72 replies to this topic

[BLimitless]

I have had incredible success with inhibiting KYNA metabolites using norharman derived from Syrian Rue seeds (Peganum Harmala), sold as esphand in Iranian/Persian grocery stores. Previously I was using sarcosine but it appears that norharman is much more efficient because it targets the actual problem which sarcosine is meant to target: the inactivation of many pathways by KYNA and its neurotoxic metabolites. Take a good look at the pharmacology below, many receptors are hit - AMPA, NMDA, kainate, the all-important alpha-7 nicotinic acetylcholine receptor.

So rather than looking for an a7 ligand, how about inhibiting KYNA, an the endogenous a7 antagonist?



KYNA does have a very important purpose. It inhibits the convulsive and excitotoxic effects of too much glutamate transmission. However its metabolites like quinolinic acid cause brain fog in the body.
Taking in copious amounts of harmala alkaloids has lead to my brain fog disappearing entirely, replaced by a crystal clarity comparable to Noopept without actually taking Noopept.


It seems somewhere in the pathways, schizophrenics have an L-tryptophan metabolism issue. Instead of getting converted to 5-HT, it might be getting used more for KYNA to neutralise whatever the hell is causing so much glutamate to be released. Yet another pointer to the fact that all disease originates from the gut. The skin shows the end result of what happens in the gut. We are all fleshy tubes with the topology of a donut. If you do not take care of the inside of the donut, there is no point using all manner of skin creams and sun tan lotions in a futile attempt at taking care of the outside of the donut.

My skin is gleaming, absolutely gleaming with vibrance ever since I balanced my gut bacteria using superfoods; started taking in copious amounts of spirulina, barleygrass and wheatgrass (10g of the three combined a day). Will add chlorella to that some time soon.



Kynurenic acid

From Wikipedia, the free encyclopedia

IUPAC Name: 4-hydroxyquinoline-2-carboxylic acid


Other names: Kinurenic acid, kynuronic acid, quinurenic acid, transtorine
CAS number 492-27-3



Kynurenic acid (KYNA) is a product of the normal metabolism of amino acid L-tryptophan. It has been shown that kynurenic acid possesses neuroactive activity. It acts as an antiexcitotoxic and anticonvulsant, most likely through acting as an antagonist at excitatory amino acid receptors. Because of this activity, it may influence important neurophysiological and neuropathological processes. As a result, kynurenic acid has been considered for use in therapy in certain neurobiological disorders. Conversely, increased levels of kynurenic acid have also been linked to certain pathological conditions.
Kynurenic acid was discovered in 1853 by the German chemist Justus von Liebig in dog urine, which it was apparently named after.^[1]
It is formed from L-kynurenine in a reaction catalyzed by the enzyme kynurenine—oxoglutarate transaminase.




Mechanism of action

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]

Role in disease

High levels of kynurenic acid have been identified in patients suffering from tick-borne encephalitis, schizophrenia and HIV-related illnesses. In all these situations increased levels were associated with confusion and psychotic symptoms. Kynurenic acid acts in the brain as a glycine-site NMDAr antagonist, key in glutamatergic neurotransmission system, which is thought to be involved in the pathophysiology and pathogenesis of schizophrenia.
A kynurenic acid hypothesis of schizophrenia has been proposed in 2007,^[8][9] based on its action on midbrain dopamine activity and NMDArs, thus linking dopamine hypothesis of schizophrenia with the glutamate hypothesis of the disease.
High levels of kynurenic acid have been identified in human urine in certain metabolic disorders, such as marked pyridoxine deficiency and deficiency/absence of kynureninase.
When researchers decreased the levels of kynurenic acid in the brains of mice, the cognition was shown to improve markedly. ^[10]

Edited by BLimitless, 30 January 2013 - 03:30 PM.

[OpaqueMind]

Very interesting find. My very basic understanding is that the holy trinity primarily responsible for higher thought is that of NMDA, AMPA and glutamate. Even if not, these are primary determinants of cognition and are modulated both directly and indirectly by first order nootropics. It seems to me then that this is an incredibly relevant avenue for further research.

As a buffer against excitotoxicity I wonder how far one could diminish KYRA before cell-death becomes problematic. As far as I know, stress is a major cause of excitotoxicity, but are there many other things that specifically cause it? It seems if you are chronically stressed then taking this would be a bad choice. However on the flipside, a seasoned meditator would perhaps gain much from this.

Do you take norharman extract or Syrian rue seeds themselves? Does the MAOI activity become noticeable at the doses you take? I may well look into this. Thanks again for your thorough investigations and clear exposition :-)

Although I think your donut topology comparison is a little off... Personally I don't walk around with my mouth glued to my anus :P

Does in only inhibit KYNA metabolites, and is it know whether they have any biological purpose?

[OpaqueMind]

Also, how much do you take at a time?

These were after thoughts posted after the initial post that merged automatically, hence the disjointment. Yep, not a real word, just made it up. Someone's gotta do it!

[BLimitless]

Do not touch KYNA. Do not touch prolactin either. I have seen people recommend prolactin inhibitors for reaching higher states of being. Yes, prolactin inhibition will cause that. But the resultant state is a state of disorder. It's like dipping your body in fire and taking heroin to dull the flames.

Rather, both prolactin and KYNA must be channeled via control of sexual thought. Channeling the energy upwards into the brain is enough to reduce prolactin and inhibit KYNA.

At present I take syrian rue full spectrum extract. The MAO-A inhibition is part and parcel of the whole experience and yes it is very noticeable. However I have been fully MAO-A inhibited for weeks upon end with no issues. I will take a rest for a week at some point soon regardless, just to let the system breathe.

The key to removing stress is to let go of all impurities holding you down: negativity, anger towards others, hate in all of its forms, vices, addictions, all of these things. The neural networks created by these activities slows down the entire processing of the brain. I have come to realise that a thought occurs EVERYWHERE in the brain at once. Not a single brain cell is left out of the picture. Every thought must traverse these pathways created by negativity, this is what slows down neurotransmission and causes the physical experience of mental fatigue & brain fog. Luckily releasing all negativity via forgiveness and compassion will preserve the networks but activate some kind of kill-switch that turns these inhibiting networks into synergisers.


Truly, the mind is a work of the entire nervous system extending all the way into the heart and then into the air. Air is the "outside" of the nervous system - it is the SKIN of the mind. Electricity is the "inside" of the nervous system - that is the Homunculus.


Once this stress goes (Samadhi) then KYNA may be fully inhibited with no complications. This is the correct approach to this problem.

Edited by BLimitless, 30 January 2013 - 05:18 PM.

[dsohei]

oh shit kundalini zen samadhi new wave magick muthafuckkaaaaaaaaaaaaaaaa

the unprovable esotericism notwithstanding, there is probably a significant portion of the population that would benefit from daily small doses of reversible mao inhibitors. since rue and rue extract is very easily and legally obtainable, this experiment is easy and safe as long as people limit the tyramine rich foods and are not taking ssri's. many famous herbs and adaptogens are RIMAs which is how they perform some of their beneficial effects. rue in high enough doses are psychedleic in nature as well, making them entheogenic.
most shamanic lineages used special herbs like rue to help them achieve their special altered states.

[Psionic]

Can you please describe 'esphand' and its consumption more in detail? It looks like just as regular Peganum Harmala seeds without any extraction.

BTW It looks like that ancient Soma was never truly uncovered by modern ethnobotanics/historians.

[machete234]

Isnt this acid or the metabolites a dissociative and one that is naturally in the body?

From my experiments with a dissociative in my case methoxetamine I got the impression that this is in some ways how I feel in the morning: dissociated.
So in my oppinion we shouldnt say "brain fog" but maybe "mildy dissociated" that racetams revert this makes sense since the dissociatives and the racetams do different things on the NMDA receptors.

[LBGSHI]

Do not touch KYNA. Do not touch prolactin either. I have seen people recommend prolactin inhibitors for reaching higher states of being. Yes, prolactin inhibition will cause that. But the resultant state is a state of disorder. It's like dipping your body in fire and taking heroin to dull the flames.

Rather, both prolactin and KYNA must be channeled via control of sexual thought. Channeling the energy upwards into the brain is enough to reduce prolactin and inhibit KYNA.

At present I take syrian rue full spectrum extract. The MAO-A inhibition is part and parcel of the whole experience and yes it is very noticeable. However I have been fully MAO-A inhibited for weeks upon end with no issues. I will take a rest for a week at some point soon regardless, just to let the system breathe.

The key to removing stress is to let go of all impurities holding you down: negativity, anger towards others, hate in all of its forms, vices, addictions, all of these things. The neural networks created by these activities slows down the entire processing of the brain. I have come to realise that a thought occurs EVERYWHERE in the brain at once. Not a single brain cell is left out of the picture. Every thought must traverse these pathways created by negativity, this is what slows down neurotransmission and causes the physical experience of mental fatigue & brain fog. Luckily releasing all negativity via forgiveness and compassion will preserve the networks but activate some kind of kill-switch that turns these inhibiting networks into synergisers.


Truly, the mind is a work of the entire nervous system extending all the way into the heart and then into the air. Air is the "outside" of the nervous system - it is the SKIN of the mind. Electricity is the "inside" of the nervous system - that is the Homunculus.


Once this stress goes (Samadhi) then KYNA may be fully inhibited with no complications. This is the correct approach to this problem.

While there's nothing wrong with MAO inhibition if that's what you know you're getting into, and I'm glad you're in a good mood and feeling clear and productive, keep in mind that chronic use can be problematic, due to the likelihood of dependence and withdrawal.

As you probably know, norharman inhibits monoamine oxidase enzymes, slowing the breakdown of dopamine, serotonin, and norepinephrine, resulting in higher overall levels of these neurotransmitters (http://international...0%26amp;id=2946). It also acts as an acetylcholinesterase inhibitor via its primary active ingredient, harmaline (http://www.ncbi.nlm....pubmed/19784581), thereby increasing overall levels of acetylcholine as well. Acutely, this is great, but in the long-term, this will result in desensitization of the receptors involved, meaning you'll reach a plateau then probably a slow descent in terms of effect, and when you stop taking norharman, you'll feel less 'well' than before you started. This will wear off, but only once your receptors resensitize.

Also, keep in mind the plethora of interactions noted to be dangerous or deleterious for MAO inhibitors (http://en.wikipedia....or#Interactions), many of which eliminate quite a few of your nootropic options while taking norharman.

All in all, I'm not sure I'd recommend it, but as long as you don't indulge in eating cheese or supplementing L-tyrosine (which metabolizes in tyramine) it's not going to do you any more harm than, say, eating some hallucinogenic mushrooms or dropping LSD

Edited by LBGSHI, 31 January 2013 - 05:07 PM.

[BLimitless]

Thanks for the tyrosine headsup.

Actually I have been dosing that stuff by the gram, like 2 grams every now and then. Here is something cool. I have a concoction of NAC, NAT, ALCAR and Taurine I mix up and take 5-8g a day of. Green superfoods taste funky. N-acetyl groups taste funky. But the two together, they leave a brilliant ZING in your taste buds!

I have tyrosine and tryptophan separate. The warning is something I should have been well aware of but I had thought "meh, reversible inhibitors, no cheese, no tyramine syndrome".


But then again, in the state I am in, all of these things just flow to their correct course of action. A younger me would probably be in the emergency room right now from the cocktail of things I'm taking. It seems living in Zen causes your metabolic cycles to just say "ahfuggit" and just start working how they damn well should have this whole time.



I'm gonna cycle off, as your advice is trully brilliant. I was aware of these things but I did not think about rebound. My plan is to run through the rebound and carve new neurotransmission channels by simulating the mindstate while easing off. Thereby associating receptor desensitisation with their immediate resensitisation. I have cultivated a few habits while fully MAO-inhibited so perhaps maintaining these habits with full effort and direction should keep those myelin networks prim and proper.

In the past I have actually noticed that the rebound seems to cause serotonin receptor UPregulation!

Platelet serotonin uptake sites increased in drinkers of ayahuasca.


I have already mastered the rebound process with serotonin downregulation (an ex girlfriend, I forgot her name... Melinda? Beats me ). Breaking up with that girl was fiendish. The anger, the sadness. But then I realised... it's just a bunch of neurotransmitters. I am physical space. I move everything exactly where I want it to move. So since then, I have channeled that anger into happiness. The serotonin rebound is incredibly psychedelic when channeled in this fashion. Dangerous flashes of insight, which seems to be all the rage when you play with the tryptophan pathways.

You control the movement of every drug in your system. Placebo is a name we give to a meditation performed with little awareness.





Live in Zen and surf the sounds of the soul.

Edited by BLimitless, 01 February 2013 - 02:39 AM.

[macropsia]

....How's that regimen proceeding Blimitless? I've also attained some pretty heightened states from periodic harmaloid use, and am contemplating throwing harmaloids back into the mix on occasion. ... I don't suppose you'v had the opportunity to play with purified norharman? I've had the other harmala alks. and I have a hunch about norharman...

[YoungSchizo]

I have no clue what you guys are talking about, some parts are English, that's all I can make of it

So, to sum it up, is Kynurenic acid good or bad, mkay?

[formergenius]

Bad, YoungS.

So, aside from psychedelics/hallucinogens/entheogens, is there any way to inhibit kynurenic acid?

[YoungSchizo]

ty m8

[macropsia]

At endogenous brain concentrations, the astrocyte-derived metabolite kynurenic acid (KYNA) antagonizes the α7 nicotinic acetylcholine receptor and, possibly, the glycine co-agonist site of the NMDA receptor. The functions of these two receptors, which are intimately involved in synaptic plasticity and cognitive processes, may, therefore, be enhanced by reductions in brain KYNA levels. This concept was tested in mice with a targeted deletion of kynurenine aminotransferase II (KAT II), a major biosynthetic enzyme of brain KYNA. At 21 days of age, KAT II knock-out mice had reduced hippocampal KYNA levels (−71%) and showed significantly increased performance in three cognitive paradigms that rely in part on the integrity of hippocampal function, namely object exploration and recognition, passive avoidance, and spatial discrimination. Moreover, compared with wild-type controls, hippocampal slices from KAT II-deficient mice showed a significant increase in the amplitude of long-term potentiation in vitro. These functional changes were accompanied by reduced extracellular KYNA (−66%) and increased extracellular glutamate (+51%) concentrations, measured by hippocampal microdialysis in vivo. Taken together, a picture emerges in which a reduction in the astrocytic formation of KYNA increases glutamatergic tone in the hippocampus and enhances cognitive abilities and synaptic plasticity. Our studies raise the prospect that interventions aimed specifically at reducing KYNA formation in the brain may constitute a promising molecular strategy for cognitive improvement in health and disease.







http://www.ncbi.nlm....les/PMC3055476/


Though the nicotinic ACH receptor blocking ability has been contradicted elsewhere.


The idea is that kyn. is neuroprotective but anti-cognitive.

Edited by macropsia, 26 December 2013 - 06:31 PM.

[Sciencyst]

Am I the only one drooling over these studies? The whole kynurenic acid thing was practically my introduction to neuropsychopharmacology. I remember reading about it in a magazine when I was younger, and being immensely interested in it. That interest has grown exponentially.. This specific topic is absolutely amazing.

OP, it's very interesting what you say about sarcosine.. I am currently taking it. KYNA antagonizes glycine binding site on NMDARs, and sarcosine increases the amount of glycine in the synapse, so while sarcosine may do well in combatting negative effects of KYNA itself, it will do nothing to prevent KYNA to quinolinic acid breakdown.

I am very wary of taking MAOIs from what I have heard from friends' experiences, in that eating the wrong thing (tyramine) will make you uncomfortably and uncontrollably "out of it." Yes, this can be prevented obviously, but my (irrational?) fear remains.

I volunteer to help search for a non-MAOI inhibitor of the KYNA->quinolinc acid pathway..

Also, found these:

http://www.ncbi.nlm....pubmed/15112034

http://www.ncbi.nlm....les/PMC3021918/

http://www.ncbi.nlm....les/PMC3026891/

This issue really is upsettingly overlooked, though. We should change that. (Does awareness dance)

[Multicultural Harmony]

Long term exposure to norharman exacerbates Parkinsonism. http://www.ncbi.nlm....pubmed/20638417

[formergenius]

Found something quite interesting:

The present study for the first time demonstrates the ability of Cerebrolysin to lower KYNA formation in rat liver as well as in rat and human brain homogenates. We propose Cerebrolysin as a compound susceptible of therapeutic exploitation in some disorders associated with elevated KYNA metabolism in the brain and/or other tissues. We suggest that the anti-dementia effect of Cerebrolysin observed in Alzheimer patients could be in part due to Cerebrolysin induced reduction of KYNA levels, thus modulating the cholinergic and glutamatergic neurotransmissions.

http://www.ncbi.nlm....pubmed/19008081

edit: TL;DR; Cerebrolysin seems to lower KYNA levels.

Edited by formergenius, 26 January 2014 - 04:51 PM.

[Mind_Paralysis]

I'm going to kick this thread back up top, because I have some ideas...

There's a lot suggesting that high levels of Kynurenic acid is one of the root causes of Schizophrenia, however... What about those that have NEGATED symptoms of Schizophrenia? What about us with ADHD, in its various forms?

Well... looks to me like we have a deficit of Kynurenic Acid instead. It would explain why NMDA-antagonists like Memantine and reversed antagonists like Fasoracetam improve OUR cognition.

 

So, I must ask, those of you who have looked into kynurenic acid more closely... what do you vaguer? Could some variant of Kynurenic acid, which IS an NMDA-antagonist, just like Memantine, be utilized to treat ADHD?

 

As per this study:

http://www.behaviora.../content/6/1/29

Fourthly, against expectations healthy controls tended to show higher levels of toxic 3-hydroxykynurenine (3 HK) than those with ADHD.

 

 

This thread is all about decreasing kynurenine production. But how does one go about increasing it, naturally?

[lostfalco]

http://www.ncbi.nlm....les/PMC4318830/

 

Springerplus. 2015 Feb 1;4:48. doi: 10.1186/s40064-015-0826-9. eCollection 2015.

Amino acids inhibit kynurenic acid formation via suppression of kynurenine uptake or kynurenic acid synthesis in rat brain in vitro.

Sekine A1, Okamoto M1, Kanatani Y1, Sano M1, Shibata K1, Fukuwatari T1.

Author information

Abstract

The tryptophan metabolite, kynurenic acid (KYNA), is a preferential antagonist of the α7 nicotinic acetylcholine receptor at endogenous brain concentrations. Recent studies have suggested that increase of brain KYNA levels is involved in psychiatric disorders such as schizophrenia and depression. KYNA-producing enzymes have broad substrate specificity for amino acids, and brain uptake of kynurenine (KYN), the immediate precursor of KYNA, is via large neutral amino acid transporters (LAT). In the present study, to find out amino acids with the potential to suppress KYNA production, we comprehensively investigated the effects of proteinogenic amino acids on KYNA formation and KYN uptake in rat brain in vitro. Cortical slices of rat brain were incubated for 2 h in Krebs-Ringer buffer containing a physiological concentration of KYN with individual amino acids. Ten out of 19 amino acids (specifically, leucine, isoleucine, phenylalanine, methionine, tyrosine, alanine, cysteine, glutamine, glutamate, and aspartate) significantly reduced KYNA formation at 1 mmol/L. These amino acids showed inhibitory effects in a dose-dependent manner, and partially inhibited KYNA production at physiological concentrations. Leucine, isoleucine, methionine, phenylalanine, andtyrosine, all LAT substrates, also reduced tissue KYN concentrations in a dose-dependent manner, with their inhibitory rates for KYN uptake significantly correlated with KYNA formation. These results suggest that five LAT substrates inhibit KYNA formation via blockade of KYN transport, while the other amino acids act via blockade of the KYNA synthesis reaction in brain. Amino acids can be a good tool to modulate brain function by manipulation of KYNA formation in the brain. This approach may be useful in the treatment and prevention of neurological andpsychiatric diseases associated with increased KYNA levels.

 

Edited by lostfalco, 01 March 2015 - 12:06 AM.

[lostfalco]

http://www.jneurosci...4/32/10592.long

 

J Neurosci. 2014 Aug 6;34(32):10592-602. doi: 10.1523/JNEUROSCI.1107-14.2014.

Reduction of brain kynurenic acid improves cognitive function.

Kozak R1, Campbell BM2, Strick CA3, Horner W3, Hoffmann WE3, Kiss T3, Chapin DS3, McGinnis D3, Abbott AL4, Roberts BM4, Fonseca K5, Guanowsky V3, Young DA3, Seymour PA3, Dounay A3, Hajos M6, Williams GV4, Castner SA4.

Author information

Abstract

The elevation of kynurenic acid (KYNA) observed in schizophrenic patients may contribute to core symptoms arising from glutamate hypofunction, including cognitive impairments. Although increased KYNA levels reduce excitatory neurotransmission, KYNA has been proposed to act as an endogenous antagonist at the glycine site of the glutamate NMDA receptor (NMDAR) and as a negative allosteric modulator at the α7 nicotinic acetylcholine receptor. Levels of KYNA are elevated in CSF and the postmortem brain of schizophrenia patients, and these elevated levels of KYNA could contribute to NMDAR hypofunction and the cognitive deficits and negative symptoms associated with this disease. However, the impact of endogenously produced KYNA on brain function and behavior is less well understood due to a paucity of pharmacological tools. To address this issue, we identified PF-04859989, a brain-penetrable inhibitor of kynurenine aminotransferase II (KAT II), the enzyme responsible for most brain KYNA synthesis. In rats, systemic administration of PF-04859989 dose-dependently reduced brain KYNA to as little as 28% of basal levels, and prevented amphetamine- and ketamine-induced disruption of auditory gating and improved performance in a sustained attention task. It also prevented ketamine-induced disruption of performance in a working memory task and a spatial memory task in rodents and nonhuman primates, respectively. Together, these findings support the hypotheses that endogenous KYNA impacts cognitive function and that inhibition of KAT II, and consequent lowering of endogenous brain KYNA levels, improves cognitive performance under conditions considered relevant for schizophrenia.

 

http://www.soci.org/..._1200_1245.ashx

KAT II Inhibitors; a Novel Approach for the Treatment of Schizophrenia 

 

Edited by lostfalco, 01 March 2015 - 09:33 PM.

[lostfalco]

http://www.ncbi.nlm....pubmed/25259918

 

Cell. 2014 Sep 25;159(1):33-45. doi: 10.1016/j.cell.2014.07.051.

Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression.

Agudelo LZ1, Femenía T2, Orhan F3, Porsmyr-Palmertz M1, Goiny M3, Martinez-Redondo V1, Correia JC1, Izadi M1, Bhat M4, Schuppe-Koistinen I4, Pettersson AT1, Ferreira DM1, Krook A5, Barres R5, Zierath JR6, Erhardt S3, Lindskog M7, Ruas JL8.

Author information

Abstract

Depression is a debilitating condition with a profound impact on quality of life for millions of people worldwide. Physical exercise is used as a treatment strategy for many patients, but the mechanisms that underlie its beneficial effects remain unknown. Here, we describe a mechanism by which skeletal muscle PGC-1α1 induced by exercise training changes kynurenine metabolism and protects from stress-induced depression. Activation of the PGC-1α1-PPARα/δ pathway increases skeletal muscle expression of kynurenine aminotransferases, thus enhancing the conversion of kynurenine into kynurenic acid, a metabolite unable to cross the blood-brain barrier. Reducing plasma kynurenine protects the brain from stress-induced changes associated with depression and renders skeletal muscle-specific PGC-1α1 transgenic mice resistant to depression induced by chronic mild stress or direct kynurenine administration. This study opens therapeutic avenues for the treatment of depression by targeting the PGC-1α1-PPAR axis in skeletal muscle, without the need to cross the blood-brain barrier.

 

Edited by lostfalco, 01 March 2015 - 10:10 PM.

[YoungSchizo]

Thanks for the study's.

 

I hate it when a molecule has a bunch of letters and numbers, it usually means that shit ain't obtainable or is way too expensive to buy.. 

 

The last study might explain why I force myself to exercise, especially in the hardest of times.

 

Though, any idea's how to counter this KYNA issue for schizophrenia?

 

 

[Mind_Paralysis]

@Youngschizo: This seems a little bit too early to actually test on yourself... yes, it seems like PF-04859989 really does work at lowering KYNA production, but if I'm not mistaken, it says it's at this moment an irreversible inhibitor, yes? They mention in the study that this could prove to be a problem, as with most irreversible inhibitors. ( of other biochemicals)

 

But, you are suffering from a most heinous disease, and you also seems to be an enterprising and intelligent individual, so I shall provide you with a link to the compound in question:

 

http://glixxlabs.com...s_p5/GLXC-03151

 

http://www.sigmaaldr...ct/sigma/pz0250

 

It would appear as if the chemical is indeed difficult to get a hold of, as bulk ordering seems to be the only available option. But a group-buy might mitigate some of those problems.
 

 

 

On another note - does anybody have some ideas on how to INCREASE Kynurenine -production? Kynurenine acid is an NMDA-antagonist, and has shown similar effects to Memanthine in some studies.

There is some growing evidence that some disorders, such as ADHD, is not caused by a sub-active NMDA-network, but rather, by a HYPER-active NMDA-network. ( hence why so many of us have OTHER cognitive and neurological problems than just ADHD - the NMDA-network isn't doing it's job properly - the brain isn't adjusting to its own deficits, it instead SUPPRESSES its own attempts to communicate properly between different centers.)

 

One of my own hypothesis as to the cause of this comes from a study I dug up that showed that ADHD-children actually have LOWER levels of kynurenic acid, than the healthy control-groups.

 

The fact that the NMDA-network is indirectly inhibited by the DRD4 dopamine-receptor in the brain, which is one of the most plausible theories as to the root cause of ADHD at the moment, seems to be lost on most medical professionals.

Hence, I want to try this - enhancing NMDA-inhibition in my brain, through some down-stream process in the production of neuro-transmitters.

Any ideas, gents?

[lostfalco]

 

 

On another note - does anybody have some ideas on how to INCREASE Kynurenine -production? Kynurenine acid is an NMDA-antagonist, and has shown similar effects to Memanthine in some studies.

 

One possibility...I haven't focused on this though. =)

 

http://www.ncbi.nlm....les/PMC4318830/

"The tryptophan metabolite, kynurenic acid (KYNA)" 

 

"Tryptophan was mainly metabolized through the kynurenine (KYN) pathway in the mammalian brain. Kynurenic acid (KYNA), a product of this pathway, is a negative allosteric modulator of the α7 nicotinic acetylcholine receptor at endogenous concentration, and a competitive antagonist of glycine co-agonist sites of the N-methyl-D-aspartic acid receptor (Kessler et al. 1989; Hilmas et al. 2001; Schwarcz and Pellicciari 2002). In particular, nanomolar increases in KYNA reduces dopaminergic and glutamatergic neurotransmission (Carpenedo et al. 2001; Rassoulpour et al. 2005), and contributes to cognitive dysfunction (Erhardt et al. 2004; Chess and Bucci 2006; Chess et al. 2007; Chess et al. 2009)."

Edited by lostfalco, 02 March 2015 - 11:59 PM.

[lostfalco]

That has been mentioned by u/shrillthrill over on reddit before...but I thought it was a fascinating mechanism for D-CYC's memory enhancing properties. http://www.reddit.co...d_formationnew/

 

http://www.ncbi.nlm....pubmed/24189377

Eur Neuropsychopharmacol. 2014 Apr;24(4):639-44. doi: 10.1016/j.euroneuro.2013.10.006. Epub 2013 Oct 18.

D-Cycloserine lowers kynurenic acid formation--new mechanism of action.

Baran H1, Kepplinger B2.

Author information

Abstract

D-Cycloserine, known as a partial agonist at the glycine modulatory site of the glutamatergic N-methyl-D-aspartate (NMDA) receptor, exerts anticonvulsive activities and improves cognitive function. The present study evaluates the action of D-cycloserine with respect to the biosynthetic machinery of kynurenic acid (KYNA) synthesis e.g. the activity of enzymes synthesizing KYNA, kynurenine aminotransferases I, kynurenine aminotransferase II and kynurenine aminotransferase III (KAT I, KAT II and KAT III) in the rat liver and brain, and human frontal cortex in the presence of the anti-mycobacterial drug D-cycloserine, in an in vitro study. We found that D-cycloserine blocked dose-dependent and significantly KAT I, II and III activities in rat liver and brain homogenates. Furthermore, the inhibitory effect of KYNA formation was observed in the frontal cortex homogenate of human post mortem tissue, as well. D-Cycloserine, at 63.7 µM concentration blocked significantly KAT II, I and III (53.2, 66.1 and 71.3% of control, P<0.001) activities in the human frontal cortex homogenate. Obtained data indicate that D-cycloserine exerts notable biochemical properties to block KYNA synthesis. Lowering of KYNA content due to D-cycloserine inhibition of KATs activities can free up more glycine sites for the actions of D-cycloserine. On the other site, it needs to be clarified, if the postulated mechanism for D-cycloserine to act as a partial agonist at the glycine site of the NMDA receptor could be mainly due to KAT's inhibition. We propose that this mechanism(s) might play a role in the improvement of memory, cognition and/or delusion in Alzheimer's, HIV-1 infected patients and schizophrenia patients.

 

Edited by lostfalco, 03 March 2015 - 12:22 AM.

[lostfalco]

http://www.ncbi.nlm....pubmed/25773161

 

Semin Cell Dev Biol. 2015 Mar 12. pii: S1084-9521(15)00045-2. doi: 10.1016/j.semcdb.2015.03.002. [Epub ahead of print]

The kynurenine pathway and neurodegenerative disease.

Maddison DC1, Giorgini F2.

Author information

Abstract

Neuroactive metabolites of the kynurenine pathway (KP) of tryptophan degradation have been closely linked to the pathogenesis of several neurodegenerative diseases. Tryptophan is an essential amino acid required for protein synthesis, and in higher eukaryotes is also converted into the key neurotransmitters serotonin and tryptamine. However, in mammals >95% of tryptophan is metabolized through the KP, ultimately leading to the production of nicotinamide adenosine dinucleotide (NAD+). A number of the pathway metabolites are neuroactive; e.g. can modulate activity of several glutamate receptors and generate/scavenge free radicals. Imbalances in absolute and relative levels of KP metabolites have been strongly associated with neurodegenerative disorders including Huntington's, Alzheimer's, and Parkinson's diseases. The KP has also been implicated in the pathogenesis of other brain disorders (e.g. schizophrenia, bipolar disorder), as well as several cancers and autoimmune disorders such as HIV. Pharmacological and genetic manipulation of the KP has been shown to ameliorate neurodegenerative phenotypes in a number of model organisms, suggesting that it could prove to be a viable target for the treatment of such diseases. Here, we provide an overview of the KP, its role in neurodegeneration and the current strategies for therapeutic targeting of the pathway.

 

[YimYam]

Would this helpful for me if I have down regulated GABA receptors? It has induced extremely severe cognitive impairment from chronic stress. I'd hugely appreciate you check out my thread if you have the time: (http://www.longecity...gaba-gone-gaga/). 

 

Because my GABA neurons are downregulated they're unable to control/inhibit my hyperactive HPA axis stress response, therefore I believe it is causing glutamate exitotoxicity. 

Edited by jdmc123, 20 March 2015 - 06:09 PM.

[lostfalco]

http://www.ncbi.nlm..../pubmed/7713164

 

Eur J Pharmacol. 1995 Jan 16;272(2-3):203-9.

Putative cognition enhancers reverse kynurenic acid antagonism at hippocampal NMDA receptors.

Pittaluga A1, Pattarini R, Raiteri M.

Author information

Abstract

Oxiracetam, aniracetam and D-cycloserine, three putative cognition enhancers, were examined in a functional assay for NMDA receptors. Rat hippocampal slices or synaptosomes were labeled with [3H]noradrenaline and exposed to NMDA or glutamate in superfusion. NMDA (100 microM) elicited a remarkable rise (about 500%) in the release of [3H]noradrenaline from slices. The effect of NMDA was antagonized by the glutamate receptor blocker, kynurenic acid. The antagonism by 100 microM kynurenate was reduced by submicromolar concentrations of oxiracetam and totally reversed by 1 microM of the drug. The concentration-antagonism curve for kynurenic acid was shifted to the right in the presence of 0.2 or 1 microM oxiracetam. Aniracetam and D-cycloserine, as well as glycine and D-serine, behaved similarly to oxiracetam: all compounds, tested at 1 microM, reversed the antagonism by 100 microM kynurenate of the NMDA-evoked [3H]noradrenaline release. In superfused hippocampal synaptosomes, 100 microM NMDA or glutamic acid elicited the release of [3H]noradrenaline; the evoked release was enhanced by glycine, but not by oxiracetam. In this preparation 1 microM glycine or 1 microM oxiracetam prevented the antagonism by kynurenate of the NMDA- or the glutamate-evoked [3H]noradrenaline release. As kynurenic acid is an endogenous glutamate receptor antagonist whose brain levels are known to increase in conditions associated to cognitive deficits, it is proposed that the putative cognition enhancers tested may act in vivo by relieving the antagonism produced by excessive endogenous kynurenate.

 

[sativa]

On another note - does anybody have some ideas on how to INCREASE Kynurenine -production? Kynurenine acid is an NMDA-antagonist, and has shown similar effects to Memantine in some studies.

I am also interested in this - how to control the production of KYN acid and reap the benefits of its alpha 7 nicotinic acetylcholine receptor antagonsism as well as NMDA antagonsism.

This causes both alpha 7 and NMDA receptors to upregulate leading to improved cognition and a reduction in ones tolerances (to both exogenous and endogenous compounds).

As an aside, recall that BDNF upregulates alpha 7:

BDNF up-regulates alpha7 nicotinic acetylcholine receptor levels on subpopulations of hippocampal interneurons.

http://www.ncbi.nlm....pubmed/17029981

Edited by sativa, 07 November 2015 - 08:57 PM.

[gizmobrain]

This thread caught my eye because of the mention of norharman (a beta-carboline) and sarcosine. Both 9-methyl-beta-carboline and sarcosine have a positive impact on my issues with low motivation, so I will be attempting to digest the information about the pathways mentioned to see if it might apply to me.

 

EDIT: Very, very interesting. What would cause endogenous brain levels of Kynurenic Acid to be high from a young age? Some type of genetic predisposition to higher levels of kynurenine aminotransferase in the brain, or maybe lower KAT in the body which leads to a higher amount of kynurenine in the brain? Time to study the kynurenine pathway, I suppose.

Edited by gizmodroid, 08 November 2015 - 12:40 AM.