we also saw side effects creeping up. Staring spells became more frequent and toe-walking suddenly appeared. After 6 weeks we pulled off and all effects and were lost (speech sounds, toe-walking, staring spells).
    I'm not sure what conclusions to draw from this, but dosing seems to be important.

    /Ling

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    Replies
    1. Hi Ling,

      Thanks so much for sharing!

      I have a new (unopened) bottle of Swanson Pterostilbene (also PteroPure) sitting on a shelf, as I purchased it but then saw good improvement via the antibiotics/Nystatin/Probiotics and the reduction of gluten / casein so have kept it on the back-burner.

      Ling, I wonder if above and beyond dosing, the fact that Pterostilbene is fat-soluble may be a contributing factor. That is, it may have been building up in her system beyond the ideal level where you see benefits but no side-effects, so that you started seeing side effects.

      Have you thought about going back to the 2*5mgs to see if you regain the benefits but to see if you can keep the side effects at bay? You can then see if you can get the speech without the bad effects, or if you do start to get the bad effects but with a much longer interval (say after 12 weeks), then you may want to lower the dosage to say 2*2.5mgs.

      I'm not an expert by any means, but I really wonder if the 1mg/kg/day of a fat soluble compound built up over time as it may be higher than an ideal dose (which may have been 2* 5mgs).

      You have certainly sparked my interest in starting PteroStilbene. My daughter at 5 isn't much bigger than yours (around 18 kg) so I think I will start with 1 * ~5mgs initially and build up to maybe 10mgs, which based on your comments, is likely a good dose. I'll keep an eye out for negative effects so I can pull back when I see them.

      Again Ling, your sharing your experience is very much appreciated as that's how we will all benefit.

      AJ

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    2. I definitely think it would be worth to make another trial. Maybe I can find a brand with less pterostilbene in it to be able to finetune dosing. Actually I don’t think this was about a build-up, because the side effects and effects vanished within one day. It would be interesting to know the half-time of pterostilbene.
      If I recall it right, for adults a dose of 100 mg had a better response than 250 mg, but I’ve also seen recommendations as low as 10 mg.
      /Ling

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  20. I forgot to mention that another effect I noticed was that she had faster movements (running more and easier) on pterostilbene.
    /Ling

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