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Reduction of kynurenic acid shows promise for improving learning


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#1 hyoomen

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Posted 06 July 2010 - 05:52 PM


Cognition and Memory Improve Dramatically in Mice When Brain Compound Levels Were Decreased

Interesting expansion of the studies regarding the impact of kynurenic acid on extracellular glutamate and the chain of impacts on learning resultant from that impact.

I'm curious what trade-off there will be from crude exploitation of this pathway. For example, the article does mention the mice are better capable of remembering unpleasant experiences -- which could ultimately be problematic (does anybody really want to make PTSD WORSE?!).

Interesting, still.
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#2 bran319

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Posted 06 July 2010 - 06:33 PM

Interesting. If KA is a byproduct of tryptophan metabolism and reduced levels lead to increases in extracellular glutamate I wonder if it would lead to a type of thought frenzied depression like seen in melancholia? Also, I wonder if KA is neuroprotective?

Edited by bran319, 06 July 2010 - 06:38 PM.


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#3 simbad

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Posted 16 July 2010 - 01:01 PM

Check out these two studies:


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


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.



Effects of putative cognition enhancers on the NMDA receptor by [3H]MK801 binding

Abstract

Piracetam, aniracetam, and Image -cycloserine were tested for their ability to reduce inhibition of [3H]MK801 (dizocilpine) binding by 100 µM kynurenate. Piracetam (100 µM-1 mM) failed to reduce inhibition by kynurenate but stimulated [3H]MK801 binding in the absence of kynurenate. In contrast, Image -cycloserine (30 µM-1 mM) and aniracetam markedly reduced this inhibition by kynurenate. Thus, cognition enhancers might function via at least some subtypes of NMDA receptors.


This is my third attempt at posting in this thread. First two times I tried posting links to the studies but my posts don't seem to be displayed despite my post count going up (possibly done to reduce the amount of spammers?). I' ll try to edit in links later.

Two questions for anyone who can anwser.

1- Do oxiracetam and aniracetam users report an increase in unpleasant memories?

2- Would Glycine be effective in reducing kynurenic acid antagonism in humans or would it have trouble crossing the BBB?

Edited by simbad, 16 July 2010 - 01:03 PM.

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#4 chrono

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Posted 17 July 2010 - 08:32 PM

Haven't had time to look into any of these mechanisms yet, but great thread.

@simbad: if you have less than 10 posts, it has to get moderator approval before it will post a link. Great post, and welcome to the forum!

I'm curious what trade-off there will be from crude exploitation of this pathway. For example, the article does mention the mice are better capable of remembering unpleasant experiences -- which could ultimately be problematic (does anybody really want to make PTSD WORSE?!).

I've seen this mentioned before with regard to things like donepezil. We have so little command over the fine neural components that I imagine anything which enhances memory will carry this risk; I really doubt this pathway specifically controls negative memories. But I haven't seen the full text yet.

My thought is that, until we have the kind of understanding to inhibit certain specific types of memories, this is a necessary consequence. And I'm not so sure it's a bad one—anyone seen Star Trek V? (not that I recommend it; they shouldn't have let Shatner direct). My admittedly non-technical understanding, based in part on my own experiences of some long, tragic experiences over the last 10 years, is that the emotional impact isn't necessarily linked to the clarity of the memory (though I'm sure it wouldn't 'help' either). If given the choice, I never would have just ditched those memories, because they're a part of who I am, and something I have learned absolutely invaluable lessons from.

Hope I get some time to research this soon. My first questions are 1) is there any drawback (immediate or downstream) to reducing KA, and 2) how can this be done, other than through reducing levels of parent compounds? Maybe I'll try to figure out how to get aniracetam to work for me again.

#5 chrono

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Posted 02 August 2010 - 06:38 AM

dubcomesaveme just posted this paper in another thread: The search for a safe Alpha7 Nicotnic Receptor Agonist?

Reduction of endogenous kynurenic acid formation enhances extracellular glutamate, hippocampal plasticity, and cognitive behavior.
Potter MC, Elmer GI, Bergeron R, Albuquerque EX, Guidetti P, Wu HQ, Schwarcz R.
Maryland Psychiatric Research Center, University of Maryland School of Medicine

At endogenous brain concentrations, the astrocyte-derived metabolite kynurenic acid (KYNA) antagonizes the alpha 7 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.

PMID: 20336058 [PubMed - in process]


As well as this news story.

I reviewed all the cognitive-related KYNA abstracts I could find a few weeks ago, one night when I had insomnia. I'll look through my notes and post what I found when I get a chance ;)

Edited by chrono, 02 August 2010 - 08:27 AM.


#6 dilenja

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Posted 02 August 2010 - 10:39 PM


Toxoplasma gondii and Schizophrenia: Linkage Through Astrocyte-Derived Kynurenic Acid?
Robert Schwarcz1 and Christopher A. Hunter2
2 Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104



Keywords: infection / kynurenine / parasite



Toxoplasma gondii is a ubiquitous food- and water-borne parasite that in most individuals is able to persist in multiple tissues, including the central nervous system (CNS), without causing an apparent clinical disease.1 During the chronic phase of toxoplasmosis, the latent stage of the parasite is found in the CNS, and studies from murine models have established that long-term resistance to the parasite is dependent on the ability to generate and maintain parasite-specific CD4+ and CD8+ T cells. Consistent with this observation, patients with primary or acquired defects in T cell–mediated immunity are susceptible to toxoplasmicencephalitis (TE). Indeed, in patients with acquired immunodeficiency syndrome,T. gondii is one of the most common opportunistic infections affecting the CNS. One of the notable features that accompanies T. gondii infection in the CNS is a prominent activation of resident glial cells, in particular astrocytes.2 We proposehere that this event may play a causative role in the development of schizophrenia.A considerable body of evidence links T. gondii infection to an increased incidence of schizophrenia.3,4,5,6 However, the association between the parasitic infection and disease, while strong, is so far exclusively correlative in nature. Based on epidemiological data, ie, statistical analyses, the hypothesis has with few exceptions ignored the cellular events and molecular mechanisms by which the infection might promote or precipitate pathophysiology associated with schizophrenia. Recent experiments in our laboratories have provided provocative clues regarding the enigmatic connection between infection and disease etiology.

Our collaboration originated from the central role that astrocytes play in the synthesis of kynurenic acid (KYNA), a metabolite of the kynurenine pathway of tryptophan degradation. When present at levels slightly above endogenous brain concentrations, this metabolite can inhibit both N-methyl-D-aspartate (NMDA) and Posted Image7 nicotinic acetylcholine (Posted Image7nACh) receptors.7 These two receptors are widely purported to have causative links to cognitive processes. Unrelated to antipsychotic medication, KYNA levels are significantly elevated in the brain of individuals with schizophrenia.8 Thus, it follows that abnormally high KYNA levels may contribute to the patients' cognitive impairment. This concept is supportedby studies in rodents, which show that experimental elevation of cerebral KYNA levels results in impaired sensory gating.9,10 Furthermore, nanomolar concentrations of KYNA, by blocking presynaptic Posted Image7nACh receptors on glutamatergic nerve terminals, have been shown to significantly reduce the extracellular levels of glutamate in rat brain in vivo.11,12 KYNA may thus contribute to the putative hyponicotinergic and hypoglutamatergic tone in schizophrenia.13,14

In view of the proposed link between KYNA and cognitive processes, it is important to understand the biochemical events leading to and regulating its formation and function in the brain. KYNA synthesis is initiated by the oxidative ring opening of tryptophan by indoleamine 2,3-dioxygenase (IDO) and/or tryptophan dioxygenase (TDO). The reaction product of IDO and TDO, kynurenine, is then irreversibly converted to KYNA. In the brain, this transamination takes place almost exclusively in astrocytes, which then rapidly liberate newly produced KYNA into the extracellular milieu,placing the metabolite in an excellent position to influence surrounding neurons.15 Interestingly, the mRNA for tryptophan2,3-dioxygenase (TDO2) is elevated in the brain of individuals with schizophrenia, and a concomitant increased density of TDO2-immunopositive astroglial cells is seen in the patients' white matter.16 Because TDO is one of the upstream enzymes responsible for the biosynthesis of KYNA, this enhanced expression could conceivably lead to an elevation of KYNA levels in the diseased brain and therefore play a part in the pathophysiology of the disorder.

As noted above, astrocyte activation is a prominent feature of TE, but it was not known whether this reaction is associated with a dysregulation of KYNA production. In a first attempt to investigate this possible link, we recently examined the brains of chronically T. gondii–infected animals for signs of impaired kynurenine pathway flux. Indeed, infected mice showed massive astrocyte activation and, concomitantly, a greater than 7-fold increase in the brain content of KYNA.17 Because this effect was accompanied by an increase in the levels of KYNA's bioprecursor kynurenine, these changes are likely due to a stimulation of upstream kynurenine pathway enzymes such as IDO and/or TDO. At present, it is unclear whether this represents a direct response to invading parasites or, as seems more likely, a secondaryconsequence of the inflammatory response that accompanies the presence of T. gondii in the brain.

These results show that T. gondii infection provides an in vivo model system to modulate a biochemical pathway associated with schizophrenia. Jointly, the links between (1) T. gondii and schizophrenia; (2) T. gondii and astrocyte activation; (3) KYNA levels and schizophrenia; (4) KYNA synthesis and astrocytes; (5) KYNA, NMDA, and Posted Image7nACh receptors; and (6) TDO2 and schizophrenia suggest the following hypothetical sequence of events: T. gondii infection, by activating astrocytes, increases KYNA formation in the brain. This effect is augmented in persons with elevated brain TDO activity, ie, individuals with a genetic predisposition for schizophrenia. Increased brain KYNA levels, in turn, causeor contribute to the excessive inhibition of glutamatergic and nicotinergic neurotransmission, which is believed to play animportant role in the cognitive impairments seen in schizophrenia.

An interesting corollary of this hypothesis is that a reduction in cerebral KYNA formation might benefit individuals with schizophrenia by indirectly enhancing transmission through NMDA and Posted Image7nACh receptors. This could be accomplished by timely interventions that attenuate or arrest the various consequences of the parasite infection1 or, more specifically, by inhibitors of KYNA biosynthesis.18 The mouse model used in our study not only provides a convenient vehicle to test such interventions but will also allow further mechanistic insights into the links between toxoplasmosis and schizophrenia.



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#7 formergenius

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Posted 16 November 2013 - 10:47 AM

From reference #18:

(S)-4-(Ethylsulfonyl)benzoylalanine is a potent and selective inhibitor of kynurenine aminotransferase II (KAT II) with no significant effect on KAT I or other enzymes of the kynurenine pathway. This compound is able to pronouncedly inhibit the formation of kynurenic acid (KYNA) in rat brain.

link

Can't seem to find much about it; but it appears it would be both a promising schizophrenia treatment and nootropic.
Anyone else interested in this?


The emerging, remarkable confluence of data from humans and animals suggests an opportunity for developing a rational pharmacology by targeting cortical kynurenine pathway metabolism for cognition enhancement in schizophrenia and beyond.

link

Don't think it has been studied in humans yet alas..

EDIT: For those interested; here's a huge PDF titled "Kynurenines in Neurological Disorders"

Edited by formergenius, 16 November 2013 - 10:54 AM.

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