POISCENTER
General Category => Articles, References and Links => Topic started by: Quantum on August 28, 2016, 10:49:38 AM
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For those wondering about what cytokines, following is an explanation I hope is easy to understand. I know this post is longer than what most POISers attention span can accept, if you have brain fog as a major symptom and you are currently in POIS, but I think it will be helpful in understanding what researchers are talking about in POIS papers. I think that Dr Waldinger may refer to cytokines as part of the cause of POIS symptoms, in his future work, so this will help you understand what he is writing about. I also had written here about the role I think cytokines have in some POIS symptoms clusters, but I think I never took the time to really explain what they are, so I thought it would be a great time to do it, considering the latest review article of Dr Waldinger ( for the link to the article, see http://poiscenter.com/forums/index.php?topic=2346.0 )
You can think of cytokines as "micro-hormones", like small hormones produced at the cells level. These micro-hormones are produced by a limited number of cells at a time, in a specific region of the body, like mast cells of the prostate region, for example ( POIS-related example!). The effect of cytokines are usually short range or limited in range, meaning they will not affect the whole body, but some specific cells, usually not so far away, and not every cells of the body. In contrast, hormones are produced by a massive amount of cells grouped in a gland, and they often have long-reaching effects, and may even affect every cells in the body ( like thyroid hormones, or insulin, which is produced by the pancreas, and affect all cells in the body ). But there is no definite frontier between hormones and cytokines in current medical science, there are gray zones and exceptions. So, some cytokines can act as immune messengers that have profound effects on the whole body... which is what Dr Waldinger is proposing as part of POIS pathophysiology, now. Cytokines like interleukin-1 (IL-1), interleukin-6, or TNF-alpha ( Tumor Necrosis Factor alpha) , and many others, are powerful and have effects on the whole body even if produced in small amount. Part of this power is due to the "domino effect" that can be seen in the immune system. For example, mastocytes cells ( mast cells, a kind of white blood cells that act as immune "sentinel") can release cytokines following a reaction in a small part of the body ( for example, like maybe the case in POIS, in the prostate region), and this reaction will spread from one region of the body to another, activating other cytokines and other hormones, spreading like a wave, and also spreading through the blood stream, which will transport those cytokines/immune messengers away, like into the brain.
This rather slow progression of the cytokines "domino effect" from one group of cell to the next may explain the delay seen for POIS symptoms to be fully activated ( the survey done by the Rutgers team with members here show a mean delay of 2 to 3 hours after ejaculation before the full POIS attack has developed). This fits exactly with a "delayed hypersensitivity reaction", the type IV hypersensitivity reactions, a term Dr Waldinger was already using as a hypothesis for POIS in his 2011 article ( part 1). He said at the time that POIS seems to imply both a Type I ( immediate) and a Type IV ( delayed) hypersensitivity reaction.
It is important to note that once this spreading wave of inflammation reach the liver, a major event occurs: the liver, in reaction, produce the powerful "acute phase proteins", another type of immune messenger, including the well-known C-Reactive protein ( CRP), that will further intensify the whole body reaction ( fever, flu-like symptoms, etc). This can be detected in blood tests, directly ( CRP levels), or indirectly ( ESR, erythrocytes sedimentation rate). I mention that because it could happen that CRP and ESR blood test results could be talked about in Dr Waldinger future papers as well. They are usually high in auto-immuen diseases, so I wouldn't be surprised if he would measure them in POIS subjects during POIS attack.
The faster spreading of some symptoms, like brain fog seconds after O for some members, could be explained by a fast delivery of some specific cytokines through the blood stream to the brain ( like a morphine injection will reach the brain quite fast through the blood stream), or by a type I, immediate hypersensitivity reaction ( but that may be the same thing than fast delivery through the blood stream !). These immediate brain symptoms could also be caused by the neurotransmitters released in the brain at the time of orgasm, but that is a neurologic cause, and that would imply that POIS could be a combination of 3 types of different causes: immediate immune effects, immediate neurologic effects, and delayed immune effects. It is still too soon to discern which are really present in POIS or not.
Do not hesitate to ask questions about cytokines or the immune system, and I will do my best to come up with a valid and easy to understand answer.
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The problem is we have no CRP positive test to prove this theory. It's a very sensitive parameter and th blood test may show something during hours after ejaculation.
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Thank you very much Quantum for your effort on this subject.
Your way in explaining things is awesome !
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The problem is we have no CRP positive test to prove this theory. It's a very sensitive parameter and th blood test may show something during hours after ejaculation.
Hi b_jim,
I do hope that Dr Waldinger will do measure CRP in his new study. He has expressed the intention to find biomarkers for POIS, so this is a good candidate, but not the only one. Maybe they also did some blood tests in the Rutgers study, I don't know. But it would be great too.
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Thank you very much Quantum for your effort on this subject.
Your way in explaining things is awesome !
Thank you for your very supportive and positive comment, Jimmy, I appreciate it ! :)
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Thank you very much Quantum for your effort on this subject.
Your way in explaining things is awesome !
(http://i858.photobucket.com/albums/ab143/demografx/4818D5B1-9D9E-491A-AC17-832E089DCAB6.gif) :)
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The problem is we have no CRP positive test to prove this theory. It's a very sensitive parameter and th blood test may show something during hours after ejaculation.
Hi b_jim,
I do hope that Dr Waldinger will do measure CRP in his new study. He has expressed the intention to find biomarkers for POIS, so this is a good candidate, but not the only one. Maybe they also did some blood tests in the Rutgers study, I don't know. But it would be great too.
I hope too. But it's difficult to think he didn't do it in tth first studies. I'm not convinced by immune system theory but in the contrary case, CRP would be the first thing I've tested.
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Thanks for certainlypois for guiding to this post. This will be great to discuss Cytokines.
I have fully read what Quantum mentioned. Unfortunately it still leaves much to be asked. I feel like I can rule out brain inflammation, at least personally, as the cause of these symptoms. I can also rule out Catecholamines depletion. I don't know where to go from here. But I've read somewhere that certain Cytokines can effect certain metabolic functions like the tryptophan pathways and the kynurenine pathway. I don't know much about this metabolic cycle, so if anyone has knowledge please say.
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I think I found it: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4141874/
It says:
"Data indicate that cytokines and their signaling pathways including p38 mitogen activated protein kinase have significant effects on the metabolism of multiple neurotransmitters such as serotonin, dopamine and glutamate through impact on their synthesis, release and reuptake. Cytokines also activate the kynurenine pathway which not only depletes tryptophan, the primary amino acid precursor of serotonin, but also generates neuroactive metabolites that can significantly influence the regulation of dopamine and glutamate."
I'm a bit confused though, and this is where my medical knowledge fails me. Can cognitive symptoms in POIS be caused by down-regulation of glutamate? Is the activation of the kynurenine pathway responsible of this down-regulation?
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Thanks for certainlypois for guiding to this post. This will be great to discuss Cytokines.
I have fully read what Quantum mentioned. Unfortunately it still leaves much to be asked. I feel like I can rule out brain inflammation, at least personally, as the cause of these symptoms. I can also rule out Catecholamines depletion. I don't know where to go from here. But I've read somewhere that certain Cytokines can effect certain metabolic functions like the tryptophan pathways and the kynurenine pathway. I don't know much about this metabolic cycle, so if anyone has knowledge please say.
Hi Nas,
About the tryptophan pathway, and the kynurenine pathway, and their possible role in POIS, you an see some explanation in this thread:
http://poiscenter.com/forums/index.php?topic=1988.msg15559#msg15559
I also recommend you study this diagram carefully ( it is presented in the thread just above):
http://fr.slideshare.net/adonissfera/tryptophan-and-madness/17-Cytokines_Come_in_Two_FlavorsProInflammatory
You can also read here, about the kynurenine pathway, and the role of IDO and TDO in my hypothesis ( put in perspective in an overall hypothesis on POIS physiopathology I described some years ago): http://poiscenter.com/forums/index.php?topic=2078.msg16431#msg16431
If you dig about the kynurenine pathways and tryptophan pathway, you will find why I have developed interest for natural TDO inhibitors, and IDO inhibitors, and are using them.
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Thanks Quantum, I've read it quite well, though I never really understood why kynurenic acid causes brain fog? Is it because of the depletion of tryptophan?
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Yes. More and more doctors think depression is mainly a problem of inflamation by this pathway .
You made a very good job.
But we know that semen is rich on serotonin, melatonin and tyrotropin releasing hormone enough to affect positively women (an negatively men?)
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Thanks Quantum, I've read it quite well, though I never really understood why kynurenic acid causes brain fog? Is it because of the depletion of tryptophan?
Hi Nas,
In addition to what B_jim said about taking away tryptophan form serotonin synthesis, kynurenic acid becomes toxic on its own when too hign level in the brain , see https://en.wikipedia.org/wiki/Kynurenic_acid#Role_in_disease ( encephalitis-like symptoms, confusion, etc...)
Kynurenic acid, by acting as a powerful NMDAr inhibitor, slows down the brain, so my hypothesis is that it it responsible for cognitive impairments in POIS ( slow thinking, cognitive issues, speech impairment, problem solving capacities decreased,...). I do not have these symtpoms, but lots of emotional symptoms, that, in my hypothesis, are linked to quinolinic acid, another branch in the kynurenins pathways. For most POISers, it seems that they get symptoms from both of these branches, kynurenic acid and quinolinic acid production.
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Quantum,
So it says it blocks glycine site NMDA receptors, so it decreases glutamate neurotransmission. But I don't understand its connection with schizophrenia; it says that it increases dopamine fire rate in midbrain, yet I can swear that POIS is more of a decrease in dopamine function. Until now no POISer reported POIS caused psychosis.
On the other hand what are the therapeutic options in this case? NMDAr agonists? Increase glutamate production? Supplementing for lost tryptophan?
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Quantum,
So it says it blocks glycine site NMDA receptors, so it decreases glutamate neurotransmission. But I don't understand its connection with schizophrenia; it says that it increases dopamine fire rate in midbrain, yet I can swear that POIS is more of a decrease in dopamine function. Until now no POISer reported POIS caused psychosis.
On the other hand what are the therapeutic options in this case? NMDAr agonists? Increase glutamate production? Supplementing for lost tryptophan?
Hi Nas,
what interest me more in the effect of kynurenic acid is the confusion and encephalite-like symptoms, showing that POIS could be a temporary, milder form of these brain problems. NMDAr is slowing down brain activity, that'S the key point. So, in my hypothesis, I see this a a continuous spectrum, but serious and chronic mental condition like psychosis would be at the other end of the spectrum.
if you look in the diagram at https://fr.slideshare.net/adonissfera/tryptophan-and-madness/17-Cytokines_Come_in_Two_FlavorsProInflammatory , see, on the bottom, that a raise in KYNA (kynyrenic acid), through the action of KYN, is shown to first produce u follow the arrows, you see that these cognitive deficits combined with emotional symptoms like depression, anxiety and impulsivity, lead to more severe conditions. Chronic mood disorders, for example, appears to me as very common among our members.
Supplementing for tryptophan is sure a good idea, and I do it as well, because it applies as well to the other branch of the kynurenine pathways,the quinolinic acid pathway ( the one I think I suffer from and causes me much emotional symptoms). I eat some pumpkin seeds every day, for example. I also avoid too much BCAA ( branched chain amino-acids), which compete with TRP for ontering the brain ( same molecular transporte thourgh the BBB).
For me, having no cognitive symptoms, and much anxiety and emotional symptoms, I use NMDAr blockers, but I guess that someone having cognitive issues may test some safe and natural NMDAr antagonists, like huperzine-A ( actually, some members had results with it for cognitive symptoms.... I cannot say, since I have absolutely zero cognitive symptoms, so cannot test this).
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For me, having no cognitive symptoms, and much anxiety and emotional symptoms, I use NMDAr blockers, but I guess that someone having cognitive issues may test some safe and natural NMDAr antagonists, like huperzine-A ( actually, some members had results with it for cognitive symptoms.... I cannot say, since I have absolutely zero cognitive symptoms, so cannot test this).
You mean NMDA receptor agonists? Antagonists seem to do the opposite of what we want it to do.
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I'm quite sure to have low tryptophan blood level but not especially during Pois episode. Sometimes I try to reduce or stop dairy products and I feel my mood go down and problems to sleep.
I have bought pumpkins seeds with carbohydrates at 5 o' clock and I really seems to improve my sleep.
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For me, having no cognitive symptoms, and much anxiety and emotional symptoms, I use NMDAr blockers, but I guess that someone having cognitive issues may test some safe and natural NMDAr antagonists, like huperzine-A ( actually, some members had results with it for cognitive symptoms.... I cannot say, since I have absolutely zero cognitive symptoms, so cannot test this).
You mean NMDA receptor agonists? Antagonists seem to do the opposite of what we want it to do.
Just want to mention this question again, don't we need NMDAr agonists to counteract the effect of Kynurenic activation?
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For me, having no cognitive symptoms, and much anxiety and emotional symptoms, I use NMDAr blockers, but I guess that someone having cognitive issues may test some safe and natural NMDAr antagonists, like huperzine-A ( actually, some members had results with it for cognitive symptoms.... I cannot say, since I have absolutely zero cognitive symptoms, so cannot test this).
You mean NMDA receptor agonists? Antagonists seem to do the opposite of what we want it to do.
Just want to mention this question again, don't we need NMDAr agonists to counteract the effect of Kynurenic activation?
Sorry Nas, I am on vacations right now and just saw your post.
You are right, I meant NMDAr agonists. ( and huperzine is not one of these, its cognitive enhancing properties come from the inhibition of acetylcholinesterase, so it boosts acetylcholine activity)
So, natural NMDR agonists would be glutamate/glutamic acid, D-Serine and glycine .
It seems that glycine have shown some positive effect on cognition (https://examine.com/supplements/glycine/ ), and D-Serine too , https://examine.com/supplements/d-serine/ .
I do not know if anyone as ever tried those for POIS cognitive symptoms. I did not dig this kynurenic acid subject a lot, since I do not have cognitive symptoms. But I have found some interesting references, like https://en.wikipedia.org/wiki/Kynurenic_acid#Role_in_disease ,and https://examine.com/topics/nmda-neurotransmission/.
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Sorry Nas, I am on vacations right now and just saw your post.
You are right, I meant NMDAr agonists. ( and huperzine is not one of these, its cognitive enhancing properties come from the inhibition of acetylcholinesterase, so it boosts acetylcholine activity)
So, natural NMDR agonists would be glutamate/glutamic acid, D-Serine and glycine .
It seems that glycine have shown some positive effect on cognition (https://examine.com/supplements/glycine/ ), and D-Serine too , https://examine.com/supplements/d-serine/ .
I do not know if anyone as ever tried those for POIS cognitive symptoms. I did not dig this kynurenic acid subject a lot, since I do not have cognitive symptoms. But I have found some interesting references, like https://en.wikipedia.org/wiki/Kynurenic_acid#Role_in_disease ,and https://examine.com/topics/nmda-neurotransmission/.
Thank you Quantum for your insight, and hope it was a happy vacation.
So about glutamate/glutamic acid, D-Serine and glycine, what are the therapeutic options for these compounds medicinally? It doesn't seem like these compounds are much available as medicine and I'm not sure about how to supplement for them.
Another question I have is that, does this only apply on the glycine site? and not other sites? Also wouldn't NMDAr antagonist opioids be bad for us then?
Thanks again Quantum, hope that this will get us somewhere.
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From wiki: https://en.wikipedia.org/wiki/Quinolinic_acid
"The fact that NMDA receptor antagonists possess antidepressant properties suggests that increased levels of quinolinic acid in patients with depression may overactivate NMDA receptors.[11] By inducing increased levels of quinolinic acid in the cerebral spinal fluid with interferon α, researchers have demonstrated that increased quinolinic acid levels correlate with increased depressive symptoms."
This is interesting, so kynurenic acid blocks glycine site NMDA receptors, yet quinolinic acid overactivates it? How would I then have them both increased? Shouldn't I be afraid that agonizing the NMDAr would induce depressive properties? That seems paradoxical a bit.
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So do you guys think Quinolinic acid serum level have any meaning in POIS? When should this be measured?
https://drive.google.com/file/d/1nLgk-A7TpkU1k7Z3GTeH9kPrR3siqKcW/view
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So do you guys think Quinolinic acid serum level have any meaning in POIS? When should this be measured?
https://drive.google.com/file/d/1nLgk-A7TpkU1k7Z3GTeH9kPrR3siqKcW/view
Not just Quinolinic acid, Kynurenic acid and tryptophan also. Since brain symptoms last the whole week, it's safe to make the test anytime after orgasm for about 3 days or so. I think the worst the brain symptoms are, the best it would be to make the test.
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Quantum! You're getting us intrigued :/
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I wonder how Dexamethasone works for this theory, probably by anti-oxdizing pro-inflammatory Cytokines.
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But I have found some interesting references, like https://en.wikipedia.org/wiki/Kynurenic_acid#Role_in_disease ,and https://examine.com/topics/nmda-neurotransmission/.
I pulled all repleys from last year in my quote ;D
Hmm, tick born teory is
https://en.wikipedia.org/wiki/Kynurenic_acid#Role_in_disease allways somwhere oround here , posible damage from one tipe of enchepalitis in some of us( cant forget tick bite in testicle).
I had a tick bite in ... penis not long before the symptoms have started. Need to revisit the Lyme disease topic here on the forum.
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Quantum! You're getting us intrigued :/
We're getting even more intrigued Quantum!
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Quantum! You're getting us intrigued :/
We're getting even more intrigued Quantum!
Ok ok ok, how much do I pay to join The Intrigued Club?
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Quantum! You're getting us intrigued :/
We're getting even more intrigued Quantum!
Ok ok ok, how much do I pay to join The Intrigued Club?
It's free! Just ask Quantum a question that'll take an entire month for him to answer and you're in!
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From wiki: https://en.wikipedia.org/wiki/Quinolinic_acid
"The fact that NMDA receptor antagonists possess antidepressant properties suggests that increased levels of quinolinic acid in patients with depression may overactivate NMDA receptors.[11] By inducing increased levels of quinolinic acid in the cerebral spinal fluid with interferon ?, researchers have demonstrated that increased quinolinic acid levels correlate with increased depressive symptoms."
This is interesting, so kynurenic acid blocks glycine site NMDA receptors, yet quinolinic acid overactivates it? How would I then have them both increased? Shouldn't I be afraid that agonizing the NMDAr would induce depressive properties? That seems paradoxical a bit.
Hi Nas, sorry for the delay, but as I have said in my previous post, I was on vacations, and just got back yesterday to do on return. Whenever you have a question for me, please be patient, it will usually takes far less than one month before I get back to you ;)
About what you see as a paradox, I refer you again at the diagram I have linked to my January 2015 post, at http://fr.slideshare.net/adonissfera/tryptophan-and-madness/17-Cytokines_Come_in_Two_FlavorsProInflammatory . If you look carefully, you will see that the 2 kynurenine pathways tryptophan is shunt to happen in two different cell types:
the KMO enzyme leading to quinolinic acid is active in the microglia and produces quinolinic acid, and causes emotional symptoms
and the KAT enzyme is present in the astrocytes, leading to kynurenic acid production, and cause cognitive symptoms
so, 2 different cell types, having a different distribution in the brain.
both enzymes, KMO and KAT, have kynurenine as substrate ( = "input" substance).
Back in 2015, I search a lot to find natural KMO inhibitor, which would have been great to test my hypothesis on quinolinic acid causing my emotional symptoms , but did not find any ( KAT inhibitor were not interesting for me since I have no cognitive symptoms). So, I then went back up in the chain and decided to work on blocking TDO and IDO, so there would be less tryptophan turned into kynurenine, so less substrate available for KMO and KAT, to turn TRP in QUIN or kynureninc acid, as explained above.
This worked for me, in addition to all other substance in my pre-pack and with my overall method, as described in detail in my detailed post on that subject, so I stayed at that.
My hypothesis have still many questions attached to it, but not a lot of discussions have followed my presentation of it on the forum, in 2015, so many stones have been left unturned. I had read dozens and dozens of scientific articles around this subject, 4 years ago, but not since. I am not an expert on this topic, so I cannot answer all questions about this. I just see that my method works for me, and it may be in part because it helps tryptophan not to be changed in kynurenine, and then in too much quinolonic acid (and too much kynurenic acid, but this is not of concern in my case).
I hope this will help you get further in your own research, Nas .
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So do you guys think Quinolinic acid serum level have any meaning in POIS? When should this be measured?
https://drive.google.com/file/d/1nLgk-A7TpkU1k7Z3GTeH9kPrR3siqKcW/view
Hi Muon,
I feel it would be a loss of money, because the serum value will say nothing about what is happening in the microglia ( for quinolinic acid) and in the astrocytes ( for kynurenic acid), in the brain, behind the blood brain barrier.
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Hi Nas, sorry for the delay, but as I have said in my previous post, I was on vacations, and just got back yesterday to do on return. Whenever you have a question for me, please be patient, it will usually takes far less than one month before I get back to you ;)
Hope you know I was joking.
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Hi Nas, sorry for the delay, but as I have said in my previous post, I was on vacations, and just got back yesterday to do on return. Whenever you have a question for me, please be patient, it will usually takes far less than one month before I get back to you ;)
Sorry I might've been inpatient, I get frustrated when I waste time not fighting against this curse.
About what you see as a paradox, I refer you again at the diagram I have linked to my January 2015 post, at http://fr.slideshare.net/adonissfera/tryptophan-and-madness/17-Cytokines_Come_in_Two_FlavorsProInflammatory . If you look carefully, you will see that the 2 kynurenine pathways tryptophan is shunt to happen in two different cell types:
the KMO enzyme leading to quinolinic acid is active in the microglia and produces quinolinic acid, and causes emotional symptoms
and the KAT enzyme is present in the astrocytes, leading to kynurenic acid production, and cause cognitive symptoms
so, 2 different cell types, having a different distribution in the brain.
both enzymes, KMO and KAT, have kynurenine as substrate ( = "input" substance).
Thanks Quantum, makes perfect seance but since I have depression and pure OCD I don't know if agitating NMDAr would be a good idea, we'll see.
Back in 2015, I search a lot to find natural KMO inhibitor, which would have been great to test my hypothesis on quinolinic acid causing my emotional symptoms , but did not find any ( KAT inhibitor were not interesting for me since I have no cognitive symptoms). So, I then went back up in the chain and decided to work on blocking TDO and IDO, so there would be less tryptophan turned into kynurenine, so less substrate available for KMO and KAT, to turn TRP in QUIN or kynureninc acid, as explained above.
Nanna recently proposed NAD+ as a good IDO inhibitor, maybe this would be a better test then Glycine.
So about NMDAr agonists, there is a guy in FB who tried Glutamic acid and it didn't work for him, I wonder since Kyneurenic acid is a glyicne site antagonist, won't glutamate be effective on NMDAr in this case?
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I saw that when I read about kynurenic acid and all the rest, but never found any reference stating that glutamate was helping cognitive functions, and many references states its excitotoxic properties, so I am not a fan of glutamate. And, for years, I have stayed away of anything containing monosodium glutamate ( MSG), as it is not healthy for the brain.
However, you can find many reference stating that D-serine, which is a glycine derivative substance, does help cognitive functions: https://examine.com/supplements/d-serine/ . Phosphatidylserine is proven to help as well ( https://examine.com/supplements/phosphatidylserine/) , and lecithin is a very cheap source of it ( there is lecithin in eggs....would that be what is helping Bulbo and others who are getting better with one or more eggs a day ? )
When it comes to IDO inhibitors, my favorite is rosmarinic acid ( which I take from rosemary essential oil, one or 2 drops in a glass of water) . . A high quality, organic rosemary oil is rather cheap here, and will last a long time, as I use it 2 drops at a time.
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Thanks Quantum,
For now I've ordered Glycine powder, we'll see if it does the trick.
About lecithin, I tried sunflower lecithin but it did nothing as I recall.
I also tried rosemary extract way when I first joined this forum and saw your post about IDO/TDO inhibitors. It also did nothing.
I think taking more direct action supplements for me is better, because if they didn't work, I can scratch them off and move on to a new theory.
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Hi Quantum,
I wonder how effective are Cox-2 inhibitors on IDO suppression? I personally had zero success with NSAID's so I'm looking forward for your response.
Thanks.
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Hi Quantum,
I wonder how effective are Cox-2 inhibitors on IDO suppression? I personally had zero success with NSAID's so I'm looking forward for your response.
Thanks.
NSAIDS are not part of my pre-pack, but some initial versions of my pack had ibuprofen in them. Because of stomach irritation effect, I have chosen not to include it as a "regular" member of my pre-pack. I prefer using turmeric and rosemary essential oil as IDO inhibitor, in addition to TDO inhibitors too.
And, I eat some pumpkin seeds every day, to sustain good tryptophan levels. For tryptophan, I also have 5-HTP in my pre-pack, which is the direct precursor of serotonin and of course a source of tryptophan, and the green tea in my pre-pack help lower the peripheral metabolism of 5-htp, so more of it make it to the brain. More Trp in the brain helps if much of it have been shunt to the kynurenine pathway ( some new Trp is needed to resume serotonin synthesis and rebalance things, in my hypothesis ).
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Yes but I have tried them personally many times and they don't seem to work, that's problematic since they're supposed to down regulate IDO.
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I I take only rosemary and curcumin, and a few others, it would not work, I need my whole pre-pack to have a real protection.
Maybe you could try adding different things together, that you think may help you, if no single supplement seems to do the job. I see POIS like a multi-headed beast, so it calls for action on different pathways at the same time. That is how I reached some results. It toolk a few months of adding and subtracting and testing, but it lead to something effective.
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Quantum I'm strictly talking about NSAID not the supplements.
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So do you guys think Quinolinic acid serum level have any meaning in POIS? When should this be measured?
https://drive.google.com/file/d/1nLgk-A7TpkU1k7Z3GTeH9kPrR3siqKcW/view
Actually B3 levels after orgasm would be a very good indicator of the validity of this theory.
Isn't it crazy that no one actually tested their B3 levels in this form, yet?
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Quoted from Nanna on the topic of kynurenic acid:
Here is some background information that might help you with the kynurenine pathway:
Glutamate (excitation) and GABA (inhibition) act as on/off switches for neurons. When the neuron is on (glutamate-NMDA) there is increased energy consumption and NAD+/NADH cycling. When the neuron is turned off (GABA) energy is conserved and there is very little cellular activity.
The main purpose of the kynurenine pathway is to produce niacin and ultimately NADH and NADPH (Ref (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252326/figure/F1/)). NADH and NADPH are a key energy redox antioxidants that allow the body to used calories as energy (ATP). NAD+ is also a required cofactor along with poly(ADP-ribose) polymerase-1 (PARP-1) for DNA repair. But if there is too much DNA damage then PARP-1 will consume and deplete NAD+, which depletes the energy of the cell/neuron and kills it. For example:
Blockade of PARP activity attenuates poly(ADP-ribosyl)ation but offers only partial neuroprotection against NMDA-induced cell death in the rat retina. (https://www.ncbi.nlm.nih.gov/pubmed/16903875)
As long as everything is normal in a neuron/cell, then the kynurenine pathway is only producing niacin/NAD as the end-product. However, there are several ways that the neuron can detect DNA damage. If a small amount of DNA damage occurs then NAD+ is consumed by PARP-1 (https://en.wikipedia.org/wiki/PARP1) to repair DNA. But if a large amount of DNA damage is suddenly detected, the cell goes into safe-mode by shutting down cellular activity (block NMDA, reduce PARP-1 activity, and increase GABA). This is partially accomplished by diverting kynurenine metabolism away from niacin production and into kynurenic acid. Kynurenic acid then blocks cellular activity by blocking glutamate receptors (NMDA, AMPA, etc...) (Ref (https://en.wikipedia.org/wiki/Kynurenic_acid#Mechanism_of_action)). The increase in kynurenic acid prevents further DNA damage and stress induced toxicity.
Kynurenic acid production is a safety-switch in the kynurenine pathway to prevent DNA damage and cell death. The side-effect of this is that it prevents DNA damage by shutting down the neuron (inhibiting glutamate receptors) so that it is no longer excited/firing (brain fog). Kynurenic acid prevents excitotoxicity at the expense of cognition. If you want to decrease kynurenic acid and brain fog, you should answer the question, "Why is there an increase in DNA damage?" Different stressors (cancer, infection, poison, emotional stress) can cause DNA damage. So I do not consider kynurenic acid a cause of anything, but rather it is a safety-reaction to a cause.
The true cause of brain fog is likely something that has nothing to do with the kynurenine pathway, but the body uses changes in the kynurenine pathway to prevent irreversible DNA damage. You can always recover from kynurenic acid induced brain fog, but you cannot recover from neuron loss (brain cell death) due to DNA damage.
In terms of autoimmune diseases, "N-acetylcysteine (NAC) treatment significantly reduced kynurenine levels relative to placebo in vivo" -Comprehensive metabolome analyses reveal N-acetylcysteine-responsive accumulation of kynurenine in systemic lupus erythematosus: implications for activation of the mechanistic target of rapamycin (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559110/)
Sure you can share that explanation. If you do, you may also want to share this quote:
"Kynurenic acid shows neuroprotective properties. (Ref12 (https://link.springer.com/referenceworkentry/10.1007%2F978-1-4614-5836-4_92)) Some researchers have posited that the increased levels found in cases of neurological degradation is due to a failed attempt to protect the cells. (Ref13 (http://publicatio.bibl.u-szeged.hu/8818/1/Zadori2009bjav%20Kyn..pdf))" -Kynurenic acid: Role in disease (https://en.wikipedia.org/wiki/Kynurenic_acid#Role_in_disease)
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Some of us do feel better on a ketogenic diet:
https://en.wikipedia.org/wiki/Kynurenic_acid#Link_to_ketogenic_diet
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From wiki:
KYNA has been proposed to act on four targets:
As an antagonist at ionotropic AMPA, NMDA and Kainate glutamate receptors in the concentration range of 0.1-2.5 mM.[2]
As a noncompetitive antagonist at the glycine site of the NMDA receptor.
As an antagonist of the α7 nicotinic acetylcholine receptor.[3] However, recently (2011) direct recording of α7 nicotinic acetylcholine receptor currents in adult (noncultured) hippocampal interneurons by the Cooper laboratory [4] validated a 2009 study [5] that failed to find any blocking effect of kynurenic acid across a wide range of concentrations, thus suggesting that in noncultured, intact preparations from adult animals there is no effect of kynurenic acid on α7 nicotinic acetylcholine receptor currents.[4][5]
As a ligand for the orphan G protein-coupled receptor GPR35.[6] Another tryptophan metabolite, 5-hydroxyindoleacetic acid exerts its effects via the orphan G protein-coupled receptor GPR35.[7]
It seems that Glycine is only going to work on agonising the NMDA receptor from the Glycine site, but what about the ionotropic site? Or the AMPA and kainate receptors?
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I think we are VERY CLOSE of the Pois secret.
it's hard for me to understand all these elements. I need some hours to work on this.
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I think we are VERY CLOSE of the Pois secret.
it's hard for me to understand all these elements. I need some hours to work on this.
I wouldn't be that optimistic b_jim, but hey, maybe we can hit some sort of Jackpot and accidentally find a universal solution? or even a bio-marker?
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I think we are VERY CLOSE of the Pois secret.
it's hard for me to understand all these elements. I need some hours to work on this.
I wouldn't be that optimistic b_jim, but hey, maybe we can hit some sort of Jackpot and accidentally find a universal solution? or even a bio-marker?
Nas, I’m hoping for the Jackpot, even after 12 years of this forum work.
b_jim, I love your Spirit!
Demo
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I think we are VERY CLOSE of the Pois secret.
it's hard for me to understand all these elements. I need some hours to work on this.
I wouldn't be that optimistic b_jim, but hey, maybe we can hit some sort of Jackpot and accidentally find a universal solution? or even a bio-marker?
Nas, I’m hoping for the Jackpot, even after 12 years of this forum work.
b_jim, I love your Spirit!
Demo
I've been recently going into an emotional spiral where I just keep thinking of all the relationships that I could've had and that was getting me horny which made me relapse alot these recent days, so I've also been taking cigarettes after orgasm, cigarettes if you don't know, give me POIS. This I think was too much of a load on my metabolic mechanism of POIS and I think that gave me some sort of anemia ( general weakness, pain in the kidneys, my throat feels rigid, dizziness, tiredness, etc.) Perhaps if I can figure out what type of anemia I'm suffering from I can trace it back to its metabolic cycle. According to this thread, it could b3 deficiency however I don't have pellagra symptoms, I think it's more similar to D3 deficiency. Maybe I'll do general serum vitamins in the future. We'll see.
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Some guys spoke about Anti-NMDA receptor encephalitis. Clearly, the symptoms are the same that Pois : flu-lik, memory, speech/cummonication, insomnia, vision, muscular....
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It's like if we lose controle of NMDA's after ejaculation.
The elements keeping controle of sex homeostasis (testosterone level, semen regeneration) might be the same keeping controle of the NMDA.
So we can keep the one the system in balance, but not both in the same time because some element might be missing (mg in my case).
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It's like if we lose controle of NMDA's after ejaculation.
The elements keeping controle of sex homeostasis (testosterone level, semen regeneration) might be the same keeping controle of the NMDA.
So we can keep the one the system in balance, but not both in the same time because some element might be missing (mg in my case).
Can be a good explanation but it has to be proven.
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It's like if we lose controle of NMDA's after ejaculation.
The elements keeping controle of sex homeostasis (testosterone level, semen regeneration) might be the same keeping controle of the NMDA.
So we can keep the one the system in balance, but not both in the same time because some element might be missing (mg in my case).
Quote from Nanna:
" Kynurenic acid (KA) prevents any activation of the NMDA receptor (NMDAR). This is how it turns off the neuron. So not even glutamate can activate NMDAR once KA blocks the glycine site. Herbs like Tribulus or Wormwood may be able to overcome this block of the NMDA receptor, but playing with NMDAR is a dangerous game due to excitotoxicity. Niacinamide is known to prevent glutamate induced excitotoxicity. So while you are trying to excite this receptor, you may want to take Niacinamide as a safety. You can look in the literature for the appropriate Niacinamide. I personally, do not think Kynurenic acid or the NMDAR is the problem in POIS. Something that might be safer to try is beta-alanine (https://poiscenter.com/forums/index.php?topic=2711.msg24334#msg24334) (see post (https://poiscenter.com/forums/index.php?topic=2711.msg24334#msg24334))."
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Where does the KYNA metabolic activation primarily occur? Is it only in the CNS, or the peripheral nervous system, or anywhere ?
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"COX-2 inhibitors down-regulate indoleamine 2,3-dioxygenase, leading to a reduction in kynurenine levels as well as reducing proinflammatory cytokine activity." from wiki (https://en.wikipedia.org/wiki/Indoleamine_2,3-dioxygenase)
I tried celebrex many times and many different NSAID's but with no success. Should this be a sign that this theory is false in my case?
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Just tested Glycine powder. I took about ~2000mg dissolved in water after orgasm and no significant effect was observed.
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https://www2.nau.edu/~fpm/immunology/lectures/Chapter012.pdf