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Friday, 31 March 2017

The Glutamate Side of Things

Some readers have suggested that since we have discovered so many ways to treat the GABAA dysfunctions common in autism, it is time to look at the glutamate side of things. Glutamate is the main excitatory neurotransmitter and has to be in balance with the opposing influence of GABA.

The chart below is really a summary of what has already been covered in this blog.  To newcomers it will look complicated, to regular readers it is just bringing together everything we have already covered, even those tauopathies appear. Tau protein tangles appear in Alzheimer’s and some autism.
Glutamate excitoxicity is what happens when things go really wrong, for example in a severe autistic regression.  I doubt you could be in a permanent state like this.



I am beginning to wonder is my son’s summer time raging, though triggered by allergy, develops to a so-called glutamatergic storm.  It fades to nothing  by using a Cav1.2 channel blocker, which does indeed stop those allergy mast cells de-granulating, but it stops the calcium influx in the above chart.  Existing dysfunction in Cav1.2 and Cav1.4 puts you at risk of excitotoxicity.
The oxidative damage to mitochondria causes lipid peroxidation and in particular the 4-HNE produced will cause tau protein, from a recent post and Alzheimer’s, to produce tau tangles, a damaging feature of so-called tauopathies.
The nitrosative stress in particular damages the production of the Complex 1 enzyme leading to mitochondrial disease/dysfunction. The damaging peroxynitrates can be quenched using high doses of calcium folinate. Oxidative stress and the reduced level of GSH can be treated with antioxidants like NAC and ALA.  

Reduced reuptake of glutamate, known to be caused by elevated TNF-α and immune dysfunction, is treatable via upregulating the GLT-1 transporter (beta-lactam antibiotics, riluzole and bromocriptine).
Elevated BDNF is a biomarker of autism and unfortunately this increases the chances of glutamate excitotoxicity.
An inactivated GABA switch that leaves neurons immature, will result in GABA acting excitatory rather than inhibitory, this itself can trigger of glutamate excitotoxicity. Use bumetanide.
Some types of autism feature NMDA hyper-function, this is treatable.  A deviation of NMDA function in either direction (hypo or hyper) leads to autism, but you need to know which way it is, to treat it.

It is also possible to have over/under expression of NMDA receptors.




23 comments:

  1. Peter ,dopaminergic hyperactivity and NMDAR underactivity are associated with enhanced glutamate release and consequent psychotic states. An NMDAR agonist is aspartic acid and L-serine. Finally I understood the sense of aspartic acid intervention and founded a very good reason to use L- serine. Thanks Peter and Tyler!
    Valentina

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    1. In a previous thread you were talking about histamine issues and since you (Valentina) were looking at other avenues of histamine modulation here is one suggesting that supplementing betaine may help as nicotanimide (not the same thing as NR to be clear) drains betaine levels (also known as trimethylglycine or TMG) and that seems to cause a rise in plasma serotonin and histamine.

      https://www.ncbi.nlm.nih.gov/pubmed/23426511

      TMG along with methyl B-12, folinic acid and/or methylfolate are some of the oldest and most popular autism interventions so this is not really a novel suggestion on my part here, but if you are really still concerned about high levels of histamine, one way of possibly lowering it would be to try and make sure methyl donors are not being depleted via supplementation.

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    2. Tyler, methylation is a key factor in my life as I told you some time ago,but I have never tried folate, b12 and tmg in my son,he sure has the mut MTHFR,so methyl donors are probably depleted. I don´t think that he is homocygote like me, this would be a very bad thing, one more.So,I have been postponing this intervention on him, knowing that a bad reaction is probably expected, as it is the common reaction of many. I have TMG at home, but I have only one bottle left, but since I have been taking it since many months ago I can give it to him.What sounds me more interesting about TMG is that it is the aminoacid glycine with 3 methyl groups attached, so I think that not only should help with histamine but also as an NMDA agonist. What do you think?
      Valentina

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    3. If you just want glycine, you can supplement it directly or else just eat lots of jello (gelatin). A non-gelling version of gelatin is what I use because I can mix it in drinks without it doing what gelatin does and this product is called hydrolyzed collagen (basically heat treated gelatin to break some of the protein bonds).

      TMG is used specifically because it has 3 methyl donors which makes it good for this particular use. There are plenty of other methyl varieties of supplements and even though they can be methyl donors as well, the primary reason they are created with a methyl group is to help catch a ride across the blood brain barrier (which is why some people think methyl-B12 is a better form of B-12 or methylfolate is a better form of folate which of course it can be in some circumstances).

      I am not sure why you think glycine will do anything with regards to NMDA function even though it is a co-agonist. You can of course increase NMDA neurotransmission with megadoses of glycine (or at least it has been done in mice), but you can do the same thing with injecting massive amounts of glutamine directly into the brain. Glycine participates as a neurotransmitter in inhibitory and excitatory functions in different parts of the body and brain and it is most useful (supplementing) for tissue repair. Some people feel they sleep better with glycine because while it has an excitatory role in the brain, in the spinal cord and muscles it functions like GABA. It also helps keep methionine levels normalized, that is if there is excess methionine in your diet (methionine is an essential amino acid).

      Long story short, you are going to want to use TMG for methylation support, not really for anything else.

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    4. Tyler,I can get hydrolized collagen,if it helps. About increasing NMDA neurotransmission in my son, is something about I have a strong hunch and can´t be guessed lightly . Nevertheless it is not something that one can achieve easly, as you say, megadoses of glycine or injecting massive amounts of glutamine are needed. I am doing l serine 1300 mg with noticeable improvement,is not a megadose, but as he recently started NR, both of them could be helping.You do aspartic acid, do you think that it could be increasing NMDA neurotransmission? I remember that you use it in large amounts.
      Valentina

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    5. I have never given L-Aspartic Acid for the purposes of NMDA agonism, rather as an opioid antagonist akin to the effects of naloxone or naltrexone. I would not give megadoses of glycine or glutamate (I said glutamine by accident in the above post), rather I was just trying to explain in context what glycine is typically used for (sorry for the confusion).

      The L-Aspartic Acid helped most with SIB, repetitive behaviors and anxiety and my best hypothesis is that is likely due to mu-opioid antagonism in the subcortical areas of the brain with a high density of those receptors (amygdala nuclei, nucleus accumbens, etc.).

      The thing with NMDA receptors is it depends on which types of neurons are being driven, which is one of many reasons it is so hard to develop effective drugs that don't have very negative side effects or even just side effects that counterbalance the primary effect of the drug making it largely neutral as far as exictatory/inhibitory transmission is concerned.

      On top of that, you can have groups of interneurons that inhibit other interneurons which inhibit excitatory neurons. By inhibiting one group of inhibitory interneurons with another you "disinhibit" them, leading to downstream excitation.

      The opioids do many things in the body and brain, but one of the primary things opioids do and depending on which type of receptors are activated is to indirectly regulate dopamine signaling which is why I suggested aspartic acid to you, not because of any effects on NMDA transmission.

      How L-Aspartic Acid seems to effect opioid transmission is not clear because my investigations into it are based upon long forgotten 30+ year old research and it is likely the original researcher is dead now considering I could not find him anywhere professionally (he was out of Turkey originally, but moved to Germany at one point). And it is unlikely NMDA agonism is what is going on here unless it involves the arcuate nuclei of hypothalamus which has a pseudo-blood brain barrier access that allows it to sample the blood for nutrient levels because L-Aspartate itself just as L-Glutamate which share the same BBB transporter are tightly regulated which is why most pretty much all glutamate in the brain is derived from a recycled pool of GABA, glutamine, and aspartate that are interconverted back and forth via various enzymes (which of course includes glutamate in that pool). This is why people talking about MSG (mono-sodium glutamate) being a "brain killer" don't know what they are talking about. Same thing goes with people who go crazy about aspartame as well.

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    6. Tyler, I will try ZMA, since that is what I can find here, but the amounts are low,260 mg magnesium aspartate per capsule,may be is better than nothing,3 capsules a day can be effective? I didn´t remember the reason why you suggested it to me and couldn´t find the comments, it is a shame that many important comments get lost in the ¨twilight zone¨ of the blog.
      Valentina

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    7. Valentina,

      I too face lots of problems in accessing valuable information present in many of the comments. If I am lucky, googling the keyword and then epiphanyasd.blogspot.in sometimes gets me to the specific comment but not always. It would be really helpful if Peter could somehow devise a mechanism where we could access comments by some of the knowledge pillars, Tyler, Agneiszka, RG, Roger, AJ, Tanya, Petra for instance. But I do not know if it's possible.

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    8. Kritika, I have thought the same but only with Tyler comments, or could be of any person,the section could be called Higlighted threads,Peter should decide which comments or threads deserve to be included in that section.But it is only a thought.
      Valentina

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  2. Peter and all,
    How do we identify the hyper/hypo NMDA function and NMDAR expression? Do we try agonists and antagonists?

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    1. I do not think there is any simple test, other than to make trials and see. Many NMDAR agonists/antagonists have other effects, either on different types of glutamate receptors or on non-glutamate receptors. So you might easily draw the wrong conclusion.

      So you would want a selective NMDAR agonist/antagonist.

      A complication is that mGluR5 receptors also modulate inhibition of NMDA receptors. So they might be the problem and some experimental therapy targets mGluR5. In some people this therapy makes a big impact, but not in enough people to make clinical trials appear successful, as was the case in a fairly recent Fragile-X trial.

      It really is a case of personalized medicine. So your Grandson needs to be considered as a unique case.

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  3. Hi everyone,

    Happy Saturday :)

    I wanted to add my Canadian 2 cents (that's about 1.5 cents US)to Peter's recent post about eIF4e. Ribavarin was an option to address the eIF4e issue, but this is not easily accessible, and not fun to take long term.

    So I've been looking at natural options and think I may have found something, but would really appreciate the input of the really knowledgeable people here (i.e. Peter, Tyler, and others). Am I on the right track?

    First, the relevant paper:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053690/

    So Icariside II looks to me like it could be helpful with respect to the eIF4e issue.

    So where do we find Icariside II?

    https://www.researchgate.net/publication/308088133_The_Anticancer_Properties_of_Herba_Epimedii_and_Its_Main_Bioactive_Componentsicariin_and_Icariside_II

    So Herba Epimedii has Icariin and Icariside II - that's good! Here's where you'll get a chuckle ... Herba Epimedii is better known as ... Horny Goat Weed. Seriously. I know it's April 1, but this is for real. And the good news is, it is a very common supplement.

    Here is more on what is in Horny Goat Weed:

    "Composition of the herb, chemicals and substances in the plant
    Horny goat weed herb has a number of substances including prenylated flavonol glycosides, ikarisoside A, icariside II, epimedoside A, icariin, epimedin B, yinyanghuo A - E, and epimedokoreanoside. Flavonoids include chrysoeriol, quercetin, apigenin, kaempferol, and luteolin. Icariin appears to be the primary substance that has some PDE5 inhibiting properties."

    http://www.raysahelian.com/hornygoatweed.html

    So I decided to see if the key ingredients (Icariin and Icariside II) show up in any other research with respect to brain health:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340752/

    https://www.ncbi.nlm.nih.gov/pubmed/26939761

    https://www.ncbi.nlm.nih.gov/pubmed/24858929

    https://www.ncbi.nlm.nih.gov/pubmed/26584824

    I'd appreciate any input - thanks everyone!

    AJ

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    1. AJ, It is complicated

      Your paper refers to 4E-BP1. The full name is EIF4E-BP1. (BP stands for binding protein and there are 3)

      I think the one we are interested is EIF4E-BP2. Which appears in the chart in my post.

      EIF4E-BP2 knockout mice have been used as an animal model of autism. Mice without the EIf4E-BP2 gene exhibited autism-like symptoms, including poor social interaction, altered communication and repetitive behaviors. Knockout mice have high levels of Neuroligins.

      EIF4E-BP1 and EIF4E-BP2 are very similar, but will a 4E-BP1 inhibitor also inhibit 4E-BP2?

      As I understand it, you would want an inhibitor of eIF4E or EIF4E-BP1.

      The Fragile X mental retardation protein, or FMRP, which you need to have enough of to prevent mental retardation/ID acts at eIF4E. So clearly eIF4E is important, but the nuances of a EIF4E-BP1/2/3 probably do matter.

      I think the researchers ended up with Ribavirin, because there is not much else.

      More generally you could down regulate mTORC1.

      You would want a downstream mTORC1 inhibitor.

      Inhibition of PI3K/Akt/mTOR Signaling by Natural Products
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3775843/

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    2. Hi Peter,

      Thank you for clarifying that there are 3 binding proteins, and that we are looking for an inhibitor of BP2 (whereas the paper I had related to BP1).

      Also appreciate your providing the link for natural products inhibiting the PI3K/akt/mTOR!

      AJ

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  4. Hi everyone,

    As it's a Saturday, I finally have some time to go over some of the interesting papers of the week and I think I've found a really good one. Still poring over it, but wanted to share:

    http://www.readcube.com/articles/10.3389/fped.2017.00043

    It has to so with increased activity in the akt/mTOR pathway.

    I'll share any interesting tidbits I derive, and ask the community (and knowledgeable lurkers) to post key findings.

    Enjoy!

    AJ

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  5. Hi there all , first post here after years fighting against the vaccine machine (which I believe to be the cause of all this autism\carnage) . So having wasted my time probably down the wrong political avenues I now find myself here , but its hard to know where to start with this blog . I only know one way , to read it and try to understand the theories . Thanks to all .
    Hans Litten

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  6. For those people who don't want to use Broccoli Sprout Extract for NRF2 activation, here are some very informative videos I came across from a YouTuber that discuss this particular subject:

    Discusses Sulphoraphane

    https://youtu.be/zz4YVJ4aRfg

    Discusses here idea for increasing sulphoraphane yield in broccoli sprouts via heating.

    https://www.youtube.com/watch?v=Z7buU-PK7_I

    Also, her channel also seemed to have an interesting interview with Dr. Valter Longo whose work I mentioned previously here with regards to "resetting" the immune system via fasting as well as his new "fasting mimicking diet".

    On another note, I also still get hyperactivity in my son from the Enduracell Pomgenex still, but it is not the anxiety type of hyperactivity that increases SIB and this is pretty consistent now.

    Other people have reported paradoxical findings that methyl donors (which increase AMPK) cause hyperactivity in their children so I am wondering if AMPK seems to be the issue.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4099513/

    On top of that, a paper suggesting Ghrelin induction of AMPK via calorie restriction increases activity in the striatum (which tends to already be hyperactive and enlarged in autism) is my best guess as the mediating effect of this weird behavior at the moment:

    http://www.jneurosci.org/content/jneuro/36/10/3049.full.pdf

    It is really frustrating because it is like there are some positive cognitive symptoms with the Pomgenex (which has Broccoli Sprout Powder), but too much hyperactivity so I am wondering if interventions to tone down the striatum at the same time as broccoli sprout/NRF2 interventions might solve the problem here.

    Any ideas from anyone on this subject would be very appreciated in this regard.

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  7. Research Shows Benefits Of Apple Juice On Neurotransmitter Affecting Memory

    New research demonstrates that apple products can help boost brain function similar to medication. Animal research from the University of Massachusetts Lowell (UML) indicates that apple juice consumption may actually increase the production in the brain of the essential neurotransmitter acetylcholine, resulting in improved memory.

    Peter, I thought this may be interesting and easy to try.

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  8. hello all, i have a son with refractory myoclonic epilepsy who had this at 8 months together with severe constipation. i have many tests and explored diets boosting immune system with ivigs and biomed. nothing to date has allowed seizures to go although it got close on the first and second ivig.i havent gone down metal detox due to being afraid of worsening seizures but the gut we have worked on. he has comt gene homozygous aswell as mtrr homozygous for snps. he is very sleepless at nite and very ocd, when he cant get what he wants he is v v aggressive.also is still non verbal but very challenging in behaviour. Is there any test that could tell us where to go from here? he is on probiotics vit d, cbd oil enzymes but when i attempt to give any methyl folate plus methyl cobolamin he reacts within hours of giving this even at low dose by having very strong seizures. he has clostridia and pathogenic load in gut but how to deal with this and to get the gut cleaner is problematic due to high tendecy for seizures. is ther a safe way to go?

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    1. There are no tests than can tell you exactly what to do.

      Very many people respond to the antioxidant NAC, which takes effect within hours. Dosage used is about 2-3g a day in 3-4 doses.

      Bumetanide can have a profound effect but will take 10+ days to show effect.

      High dose melatonin (10mg +) can help greatly with GI issues.

      Some people's GI issues vanish with Verapamil.

      Some probiotics actually make things worse. They all have different effects, and some start out with a good effect and then it turns negative later.

      Some people with autism have so many therapies the end result is worse than no therapies. So you cannot throw everything at the problem hoping that something sticks.

      It needs careful thought.

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    2. The methyl groups I have noticed I have to be careful with for my son who has seizures as well. He has many different types of seizures ..starting at 9 months. I use a small amount of methyl groups from his multi and a low dose leucovorin. I have to use the methylcobalamin very sparingly but some people use up methyl groups too fast and this causes more problems. Its sort of like excitotoxic when it happens so you have to be careful and then some individuals are sensitive to methylgroups. There are other cobalamins that have to go through some extra steps before converting to a methyl which might help slow this. So maybe thinking along the lines of trading the methyl group supplements to some of those supplements you need that have to go through some extra steps to slow things down. I find with my son everything is tooo fast way to fast. Processing, movement, regulation. I often wonder if he is hyperlexic. His sensory system is dysregulated and at times it is as though he is taking in information from too many inputs too quickly and his processor wants to shut down.......Busy stores with too many people.....Not going to happen. He says too many people, reaches up for me and his eyes get large. His skin turns shades of pink and respiration increases. Before it turns into panic mode or a seizure we often leave. I feel really bad because its likely that I passed down some of this too him. I am processing like this often as well so I get it and I have multiple extreme sensory issues that I have adapted to over the years. I have precognitive ability as well. I have never thought it very necessary or ever really felt alone like I need many friends. I can socialize if I have to but I am comfortable not doing it at all. There are many instances where I have to employ a filter and think very hard before I interact with people. I often over elaborate and get really detailed overwhelming people with information beyond there comprehension or ability to understand. When I face these challenges I feel in that way I can relate to my son. My son and I communicate at an almost telepathic level. We feel emotions but we don't have to really go into great detail verbally with one another. It is the same with our dog. The dog responds to us without much speaking and understands us. It is as though we have to have these filters and processes for society and those that we can have at home....Society has many facades that are easily decoded.

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  9. Peter, I Have a doubt about the diagrama above, it says NMDAR hyperfunction and NMDAR overexpression, which is the same, leads to glutamate excess but it happens the same with NMDAR hypofunction or underexpression wich leads to more excitatory signaling.
    Valentina

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    1. Valentina, everything in this blog regarding hypo/hyper GABA/NMDA is a gross simplification. That is why I say in the next post not to worry if hypo and hyper get confused.

      In this highly cited paper they address this exact point:-

      NMDA Receptor Hypofunction Produces Opposite Effects on Prefrontal Cortex Interneurons and Pyramidal Neurons
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2954603/

      "NMDA receptors mediate excitatory postsynaptic potentials throughout the brain but, paradoxically, NMDA receptor antagonists produce cortical excitation"
      "NMDA receptor hypofunction, which has been implicated in the pathophysiology of schizophrenia, diminishes the inhibitory control of PFC output neurons."

      You either have to go into a huge amount of detail to figure it all out, or just accept that both hypo/hyper are bad, and in some cases the opposite therapy of what you had expected is effective.

      The chart above is correct, regarding glutamate excitotoxicity. However, too little NMDA signaling can also lead to excitation, which does indeed look counter-intuitive (odd).

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