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Wednesday, 25 April 2018

Arginine and its Derivatives in Cognitive Impairment


Source: Epiphany ASD Blog

Today’s post is very relevant to dementia, relevant to schizophrenia and diabetes and I believe some autism, including that of my son; agmatine is part of his Polypill therapy.
Arginine is highly versatile amino acid and you need the arginine metabolism to be working correctly, particularly in your brain.
Arginine is a widely available from diet and can be produced from citrulline and indirectly from glutamine; so you are unlikely to be deficient in arginine, except in your brain and particularly if you have Alzheimer’s.
In Alzheimer’s it has been shown that the microglia in effect destroy arginine in the brain and this may play a role in what initiates the disease.
Research has suggested that a deficiency in polyamines, another derivative of Arginine, is a feature of dementia.
A deficiency of arginine in the brain will likely cause a deficiency of polyamines.

Your body needs nitric oxide to maintain a healthy blood pressure and this requires arginine to follow the blue line in the above chart towards citrulline and be converted by eNOS.  In most older people this does not happen and oxidative stress appears to be a big part of the problem.

Agmatine – good 
Agmatine has been shown in research to have a benefit in Alzheimer’s.  

This could be due to increased eNOS improving blood flow, an increase in Polyamines, or by reducing insulin resistance in the brain. Recall those studies of intranasal insulin? We had "type 3 diabetes", which was a brain-specific blunting of insulin.

https://www.ncbi.nlm.nih.gov/pubmed/27810390 
"Agmatine administration rescued the reduction in insulin signalling, which in turn reduced the accumulation of Aβ and p-tau in the brain. Furthermore, agmatine treatment also reduced cognitive decline. Agmatine attenuated the occurrence of AD in T2DM mice via the activation of the blunted insulin signal"

Methylarginines – not good
Two by-products of arginine are bad for you in the way Agmatine is good for you.
Nitric Oxide is produced via iNOS, nNos and eNOS. In simple terms we want nitric oxide to be produced in the endothelium, the name for cells that line the interior surface of blood vessels and lymphatic vessels, To achieve this we needs lots of the enzyme eNOS and not much iNOS or nNOS, this is one of Agmatine’s jobs.
Two derivatives of arginine/proteins in the body with very long names are abbreviated to NMMA and ADMA. They both inhibit eNOS and so will restrict blood flow and this will appear as elevated blood pressure.   


Endogenous methylarginines, N(G),N(G)-dimethyl-L-arginine (asymmetric dimethylarginine, ADMA), N(G)-N('G)-dimethyl-L-arginine (symmetric dimethylarginine; SDMA), and N(G)-monomethyl-L-arginine (monomethyl arginine; NMMA) are supposed to be produced in human body through the methylation of protein arginine residues by protein arginine methyltransferases (PRMT) and released during proteolysis of the methylated proteins. Micromolar concentration of ADMA and NMMA can compete with arginine for nitric oxide synthase (NOS) reducing nitric oxide (NO) formation, whereas SDMA does not. Indeed, increased ADMA and SDMA plasma levels or a decreased arginine/ADMA ratio is related with risk factors for chronic kidney disease and cardiovascular disease. To the best of our knowledge the exogenous presence of methylarginines, like that in fruits and vegetables, has never been described so far. Here, we report the finding that methylarginines are ubiquitous in vegetables which represent an important part of human daily diet. Some of these vegetables contain discrete amounts of ADMA, SDMA, and NMMA. Specifically, among the vegetables examined, soybean, rye, sweet pepper, broad bean, and potato contain the highest ADMA and NMMA mean levels. Our results establish that the three methylarginines, in addition to being produced endogenously, can also be taken daily through the diet in conspicuous amounts. We propose that the contribution of the methylarginines contained in the vegetables of daily diet should be taken into account when the association between vegetable assumption and their levels is evaluated in clinical studies. Furthermore, a comprehensive understanding on the role of the digestive breakdown process and intestinal absorption grade of the methylarginines contained in vegetables is now needed. 

ADMA
Asymmetric dimethylarginine (ADMA) is a naturally occurring chemical found in blood plasma. It is closely related to L-arginine. ADMA interferes with L-arginine in the production of nitric oxide (NO), a key chemical involved in normal endothelial function and, by extension, cardiovascular health. ADMA inhibits eNOS, which in simple terms is the good NOS, the other two being iNOS and nNOS.
ADMA is considered a marker for vascular disease

NMMA (NG-monomethyl-l-arginine, or just called Targinine) 
The following study is very interesting for your older relatives. As we already know oxidative stress is a feature of aging. Many people have high blood pressure in old age. Nitric Oxide (NO) is needed keep blood vessels wide open. In old age (>60) oxidative stress reduces NO availability to nothing. 
Since oxidative stress is reversible (in this study vitamin C was used) you wonder why more older people, particularly with high blood pressure, do not take entioxidants. 


A novel finding of the present study is that in normotensive subjects, the reduction in endothelial function associated with aging seems to be mediated by a progressive reduction of NO availability, inasmuch as the inhibiting effect of L-NMMA on acetylcholine-induced vasodilation was progressively impaired by advancing age. It is worth noting that after the age of 60 years, the inhibiting effect of L-NMMA on response to acetylcholine was very weak, suggesting that in aged individuals NO availability is almost totally compromised. To assess the possible role exerted by oxidative stress, we tested the antioxidant vitamin C.19 Up to the age of 60 years, despite the evident decline in endothelium-dependent vasodilation, vitamin C did not modify the response to acetylcholine. In contrast, in the oldest individuals (age >60 years) characterized by a profound alteration in NO availability, vitamin C not only enhanced the response to the endothelial agonist but also restored the inhibiting effect of L-NMMA on vasodilation to acetylcholine. Thus, in the present study, the use of L-NMMA and vitamin C, never tested before in investigating the mechanisms responsible for the previously demonstrated age-related endothelial dysfunction in humans,17 seems to indicate that the progressive impairment in endothelium-dependent vasodilation is caused by a progressive alteration of the l-arginine-NO pathway. Only in old age (after ≈60 years) does the production of oxidative stress appear, leading to the complete compromise of NO availability.  

Arginase
Arginase is an enzyme that acts as the catalyst for the reaction.
 arginine + H2Oornithine + urea 

People with schizophrenia and also people with diabetes tend to have high levels of Arginase. This will affect how arginine is metabolized. If arginase is increased there is less arginine that can go towards creatine, citrulline or agmatine. 
Going towards citrulline involves the production of nitric oxide NO. Now in schizophrenia we see a reduction in the good type of NO, that produced in the endothelium, the cells that line the interior surface of blood vessels and lymphatic vessels. As a result, we vascular dysfunction in schizophrenia.
Agmatine is also elevated in schizophrenia, which may be one of those feedback loops since agmatine will inhibit iNOS, nNOS while increasing eNOS
So where is there a reduction in Arginine in schizophrenia?
Well it looks like it is creatine which takes the hit.


“Patients with schizophrenia had a statistically significant reduction in Cr levels as compared with controls; bipolar disorder patients showed no difference in Cr as compared with controls”

In people with elevated arginase a useful strategy might be to use an arginase inhibitor.


The next paper highlights the arginase inhibitor I favour, which is L-norvaline. The paper is from Kursk university. Kursk gave its name to the nuclear-powered submarine that was lost in the Barents Sea in 2000 and triggered a new international cooperation to rescue stricken submarines. The Battle of Kursk was the largest tank battle of all time and the final major offensive by the Germans against the Russians in World War 2, where Hitler wanted to cut off a large bulge in the front line and trap a lot of Russians. Thanks to some clever English mathematicians, encrypted German communications were readable and the Russians repositioned their forces in advance, allowing them to counter attack. The Allies then invaded Sicily and that was the end for the Germans in Russia. 

The present research shows expressed endothelium-protective property of arginase inhibitor, L-norvaline, characterized by decrease of coefficient of endothelial dysfunction and the approached its application to a group of intact animals. In other words, L-norvaline prevents the development of systemic endothelial dysfunctions in L-NAME- and methionine-induced NO deficiency.

Age-induced memory impairment (AMI)

Now we move to Polyamines that are on the bottom left my graphic at the start of this post. Spermidine and Spermine are very beneficial derivatives of arginine that most older people will be lacking. Autophagy is the cellular garbage disposal service that is dysfunction in many neurological disorders. We generally want more autophagy.

The aging process drives the progressive deterioration of an organism and is thus subject to a complex interplay of regulatory and executing mechanisms. Our understanding of this process eventually aims at the delay and/or prevention of age-related pathologies, among them the age-dependent decrease in cognitive performance (e.g., learning and memory). Using the fruit fly Drosophila melanogaster, which combines a generally high mechanistic conservation with an efficient experimental access regarding aging and memory studies, we have recently unveiled a protective function of polyamines (including spermidine) against age-induced memory impairment (AMI). The flies’ age-dependent decline of aversive olfactory memory, an established model for AMI, can be rescued by both pharmacological treatment with spermidine and genetic modulation that increases endogenous polyamine levels. Notably, we find that this effect strictly depends on autophagy, which is remarkable in light of the fact that autophagy is considered a key regulator of aging in other contexts. Given that polyamines in general and spermidine in particular are endogenous metabolites, our findings place them as candidate target substances for AMI treatment.  


Aging is the most important risk factor for cardiovascular disease (CVD). Slowing or reversing the physiological impact of heart aging may reduce morbidity and mortality associated with age-related CVD. The polyamines, spermine (SP) and spermidine (SPD) are essential for cell growth, differentiation and apoptosis, and levels of both decline with age. To explore the effects of these polyamines on heart aging, we administered SP or SPD intraperitoneally to 22- to 24-month-old rats for 6 weeks. Both treatments reversed and inhibited age-related myocardial morphology alterations, myocardial fibrosis, and cell apoptosis. Using combined proteomics and metabolomics analyses, we identified proteins and metabolites up- or downregulated by SP and SPD in aging rat hearts. SP upregulated 51 proteins and 28 metabolites while downregulating 80 proteins and 29 metabolites. SPD upregulated 44 proteins and 24 metabolites and downregulated 84 proteins and 176 metabolites. These molecules were mainly associated with immune responses, blood coagulation, lipid metabolism, and glutathione metabolism pathways. Our study provides novel molecular information on the cardioprotective effects of polyamines in the aging heart, and supports the notion that SP and SPD are potential clinical therapeutics targeting heart disease                                                               


Figure 1. summarizes the suggestion that spermidine-triggered restoration of autophagy protects synapses from age-induced changes, and thus delays the normally occurring decline of memory formation. Given that spermidine is a physiologic, easy administrable substance, future research may consider its supplementation to counter age-dependent dementia.
Spermidine operates directly at presynaptic active zone scaffolds (composed of Brp/bruchpilot protein) to allow for an autophagy-dependent homeostatic regulation of these specializations. In effect, spermidine protects learning efficacy from aging-induced decline.                                      


 Having your longevity and eating too
Although caloric restriction has clear benefits for maximizing health span and life span, it is sufficiently unpleasant that few humans stick to it. Madeo et al. review evidence that increased intake of the polyamine spermidine appears to reproduce many of the healthful effects of caloric restriction, and they explain its cellular actions, which include enhancement of autophagy and protein deacetylation. Spermidine is found in foods such as wheat germ, soybeans, nuts, and some fruits and vegetables and produced by the microbiota. Increased uptake of spermidine has protective effects against cancer, metabolic disease, heart disease, and neurodegeneration. 

Although spermidine induces autophagy and autophagy inhibition curtails many of the health-promoting effects of spermidine, additional mechanisms have been proposed to explain the beneficial effects of spermidine on aging. These potentially autophagy-independent mechanisms include direct antioxidant and metabolic effects on arginine bioavailability and nitric oxide (NO) production. However, it has not been formally determined whether these routes act in a completely autophagy-independent manner or are interrelated with autophagy (in an additive or synergistic way) (see the figure), and it will be important to define actionable molecular targets that explain the beneficial effects of spermidine in diverse pathophysiological settings. In this sense, it will also be of interest to explore synergisms of spermidine with other CRMs that initially act through different mechanisms.






It is a surprise that those long-lived Japanese eat Natto? Also, it is a good source of vitamin K2 and importantly it is an estrogen and so an ERβ agonist.


Not all probiotics are helpful to produce polyamines and one well known probiotic, VSL#3, has been shown to reduce their level. Choose your bacteria very carefully. 
Here the probiotic strain Bifidobacterium animalis subsp. lactis LKM512 is used to increase polyamine production



Alzheimer’s and Arginine
In a fairly recent study it was suggested that the immune system in the brain is being suppressed and the microglia are slightly mutated along with the over-expression of arginase. Arginase is the enzyme that coverts arginine to ornithine plus urea.

So, in Alzheimer’s there will be a lack of arginine available for its other purposes. 


So, we would expect a lack of creatine, agmatine and citrulline. Along the way we should see less Nitric Oxide.
Based on my graphic above, it would seem that L-Norvaline should improve the outcome in Alzheimer’s mice.
We already know that Agmatine improves Alzheimer’s mice, as we now should expect.
So, my cocktail for an aging mouse would be: - 

·        L-Norvaline (used by body builders)

·        Agmatine (used by body builders)

·        Creatine (used by body builders)

·        Natto/wheatgerm/ LKM512 probiotic

·        Vitamin C or NAC

·        Citrulline (used by body builders)

·        Betanin (an approved food colour additive, see below)

Served with cheese, naturally.

A New Potential Cause for Alzheimer’s: Arginine DeprivatiON

Alzheimer’s study suggests immune cells chew up an important amino acid 
Increasingly, evidence supports the idea that the immune system, which protects our bodies from foreign invaders, plays a part in Alzheimer’s disease. But the exact role of immunity in the disease is still a mystery. A new Duke University study in mice suggests that in Alzheimer’s disease, certain immune cells that normally protect the brain begin to abnormally consume an important nutrient: arginine. Blocking this process with a small-molecule drug prevented the characteristic brain plaques and memory loss in a mouse model of the disease. Published April 15 in the Journal of Neuroscience, the new research not only points to a new potential cause of Alzheimer’s but also may eventually lead to a new treatment strategy. “If indeed arginine consumption is so important to the disease process, maybe we could block it and reverse the disease,” said senior author Carol Colton, professor of neurology at the Duke University School of Medicine, and a member of the Duke Institute for Brain Sciences. The brains of people with Alzheimer’s disease show two hallmarks -- ‘plaques’ and ‘tangles’ -- that researchers have puzzled over for some time. Plaques are the build-up of sticky proteins called beta amyloid, and tangles are twisted strands of a protein called tau. In the study, the scientists used a type of mouse, called CVN-AD, that they had created several years ago by swapping out a handful of important genes to make the animal’s immune system more similar to a human’s. Compared with other mice used in Alzheimer’s research, the CVN-AD mouse has it all: plaques and tangles, behaviour changes, and neuron loss. In addition, the gradual onset of these symptoms in the CVN-AD mouse gave researchers a chance to study its brain over time and to focus on how the disease begins, said the study’s first author Matthew Kan, an MD/PhD student in Colton’s lab. Looking for immune abnormalities throughout the lifespan of the mice, the group found that most immune system components stayed the same in number, but a type of brain-resident immune cells called microglia that are known first responders to infection begin to divide and change early in the disease. The microglia express a molecule, CD11c, on their surface. Isolating these cells and analyzing their patterns of gene activity, the scientists found heightened expression of genes associated with suppression of the immune system. They also found dampened expression of genes that work to ramp up the immune system. “It’s surprising, because [suppression of the immune system is] not what the field has been thinking is happening in AD,” Kan said. Instead, scientists have previously assumed that the brain releases molecules involved in ramping up the immune system, that supposedly damage the brain. The group did find CD11c microglia and arginase, an enzyme that breaks down arginine, are highly expressed in regions of the brain involved in memory, in the same regions where neurons had died. Blocking arginase using the small drug difluoromethylornithine (DFMO) before the start of symptoms in the mice, the scientists saw fewer CD11c microglia and plaques develop in their brains. These mice performed better on memory tests. “All of this suggests to us that if you can block this local process of amino acid deprivation, then you can protect -- the mouse, at least -- from Alzheimer’s disease,” Kan said. DFMO is being investigated in human clinical trials to treat some types of cancer, but it hasn’t been tested as a potential therapy for Alzheimer’s. In the new study, Colton’s group administered it before the onset of symptoms; now they are investigating whether DFMO can treat features of Alzheimer’s after they appear. Does the study suggest that people should eat more arginine or take dietary supplements? The answer is ‘no,’ Colton said, partly because a dense mesh of cells and blood vessels called the blood-brain barrier determines how much arginine will enter the brain. Eating more arginine may not help more get into the sites of the brain that need it. Besides, if the scientists’ theory is correct, then the enzyme arginase, unless it’s blocked, would still break down the arginine. “We see this study opening the doors to thinking about Alzheimer’s in a completely different way, to break the stalemate of ideas in AD," Colton said. "The field has been driven by amyloid for the past 15, 20 years and we have to look at other things because we still do not understand the mechanism of disease or how to develop effective therapeutics

The full study: -

The pathogenesis of Alzheimer's disease (AD) is a critical unsolved question; and although recent studies have demonstrated a strong association between altered brain immune responses and disease progression, the mechanistic cause of neuronal dysfunction and death is unknown. We have previously described the unique CVN-AD mouse model of AD, in which immune-mediated nitric oxide is lowered to mimic human levels, resulting in a mouse model that demonstrates the cardinal features of AD, including amyloid deposition, hyperphosphorylated and aggregated tau, behavioral changes, and age-dependent hippocampal neuronal loss. Using this mouse model, we studied longitudinal changes in brain immunity in relation to neuronal loss and, contrary to the predominant view that AD pathology is driven by proinflammatory factors, we find that the pathology in CVN-AD mice is driven by local immune suppression. Areas of hippocampal neuronal death are associated with the presence of immunosuppressive CD11c(+) microglia and extracellular arginase, resulting in arginine catabolism and reduced levels of total brain arginine. Pharmacologic disruption of the arginine utilization pathway by an inhibitor of arginase and ornithine decarboxylase protected the mice from AD-like pathology and significantly decreased CD11c expression. Our findings strongly implicate local immune-mediated amino acid catabolism as a novel and potentially critical mechanism mediating the age-dependent and regional loss of neurons in humans with AD.

So Arginine for Alzheimer’s? Not so simple
Eating more arginine is not an effective way to increase the level of arginine in your brain and also the high level of arginase might just soak it all up anyway.
Other science does suggest that there are other ways to increase the amount of arginine in your brain, such as L-citrulline.  We have already seen that we can inhibit arginase with L-norvaline among other things.

Betanin for Alzheimer’s
Since we are on Alzheimer’s, we might as well include another clever idea.
Our reader Tyler highlighted another interesting Alzheimer’s study, which suggests preventing/treating Alzheimer’s with Betanin, the pigment in beet root.
This might sound mad, but is deadly serious. The research showed that Betanin inhibits the formation of the trademark beta-amyloid plaques that define Alzheimer’s. No plaques, no Alzheimer’s.


Beetroot has already been featured in this blog; it has numerous health benefits.

To lower blood pressure and increase exercise endurance it is the nitrates that are helpful, but beetroot has numerous other effects; it even increases insulin sensitivity, so is a good choice for diabetics and pre-diabetics.








Betanin without the beetroot?
Betanin has such a strong colour it is used commercially as a food colourant, it appears as E162 on the label. In Europe it is called Beetroot red E162 and is inexpensive.
Personally, I take my betanin with the rest of the beetroot. 

Vascular Dementia - before I forget

Vascular dementia is the easiest type of cognitive impairment to understand. Reduced blood flow to the brain, most likely due to reasons including a loss of endothelial nitric oxide, effectively starves the brain. We saw how cocoa flavanols improve blood flow and hence mild cognitive impairment, this is via an NO-dependent mechanism that nobody fully understands. In autism things get more complicated and we saw in earlier posts that we seem to have unstable blood flow rather than just reduced blood flow. Nonetheless, improving cerebral blood flow may well be useful for some people with autism; so more eNOS and not too much arginase, cocoa flavanols may well be beneficial. Antioxidants are hopefully already being taken.


Conclusion
I was surprised just how much in the post can be implemented today with no prescription medication.
It is no surprise that certain diets (Mediterranean/Okinawan) promote not only longevity but also an extended healthy life expectancy.
I think there are some tips here for fine tuning out of balance brains found in autism, schizophrenia and bipolar.
I hope someone trials my cocktail on an Alzheimer’s mouse and a regular older mouse. 

·        L-Norvaline and Citrulline

·        Agmatine

·        Creatine

·        Natto/wheatgerm/ LKM512 probiotic

·        Vitamin C or NAC

·        Betanin


I suspect this cocktail would be more effective than Donepezil or Memantine, neither of which address the underlying cause of Alzheimer's disease. In reality some of the above might not even be needed (e.g. creatine and citrulline).

Agmatine as an alternative for some people who respond to intranasal insulin is an interesting idea. Research seems to have stalled because the preservative in the insulin causes irritation inside the nose.

Note: Creatine deficiency is a known cause of MR/ID/Autism and some types are treatable  https://creatineinfo.org/. It is detectable by Magnetic Resonance Spectroscopy or by measuring creatine levels in plasma and urine. Babies born with creatine deficiency may exhibit hypotonia (floppy baby syndrome) due to weak muscles. 





52 comments:

  1. Great post. Thank you.

    ReplyDelete
  2. Hi Peter,

    Hope all is well.

    Peter, I have a very important item I would like to connect with you on privately. Would you kindly provide an e-mail address that I can contact you with?

    It would be greatly appreciated Peter, and I wouldn't ask if it wasn't important.

    Alternatively, I can provide you with my e-mail if you would prefer.

    Thanks Peter!

    AJ

    ReplyDelete
  3. Great Post! Are you taking Agmatine for you? It seems like somethings are for cognitive repair/maintenance to ward off Alzheimers and somethings might be for neurogenesis and cognitive growth. How would you think about those "middle age supplement cocktail" you mentioned for spectrum kids?

    ReplyDelete
    Replies
    1. I bought Agmatine for my mother, but I am not taking it myself. People who benefit seem to show the effect very clearly. I do believe in the chemoprotective and anti-inflammatory benefit of long term Atorvastatin use. I do take beetroot juice every day and it would be smart to also take broccoli sprouts powder.

      For middle aged NT people diet and exercise are what matter.

      For kids with autism you have to address exactly what is dysfunctional. I think elements of this post will apply to many kids with autism. You just need to figure out which one(s), if any, in each individual.

      Delete
  4. Based on an earlier post that you did, I take beet root capsules. It may be placebo (I don't think so...) and I feel happier and lighter -- less anxious. It has no effect on my son. Do you have a silver bullet for many cases of anxiety for spectrum kids (not all, but the one that seems to work for many)?

    ReplyDelete
    Replies
    1. I am glad the beet root helps you.

      In kids with autism I think many different things end up causing what we parents identify as "anxiety". If it was possible to be more specific, then we might find that magic bullet, or rather magic bullets.

      In some people NAC helps, at least some of the time.

      I think in many it is inflammation, or rather the body's inflammatory response that is the problem. Different people respond well to different immunomodulatory therapies, because their odd immune systems are odd in different ways. So it is trial and error if you are doing this in 2018, there should be a better way.

      Delete
    2. https://www.sciencedaily.com/releases/2018/04/180425093745.htm

      Peter, this one seems interesting,just connect the dots

      Delete
    3. Yes, very interesting and one other reader has already pointed it out. In effect it is vagal nerve stimulation by drinking baking soda.

      Delete
    4. Peter

      I could not understand how the study links baking soda to vagal nerve stimulation....

      If true, this could be really helpful for us. Even if vagus nerve is not involved, baking sodas ability to dampen histamine response and now autoimmune too, seems quite interesting. Should we start giving it to our kids?

      Delete
    5. Kritika, you need to read the full study.

      "Our data indicate that oral NaHCO3 loading may provide a cheap, relatively safe, effective, and easily accessible and/or noninvasive method to activate cholinergic anti-inflammatory pathways in humans, which may be of benefit to patients suffering from a multitude of inflammatory disease states. As such, our findings could potentially have significant clinical application to the treatment of human disease. Future studies testing the efficacy of oral NaHCO3 to limit injury in models of inflammatory disease will be required to determine the therapeutic potential of this stimuli."

      Delete
  5. Highly enjoyed reading this post Peter! That paragraph on Kursk almost made me forget that we were on the subject of L-Norvalin.

    I have been thinking about food intake vs brain function for a while. The only time of the day that my youngest daughter "talks" (make sounds) is directly after meals. We also used to joke about her NT sister that she was eating birdseeds because food would always make her tweet or chatter.
    Myself, I definitely feel that it is hard to think or sometimes even get a headache before lunch that is relieved soon afterwards. It is as if my brain eats most of the energy I consume.
    Is this just as simple as low blood-sugar? We don't eat a lot of sugar in the family, neither do we have any diabetic relative.

    /Ling

    ReplyDelete
    Replies
    1. Ling, i tried to reply to this earlier, but i guess it failed.
      Maybe it's just a lack of energy. Try googling for "fat adaptation". The theory is that the body should switch easily into using fatty acids/ketones if glucose runs low, but some people lose this ability. You may need to do some proper low carb/keto eating for a couple of weeks or so to retrain this ability. (Or just eat more carbs more often, but i don't recommend this.)
      Eating MCTs, e.g. coconut oil, or some other fatty snack is another way to get a quick boost without spiking glucose and insulin.
      Aspie2.

      Delete
    2. Thank you Aspie2 for some ideas on the matter! :)

      /Ling

      Delete
  6. Peter, do you know anything about something called Nitromemantine?

    /Ling

    ReplyDelete
    Replies
    1. Ling, they changed its name to nitrosynapsin, to sound less like Memantine.

      Memantine does not work as well as expected and this new variant of it apparently works better.

      NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism
      https://www.nature.com/articles/s41467-017-01563-8


      Delete
  7. Hi Peter, when a study says the VPA model -- valproic acid induced model of autism -- what does that mean? Is that for early -onset vs. regressive, etc? For instance does that mean that the agmatine will be better therapy possibly for the type of autism it is addressing. Also are these studies (if they have not mentioned age of rats/mice ) for younger ages? Thanks MH

    ReplyDelete
    Replies
    1. MH, the VPA mouse is a model of environmental autism, when there is no simple genetic defect. There was an insult prior to birth that leave epigenetic markers on otherwise perfect genes. The end result is altered gene expression, which is what causes autism.

      I think it may be a mistake to make deeper comparisons with human autism. If a drug works in 2 or 3 models of mouse autism it is worth trying in humans.

      Delete
  8. Hi Peter,I hadn´t had lack with my last interventions.The effect of Sarcosine wasn´t so clear, it was a mixture of good and bad effect.He was inattentive and hyperactive these days but he answeared difficult questions.Small tics appeared. I decided to give up glycine agonists and try glutamate inhibitors.I returned to Tizanidine,didn´t know how much I was missing it.I will never leave it again.It is one of my best interventions with bumetanide and BCAAs. Of course each child is different but I learnt my lesson.
    Valentina

    ReplyDelete
    Replies
    1. Valentina, Have you ruled out pans/pandas? does your child have flares with new tics? Have you asked your doctor about a short course of steroids and see if that dampens some inflammatory response?

      Delete
    2. No,he does not have flares with new tics, only appeared an old one that left when stopped some new interventions.His GI dysfunction/constipation plays a huge role here,not Pans or Pandas,yes inflammation.I wouldnt give him steroids,there are many alternatives.Valentina

      Delete
    3. I completely understand the lack of wanting to do a short dose of steroids -- I had been in the camp. It also had terrible side effects for a few days for us (known side effect) but it did work stem the flares and tics (he had infection triggered illness second tap). I was only mentioning that since it changed our course significantly and if it would be useful.

      Delete
    4. Valentine I tried it for a day, the first 2 hours after dosing I felt very good, but after that the effect seems to wear off and Im left with a headache that takes about 2 days to full recover.

      Delete
    5. Aspie, yes,the first dose had a calming effect but the following days was getting more anxious.I think high glutamate is still an issue and he is not prepared to receive glysine or acetylcholine agonists.I was thinking of using noni extract as a mild antipsichotic, 800 MG,i don't think that it has the strenght of risperidone, it has also many other properties.What do you think?
      Valentina

      Delete
    6. Hi Valentina, personally I do not respond well to antipsychotics as they literally drain the life out of me and drastically decrease my quality of life so I cannot comment on that for your situation.

      I only tried sarcosine for 1 day, 2x 500mg it was and it felt like glutamate relieve on the first 2 hours of intake, then it felt like a glutamate headache like rebound, like you I had high expectations of it aswell however it seems to not be for me :/

      Delete
  9. Hi everyone,

    My 23andme results are in! and confirmed alot of what I allready suspected!

    I ran it through promethease, but Im looking for a better website which can give advice more specifically for brain health.


    * rs1800497(C;C) - Normal (A2/A2) Better avoidance of errors. Normal OCD risk, normal Tardive Dyskinesia risk, lower ADHD risk. Less Alcohol dependence. Higher risk of Postoperative Nausea. Lower obesity. Bupropion is effective. This DRD2 TaqIA A2/A2 version causes a normal amount of Dopamine Receptors. Learns from mistakes more easily. Men may have a higher risk of Obsessive Compulsive Disorder but lower risk of ADHD. Women have higher Persistence. Higher risk of Tardive Diskinesia when taking dopamine receptor antagonists. Lower risk of alcoholism and smoking addiction. (good)
    * rs4680(G;G) - (warrior) multiple associations, see details You have the VAL/VAL version of the snp discussed in this news article. It is able to perform better in a test where the optimal strategy changes. (this is considered good, but from what I have read it means I break down dopamine faster and val/val individuals have less joy in life...).
    * rs53576(A;G) - Lack of empathy? You have a SNP in the oxytocin receptor which may make you less empathetic than other people. When under stress you may have more difficulty recognizing the emotional state of others which impacts loneliness, parenting, and socializing skills. Some studies have suggested that the A;G genotype is associated with an intermediate level of empathy (compared to the G;G and A;A genotypes), although most report that A;G and A;A individuals have similar levels of empathy and stress handling capabilities. (bad obviously)
    * rs1129844(A;G) - Significant delay in onset of early-onset Alzheimer's; possibly a 2.5 year delay in onset of late-onset Alzheimer's (good)
    * rs4474514(A;A) - >3x increased testicular cancer risk for men found in 65% of caucasians but linked 3x higher risk of testicular cancer than the (G;G) form (bad..)
    * rs995030(G;G) - non-protective against testicular cancer (bad...)
    * rs4149274(C;C) - Associated with higher HDL (good) cholesterol.
    C allele is associated with 1.51mg/dl increase in HDL cholesterol (good cholesterol).

    ReplyDelete
  10. * rs9286879(A;A) - DeCode reports that rs9286879 is associated with susceptibility to Crohn's disease. (tada... my mother has crohn's)
    * couple more genes that increase the chance of crohn...
    * rs16891982(G;G) - Generally European; Light skin; Possibly an increased risk of melanoma
    * rs2854464(A;A) - higher muscle strength the high muscle strength mutation at ACVR1B, specifically tested on the knees
    * rs2281617(C;C) - Normal (better) response to amphetamine The main finding of the study is that subjects with genotype C/C at rs2281617 scored significantly higher on Euphoria and Energy than subjects with genotypes C/T and T/T after 10 mg amphetamine, and trends were also observed with measures of Stimulation and (lower) Sedation.
    * rs7442295(A;A) - ~4x higher risk for hyperuracemia <-----
    * rs2188380(A;A) - slightly higher risk for gout (tada, explains my preferance for drugs that lower urea?)
    * rs1734791(A;A) - 1.4x increased risk for lupus
    * Gs290 - You might have two short form 5-HTTLPR. (this means I have high serotonin levels?)
    * rs2547231(T;T) - Increased blood metabolite levels 5alpha-androstan-3beta,17beta-diol disulfate - 0.081 unit increase X-12850 - 0.059 unit increase X-12456 - 0.041 unit increase X-11440/4-androsten-3beta,17beta-diol disulfate 2 - 0.141 unit increase (absolutely no clue what this would or what consequences this could have, however by clicking on the snp on snpedia: https://www.snpedia.com/index.php/Rs2547231, it says the gene name is SULT2 -> https://en.wikipedia.org/wiki/Bile_salt_sulfotransferase, would this indicate low or high sulfur levels? should I start on epsom salt foothbaths again?)
    * rs2108622(C;C) - lower warfarin dosing (remember the vitamin k and nosebleeds from NAC?)
    * gs156 - NAT2 Rapid metabolizer (this is good apparantly)
    * gs269 - APOE E2/E3 Apo-ε2/ε3 in the APOE gene. Slightly lower risk of Alzheimer's disease. (good)

    ReplyDelete
  11. * gs100 - Lactose intolerance risk 77% of Europeans with this genoset are lactose intolerance It is detected by 2 genotypes
    * gs157 - More stimulated by coffee You appear to have a common genotype in the gene CYP1A2 which Drug Metabolism coffee more slowly than some other forms. The same amount of caffeine will tend to have more stimulating effect on slow metabolizers than on fast metabolizers. (allready knew this as I knew I was sensitive to genes, CYP1A2 controls this and tada this is regulated by the arylhydrocarbon receptor, slow caffeine metabolizers have more chemical sensitivities? just a thought)
    * gs282 - claimed to be part of the 12% of the population who can lose weight with any type of exercise (good)
    * gs284- any diet works for you (good)
    * rs3129934(C;C) - Normal lower risk of Multiple Sclerosis. (good)
    * rs5186(A;C) - ~1.4x increased risk of hypertension (bad)
    * rs2494732(C;C) - greater odds of cannabis-associated psychosis (bad)
    * rs776746(G;G) - CYP3A5*3 homozygote; CYP3A5 non-expressor Impacts metabolism of tacrolimus, an immunosuppressive drug used in organ transplantation. (bad)
    * rs1805009(C;G) - Red hair carrier, higher risk of melanoma (bad) - Im blonde, but I guess I have this gene, which would also explain my increased amount of sunspots/moles.

    ReplyDelete
  12. Thanks for sharing Aspie, I always wondered what kind of data you could get out of a 23andme result.

    How does this work when you are situated in Europe?

    /Ling

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    Replies
    1. Think the problems is most doctors, wont 'accept' it yet as a form of 'evidence'. However research in genetic material is rapidly evolving, I mainly did it for myself as a form of self analysis.

      Apparantly there are other websites (genetic genie I have heard?) that can give 'advice' based on your own genes, such as all the MHTF stuff n all that.


      Couple of more things confirming what I suspected:

      * rs7501331(C;T) - Reduced conversion of beta-carotene to retinol Reduced BCMO1 activity results in 32% lower ability to convert Beta-carotene to retinyl esters and higher serum beta-carotene levels. See also rs12934922 (remember Peter's post about RORA which is needed for cd38 related oxytocin production?)

      And here we go with my negative vitamin k2 reaction:

      * rs9923231(C;T) - reduced warfarin dose if treated for VTE - Several SNPs in the VKORC1 gene have been linked to warfarin sensitivity, with perhaps the most common being this SNP rs9923231. Note that the orientation as published in scientific articles is often on the opposite strand compared to the orientation in dbSNP, so you will sometimes see it as a G>T snp.

      * rs12934922(A;T) - Reduced conversion of beta-carotene to retinol Associated with Rs7501331 and reduced BCMO1, lower ability to convert beta-carotene to retinyl esters and higher serum beta-carotene levels. See also Rs7501331

      * rs2236624(C;C)- Association between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety. Adenosine A(2A) receptor gene (ADORA2A) variants may increase autistic symptoms and anxiety in autism spectrum disorder.

      See: https://www.ncbi.nlm.nih.gov/pubmed/19565319?dopt=Abstract
      "Nominal association with the disorder was observed for rs2236624-CC" <<-----

      * rs3780412(A;G) -
      Association testing of the positional and functional candidate gene SLC1A1/EAAC1 in early-onset obsessive-compulsive disorder. Association of the SLC1A1 glutamate transporter gene and obsessive-compulsive disorder. A haplotype containing quantitative trait loci for SLC1A1 gene expression and its association with obsessive-compulsive disorder. Family-Based Association Testing of OCD-associated SNPs of SLC1A1 in an autism sample. Polymorphisms in the glutamate transporter gene SLC1A1 and obsessive-compulsive symptoms induced by second-generation antipsychotic agents.

      * rs167771(A;A) - Possibly more "Insistence on Sameness" on ADI-R test. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324694/ Possibly increased FTND nicotine dependence. http://www.ncbi.nlm.nih.gov/pubmed/22309839?dopt=Abstract
      rs167771 was significantly associated with autism spectrum disorder in a study of 144 patients. G allele associated with increased extra-pyramidal symptom risk as a result of risperidone treatment in a study of 321 psychiatric inpatients (81 presenting with EPS and 189 without)

      * rs4307059(C;T) - 1.19x risk of Autism Slightly increased risk of Autism due to worse brain cell adhesion.
      23andMe blog rs4307059— compared to two copies of a C, each copy of the more common T version increased the odds of autism by 1.19 times. http://dx.doi.org/10.1038/nature07999

      Delete
    2. Hi all, My 23andme results are back. I'm in England and the process was easy enough, the test came in a box to post it to Amsterdam (I think, forgotten already) for processing. Took about 5 weeks. So far I'm using codegen.eu to look at the results, these are some of the snps it is highlighting.
      Aspie2

      rs1800460(A;G) bad:4.77 2.52%(rare) (TPMT*3B) impaired drug metabolism
      rs1800460 is a SNP in the TPMT gene, potentially encoding a variant incapable of detoxifying byproducts of certain antineoplastic and immunosuppressant drugs. ...

      rs3135391(C;T) bad:4.50 HLA-DRB1*1501 carrier; higher multiple sclerosis risk

      rs10490924(T;T) bad:4.23 8.21% 8.2x risk for age related macular degeneration

      rs3135388(C;T) bad:4.05 3x higher risk of multiple sclerosis [another!]

      rs1142345(A;G) bad:3.93 7.52% TPMT*3C . impaired drug metabolism ... [combines with earlier one, hope i don't need to take those drugs!]

      rs1421085(C;C) bad:3.90 5.23% ~1.7x increased obesity risk

      rs1801282(G;G) bad:3.87 0.49%(rare) watch out for high fat in diet
      rs78378222(A;C) bad:3.61 0.52%(rare) cancer risk


      rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10?17). rs78378222 is in the 3? untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, ...

      gs191 bad:3.60 problem metabolizing NSAIDs
      impaired NSAID drug metabolism ...

      rs10830963(G;G) bad:3.57 6.77% increased type-2 diabetes risk; ...

      rs2305480(T;T) bad:3.54 8.22% if 4 years old or younger, ~3x increased asthma risk if exposed to smoke ...

      rs9939609(A;A) bad:3.46 11.56% obesity risk and 1.6x risk for T2D
      This genotype produces higher levels of the appetite-stimulating hormone ghrelin ...

      Delete
    3. And some more ...
      Aspie2

      gs161 info:3.44 CYP2C9 Intermediate Metabolizers

      CYP2C9 intermediate metabolizers are 30% of the population. May require slightly different dosages for drugs such as tamoxifen, warfarin, fluvastin, and many nsaids ...

      rs664143(T;T) bad:3.41 13.82% Higher risk for number of cancers ...

      rs2236225(T;T) bad:3.38 11.69% Slightly (~1.5x) higher risk for Caucasian mothers to give birth to NTD children [male, so not likely to give birth! but is this folate? See later]

      gs127 info:3.22 Intermediate warfarin metabolizer
      Approximately 30% of people are intermediate metabolizers of the popular anticoagulant Warfarin and would probably need a decreased dosage. ...

      rs4762(C;T) bad:3.02 18.26% 1.9x risk for pre-eclampsia
      rs4762, a SNP in the angiotensin II AGT gene ...

      rs780094(A;A) info:3.02 9.10% metabolic consequences ...

      rs9469220(A;G) bad:3.02 1.1x risk of Crohn's disease

      rs9469220 has been reported in a large study to be associated with Crohn's disease.

      rs9257809(A;A) bad:3.02 ; barrett's esophagus (you have the risk allele A) ...

      rs12720067(A;G) good:3.00 16.36% 7x more likely to respond to certain antidepressants ... [several others connected with this, I'll skip them]

      rs518147(C;-) info:3.01 47.25% less weight gain if taking olanzapine


      rs518147, also known as -697G/C, is a SNP in the 5-hydroxytryptamine (serotonin) receptor 2C HTR2C gene ...

      rs6974491(A;A) warning:2.98 0.73%(rare) Higher risk of coeliac and/or inflammatory bowel disease ...

      rs1260326(T;T) warning:2.79 8.60% slightly higher risk for gout
      The T allele of rs1260326 has been associated with type 2 diabetes and hypertriglyceridemia. ...

      rs6311(C;C) warning:2.70 30.97% 3.6x increased risk of sexual dysfunction when taking SSRI Antidepressants. [Being single and not depressed i won't worry about this too much :-)]

      rs1801260(C;T) info:2.65 35.38% Normal risk of ADHD symptoms.

      This is one normal and one rare form of the CLOCK gene. In addition to possibly affecting evening preference, it has been linked to normal Attention Deficit Hyperactivity Disorder symptom scores.

      Delete
    4. More ...
      Aspie2

      rs762551(A;A) info:2.32 39.66% Fast Caffeine Metabolizer.

      rs53576(A;G) warning:2.31 47.55% Lack of empathy?
      You have a SNP in the oxytocin receptor which may make you less empathetic than most people. When under stress you may have more difficulty recognizing the emotional state of others ... [yep]

      rs1801133(C;T) warning:2.23 37.04% 1 copy of C677T allele of MTHFR = 60% efficiency in processing folic acid = could have somewhat elevated homocysteine and low B12 and folate levels ... [now! These could be important ...]

      rs460000(C;C) info:2.07 33.60% Better response to amphetamine
      Individuals with the C/C genotype at rs460000 (N = 83) reported approximately twofold higher ratings of stimulation and euphoria ... [haven't tried]

      rs6277(C;T) warning:2.01 36.89% 1.4x higher schizophrenia risk

      rs6277 (957C>T, Pro319Pro) is one of several SNPs in the dopamine receptor DRD2 gene. ...

      rs10239794(C;T) info:2.01 49.82% 1.3x risk for ALS

      rs2653349(A;G) warning:2.01 21.30% ~1.5x? increased risk for cluster headaches

      rs2653349, also known as G1246A, is a SNP in the HCRTR2 hypocretin-orexin gene. It has been linked primarily to cluster headaches.

      rs4648317(C;T) info:1.79 34.33% prone to higher nicotine dependence?

      rs2298383(C;C) info:1.78 35.93% increased anxiety in response to caffeine

      rs7076156(A;A) info:1.74 1.66%(rare) associated with Crohn's disease

      rs4680(A;G) info:1.70 46.58% multiple associations, see details [balance of worrier and warrior]

      rs4570625(G;G) info:1.46 41.93% maybe: higher scores on anxiety-related personality traits; greater placebo response

      rs1328674(A;G) info:1.30 9.88% higher risk for RA
      rs1328675 is part of a 4-SNP haplotype in the serotonin 2A receptor ...

      rs167771(A;A) info:1.10 34.65% Possibly more "Insistence on Sameness" on ADI-R test. Possibly increased FTND nicotine dependence. [Ahhh, sameness. Lovely repetition!]

      rs4565946(C;T) info:0.25 40.59%

      rs4570625 and rs4565946 linked to the pathogenesis of early-onset obsessive compulsive disorder

      rs2070744(C;C) info:0.08 5.50% increased prostate cancer risk
      The NOS3 gene encodes nitric oxide synthase 3, and is also known as eNOS; [eNOS bit sounds good, not so keen on the prostate cancer part]

      rs37369(C;C) info:0.00 36.78% ; urinary metabolite measurement (you have the risk allele C) ... "Elevated levels of BAIB have been suggested to contribute to neurological and developmental problems" ...

      rs6280(T;T) info:0.00 26.38% normal
      rs6280, also known as Ser9Gly, is a SNP in the dopamine receptor D3 DRD3 ...

      I included too many common snps that lots of people have there (the % number after the good/ bad/ info number) but it gives an idea what is there. I thought i had 2 problems with MTHFR but it looks like i misread one of them, so maybe it's just "average" rather than "bad". Plenty of food for thought anyway.

      Delete
    5. Help me remind that I get back to you, my 23andme data has a strong overlap with urs, including the crohn's disease SNP's and arthritis one (5ht2a) and oxytocin one.

      Seems that arthritis is more common in aspergers too.

      Delete
  13. Peter, did you try Gaba after bumetanide? do you think that could help now?I tried it before with no success.
    Valentina

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    Replies
    1. Valentina, I tried Picamilon and it had a negative effect very quickly. Picamilon is GABA plus niacin and it does cross the blood brain barrier where it releases GABA. Oral GABA does not cross the BBB very easily.

      Delete
  14. I am a bit confused at the moment. It looks like that for a lot of "correct" interventions I am trying lately, I get the same negatives.

    Assuming that I have a decent view of the genetic dysfunctions I am dealing with, a lot is pointing at hypofunctioning NMDArs. There is nothing obvious going wrong with the GABA-system, at least not genetically.

    So, without intervention, we experience A LOT of hairpulling. But with intervention (targeting either the source problem or hypo NMDAr) we suddenly see toe walking and handflapping. Why?

    The easy answer would be that we are doing interventions in the wrong direction / treating hypo instead of hyper. But I really don't think so.

    So what is going wrong?
    Could it be possible that the KCC2 transporter was damaged by hypo NMDA from the beginning? And now, when I treat hypo NMDA and get "normal" NMDA signalling I still have damaged GABA so the net result is even more excitotoxicity?

    Or can it be that when upregulating NMDA function, I will have to wait a while for GABA system to readjust accordingly?

    Or a third possibility: I am overtreating hypo NMDA signalling and instead get hyper NMDA which shows up with a different behaviour?

    Anyone with insights on what different causes can be behind handflapping/toewalking VS hairpulling?

    It's clearly not easy to answer my questions, but clever guessing is very welcome. When I get this sorted out, I am sure there will be some very interesting findings.

    /Ling
    /Ling

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    Replies
    1. Choreas are a symptom of Huntington's disease and one main hypothesis is that this type of symptom is due to damage from the medial globus pallidum and/or substantia nigra pars reticulata which are the main basal ganglia output structures that keep the thalamus from going into overdrive. These output neurons are GABAergic so if GABA is not being expressed at the synapse or else if there are not enough postsynaptic receptor or else if there is a lesion to the axons, then these kinds of symproms have been shown to occur in various animal studies.

      With autism the answer could be all of the above as there are plenty of studies showing basal ganglia dysfunction, GABAergic signalling issues, as well as white matter anomalies in the basal ganglia and across the brain.

      With that in mind I would assume all hypotheses are true and rule them out one by one. Probably not the answer you want to hear, but I don't think there is a silver bullet here.

      Delete
    2. Thank you Tyler for taking your time to share your insights! As it looks, I will need more than one silver bullet in my armory to get anywhere.
      I have to doublecheck this, but I actually think I had more success with Ponstan (mild GABA pam among other things) + D-serine for hairpulling than without Ponstan.
      Ah, more investigation needed!
      /Ling

      Delete
  15. As I am sure everyone know by now the CDC (USA) has raised the ratio of those diagnosed with autism from 1 in 68 to 1 in 59 which was a surprise considering the rate if diagnosis had been steady for about the last 8 years.

    One interesting idea I had with respect to everything we know about MIA (maternal immune activation) models of autism is new research on the so-called hygiene hypothesis:

    Press Release:

    https://www.sciencedaily.com/releases/2018/04/180430160419.htm

    In this research they found increased levels of inflammatory IL-6 and decreased levels of anti-inflammatory IL-10 in people who grew up in urban environments without pets. In other words, if you are exposed to a sterile environment in your youth, you will grow up with low-grade chronic inflammation as an adult and be more susceptible to exaggerated immune responses as you have in asthma and allergies. So if girls are encouraged to stay indoors in an environment without pets and which is excessively clean, they may grow up to have inflammation issues during pregnancy when they are older.

    So under this hypothesis if a society has a big migration from rural to urban living you want see inflammation driven diseases in utero for another generation at least.

    Maybe in addition to increased diagnosis and awareness of autism, the rates of autism and obesity as well which has a lot of evidence suggesting low-grade chronic inflammation being the culprit, may continue to increase as children nowadays are more sedentary and urban as ever, as are their parents.

    ReplyDelete
  16. Very interesting on mannitol (both medicine and sweetener)

    Came accross a link on longecity showing the use of mannitol for parkinson disease:

    http://www.outthinkingparkinsons.com/articles/mannitol

    _______

    Turns out, mannitol has several modes of action in parkinson models and it is actually used by people.

    On top of that it:

    Injection of hypertonic saline or mannitol accelerates the dehydration-induced activation of dopamine synthesis in the neurointermediate lobe of the rat hypophysis

    https://www.ncbi.nlm.nih.gov/pubmed/6818486

    " DOPA accumulation in the NIL was also increased after an intravenous infusion of mannitol (25 ml 20% mannitol/kg) plus 24 h of water deprivation. These results suggest that the dehydration-induced activation of tuberohypophyseal DA neurons which is normally seen after 2-3 days of water deprivation can be accelerated if water deprivation is preceeded by injections of hypertonic saline or mannitol."

    Now as I was interested in mannitol it turns out that mannitol is an osmotic diuretic:
    https://en.wikipedia.org/wiki/Osmotic_diuretic

    Just google: 'mannitol oxytocin' or 'mannitol vasopressin'
    You will find that literally every study (also alot of hospitalized settings on humans), shows it potentiates oxytocin release by affectings.

    Osmoregulation of vasopressin and thirst: comparison of 20% mannitol with 5% saline as osmotic stimulants in healthy man.
    https://www.ncbi.nlm.nih.gov/pubmed/7923825

    "CONCLUSIONS: Twenty per cent mannitol infusion is an effective osmotic stimulant to thirst and vasopressin release in normal individuals, but is less potent than 5% saline infusion."

    Thermal stimulation of vasopressin and oxytocin (VP/OT) release from explants of the hypothalamo-neurohypophyseal system (HNS)
    https://www.fasebj.org/doi/abs/10.1096/fasebj.26.1_supplement.900.3

    "We used HNS explants from adult rats to study the impact of increases in temperature on stimulation of VP/OT release. Increasing the temperature from 37 to 39.5°C over 1 hr caused a dramatic increase in VP (850%) and OT (405% of basal) release (both p<0.001). Simultaneously exposing explants to a ramp increase in osmolality --->>> (25mOsm/2.6 hrs WITH MANNITOL) <<<---doubled the response to temperature alone (VP- 1780%; OT-860% of basal). Thermal stimulation of VP/OT release was significantly attenuated by combined exposure to gadolinium (100μM), a non-specific blocker of mechanosensitive channels, and capsazepine (10μM), a selective antagonist of TRPV1 channels, but not by capsazepine alone. This is consistent with other evidence that modified and capsazepine-insensitive TRPV1 and TRPV4 channels participate in thermal regulation of VP/OT release."

    Mannitol is easily accessable, considered save, why isnt this talked about before on boards.

    ReplyDelete
  17. An interesting bit of research claims that serotonin acts as a signal dampener to dopamine in the sense that serotonergic activity mutes highs and lows in terms of reward outcomes.

    Press Release:

    https://www.sciencedaily.com/releases/2018/04/180430131857.htm

    Paper:

    https://www.nature.com/articles/npp2017304

    This research focused on serotonin levels itself in the striatum of Parkinson's patients undergoing implantation of deep brain stimulators, rather than on the individual classes of receptors themselves which is a much more complicated thing to do in live human beings.

    Nevertheless, it is interesting as in a healthy brain, serotonin and dopamine are supposed to work in a yin and yang system (according to this research), and some of the acute side effects of SSRI's including blunt affect and impotence make sense with respect to this research in the sense that serotonin prevents strong responses from both positive outcomes (happiness) as well as negative outcomes (depression). In a sense this may be why many people feel like a robot or "not themselves" when on SSRI's. Long-term effects of SSRI's are another discussion entirely as many people claim to never recover from SSRI use and many people feel like they are "hooked" on them in the sense that they feel it is impossible for them to ever be happy again in their lives if they stop using SSRI medication. Many antidepressants also strongly drive dopaminergic and noradrenergic signaling as well (SNRI's), but then again so do many illegal drugs (MDMA for instance).

    Another issue with excessive serotonegic signaling may be why some people develop sociopathic behaviors in the sense that they are unable to learn from negative outcomes due to negative reward outcomes being suppressed which means when it comes to social behavior, someone using SSRI's will keep making the same social mistakes or just ignore social conventions altogether because they never "feel" bad about their actions or at least they are unable to learn from their poor behavior at least through emotional learning rather than cognitive learning.

    Another takeaway from the study suggests that serotonin also seemed to be associated with the persistence of ongoing strategies from environmental challenges (i.e. being calm under pressure). Of course, taken to an extreme this might suggest obsessive compulsive behaviors, which are a hallmark of autism itself.

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    1. Tyler,what do you think about the enhancement of striatal dopamine release by 5HT4 serotonin agonists? I thought that increasing serotonin would decrease dopamine.My son has chronic constipation, it is really an issue and AJ had suggested me black garlic,but i read that increases dopamine,could I use it or is better stay away?
      Valentina

      Delete
    2. Quite a few serotonin receptors actually increase dopamine, just like psychedelics activate d2 dopamine release (through the heterodimers of 5-HT2AR and mGluR2 receptor).

      Its not as easy as just lowering serotonin... or lowering dopamine... if it was that easy the cure for things such as depression n the whole lot would have been here decades ago. Also theres specific brain regions where you either want to decrease or increase serotonin. On top of that you have the 5ht1a autoreceptor in DRN which decreases pretty much whole brains serotonin when it gets activated.

      Delete
    3. Thanks Aspie,I knew that I was oversimplifyng,like when I keep asking about dopamine antagonists and I know the answear because the risk of tardive dyskinesia is extremelly high in my son.Maybe I am looking for a Grey zone,that is way I asked Tyler's opinion about black garlic,may be I can use it because dopamine can be low in other areas.
      Valentina

      Delete
    4. I don't know anything about black garlic with respect to dopamine. Garlic has many interesting properties, but is not selective in any way. For all I know you could have one substance that is pro-dopamine and another that is anti-dopamine just like you do with marijuana where you have THC which agonizes the mu-opioid receptors while cannabidiol agonizes kappa opioid receptors which seem to act as the ying to mu-opioid receptors yang.

      Delete
  18. Valentina, In one of your previous comments I saw that you used zinc. Zinc is a natural dopamine reuptake inhibitor.
    Do you remember how your son responded?
    I just thought this might give you a clue.
    Petra

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    1. Hi Petra, how is doing your son? there is a review article of Neural plasticity journal"Zinc in gut-brain interaction in Autism and Neurological Disorders", it shows how alterations in the maternal zinc status, systemic inflammatory events, might pathologically impact the offspring brain associated with GI disorders. I remember that he had not a bad reaction, I could try it again in low dose.
      Valentina

      Delete
  19. Tyler, does your son/kids use niagen? Any comments on that experience with that supplement?

    AJ - I hope you are ok(?)

    /Ling

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    Replies
    1. Yes he does use it (250 milligrams) pretty much every day. There is a cocktail which includes Niagen (son won't do pills/tablets) which includes Niagen in the morning as well as BCAA's, Hydrolyzed Collagen, Apigenin, Bumetanide, Potassium Gluconate, N-Acetyl-Glucosamine, Folinic Acid, P5P, Vitamin C, and a few other things. If he does not get this regimen for 3-4 days, things predictably go downhill. Missing one day or two is not the end of the world, but frustratingly every time we have stopped the regimen for whatever reason, we are quickly reminded to start it back up again.

      Other not so great tasting stuff like Agmatine and L-Aspartic Acid, I have to give separately, usually in a chocolate flavored milk drink using unsweetened cocoa, sucralose, and trehalose.

      As for experience, normal people do not need Nicotanimide Riboside because their body already produces plenty of NAD+ when they are young. However, if you suspect mitochondrial issues which can drain NAD+ reserves or else problems with NAD/NADH recycling or issues producing NAD+ directly via the kynurenine pathway, then I think Nicotanimide Riboside is one of the best, if not the best intervention. These kind of problems happen naturally as people age, so at the moment I would say you are a fool not to take it as an adult past age 30 or so if you can afford it because unless you like paying out the nose for medical bills later on, I believe NR plus other interventions can help push back the age at which your body and mind give out on you and you are the mercy of modern medicine. These are just beliefs of mine because in human beings it is problematic to do lifetime studies of people on "supplements" as opposed to a drug that people are told they have to take the rest of their life or else dire consequences will transpire (e.g. a psychiatrist scaring a patient by telling their patient they need to be on an SSRI/SNRI to keep them from relapsing into depression). Because of this the best we can do is generalize from animal research, provided the research is done on multiple types of animals and if possible primates.

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    2. Thank you Tyler, and also thanks for mentioning the other things in your daily regime because I was curious about that too!
      How would you describe the specific effects of Niagen? - I guess it is something about energy levels vs lethargy?
      My daughter has been very slow and energyless, but with a small dose broccoli powder I can see that she is starting to get some liveliness in her appearance. Just wondered if Niagen would do something similar.

      /Ling

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    3. Ling, try Agmatine if your daughter is lethargic. You have to buy it outside the EU and big US companies like iHerb may not ship it to the EU, since it is not approved.

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    4. Personally, it helps all around with skin elasticity and recovery from exercise. Improved skin elasticity is a good sign because it means other epithelial as well as endothelial tissue is likely healthier as well. There are no direct psychological or mood changes from using it. I suppose you could say it probably improves athletic performance in older people but may not do much in an elite athlete in their 20's. I do expect some athletic bodies such as the Olympic committee to ban it for this reason, though I am not sure how they would test for it because NAD+ is used in every cell in your body. In general, if your cells are under stress, more NAD+ will help them recover. Some people now take NMN (Nicotanimide Mononucleotide) to achieve the same results, but the studies using NMN I have seen all used injections. Oral NMN is available now but I don't really have any idea how effective it is relative to NR.

      NR I would expect could have a big benefit with regards to lethargy, however there are many things indpendent of NAD+ that can cause cellular energy problems so don't get your hopes up too high.

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