Kynurenine pathway (NMDA, cognition) (clickbait lol)

[Ciprofloxacin]

Hey.

Thanks to Area1255 and Helen, there is one more possible explanation to why some of us maybe having low excitatory signalling.

NMDA hypofunction could be caused by excess Kynurenic Acid; this endogenous compound blocks NMDA receptors and causes Disorganized Thought Process. Schizophrenics have high Kynurenic Acid. Kynurenic avid messes with the Frontal Cortex. Causes poor uptake of neurotransmitters in frontal Lobe.

that is because kynurenine bulds up when you are lacking Kynurenine monooxygenase

which is FAD enzyme, with a cofactor NADPH.

most PSSD people have very low b2 in blood , some undetectable. and some have very low NADPH.

kynurenic pathway is important also to make picolinic acid. Which is responsible for zinc absorption. that is why some slow oxidizers have high zinc on their hairtest. since it is not bound to picolinic acid.

These are the qutoes.

Simplified-diagram-of-the-kynurenine-pathway-Enzymes-in-italics-and-metabolites-boxed.png.jpg

Now look at this photo. Tryptophan metabolized to kynurenine, and kynurenine mainly metabolized to kynurenic acid(via KAT) and 3-hydroxykynurenine(via KMO).

https://www.ncbi.nlm.nih.gov/pubmed/21660485

After 48 h, the expression of Kat1 and Kat2 was further up-regulated, and Kmo expression was down-regulated by all antidepressants. The ratio KYNA/3-HK was increased by fluoxetine, citalopram, amitriptyline and imipramine in a time-dependent manner-the effect was not observed after 2 h, modest after 24 h and robust after 48 h incubation time. Our findings indicate that the action of antidepressants may involve re-establishing of the beneficial ratio between KYNA and 3-HK. Shift in the kynurenine pathway, observed after prolonged exposure to antidepressant drugs, may partly explain their delayed therapeutic effectiveness.

Kynurenic Acid is a NMDA antagonist. It decreases the cognitive performance. Also the excess amounts of it takes role in several cognitive diseases. But the quinolinic acid is a nmda agonist. It's highly excitatory. When you have low KMO and high KAT, you get both low QUIN and high KYNA. Double effect. It's simple I guess.

And this may explains why some pssd sufferers have low NADPH and picolinic acid (Helen's quote). As the Quinolinic acid further metabolized to NAD+(nicotinamide adenine dinucleotide). I remember that there is so much people benefitted from niacin here. Maybe it's not related but just my 2c.

https://en.wikipedia.org/wiki/Kynurenic_acid

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,[8] 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 was proposed in 2007,[9][10] 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, their cognition was shown to improve markedly.[11]

Kynurenic acid shows neuroprotective properties.[12] Some researchers have posited that the increased levels found in cases of neurological degradation is due to a failed attempt to protect the cells.[13]

https://en.wikipedia.org/wiki/Kynurenine_pathway

Acquired and inherited enzyme deficiencies

Downregulation of kynurenine-3-monooxygenase (KMO) can be caused by genetic polymorphisms, cytokines, or both.[5][6] KMO deficiency leads to an accumulation of kynurenine and to a shift within the tryptophan metabolic pathway towards kynurenic acid and anthranilic acid.[7][8][9][10][11][12]

Deficiencies of one or more enzymes on the kynurenine pathway leads to an accumulation of intermediate metabolic products which can cause effects depending on their concentration, function and their inter-relation with other metabolic products.[7] For example, Kynurenine 3-monooxygenase deficiency is associated with disorders of the brain (e.g. schizophrenia, tic disorders) and of the liver.[10][8][9][11][12] The mechanism behind this observation is typically a blockade or bottleneck situation at one or more enzymes on the kynurenine pathway due to the effects of Indolamine-2,3-Dioxygenase (IDO) and Tryptophan-2,3-Dioxygenase (TDO) and/or due to genetic polymorphisms afflicting the particular genes.[7][6][13][9] Dysfunctional states of distinct steps of the kynurenine pathway (e.g. kynurenine, kynurenic acid, quinolinic acid, anthranilic acid, 3-hydroxykynurenine) have been described for a number of disorders, e.g.:[14]

Myalgic Encephalomyelitis (CFS) Ref. Stanford Symposium 2018
HIV dementia
Tourette Syndrome
Tic disorders
Psychiatric disorders (e.g. Schizophrenia, major depression, anxiety disorders)
Multiple sclerosis
Huntington's disease
Encephalopathies
Lipid metabolism
Liver fat metabolism
Systemic lupus erythematosus
Glutaric aciduria
Vitamin B6 deficiency
Eosinophilia-myalgia syndrome

Sorry for shitty post, lol. Take this post as a main idea.

[Ciprofloxacin]

Kynurenic acid, a metabolite of the kynurenine pathway of tryptophan degradation, is an antagonist at N-methyl-d-aspartate and α7 nicotinic acetylcholine receptors and modulates glutamate, dopamine, and acetylcholine signaling. Cortical kynurenic acid concentrations are elevated in the brain and cerebrospinal fluid of schizophrenia patients. The proximal cause may be an impairment of kynurenine 3-monooxygenase (KMO), a rate-limiting enzyme at the branching point of the kynurenine pathway.

Impairment of the kynurenine pathway (KP) of tryptophan metabolism has been suggested to play a role in the pathophysiology of schizophrenia and related cognitive deficits.1-5 The KP generates 3 neuroactive metabolites with purported links to neuropsychiatric diseases.6-8 These compounds—kynurenic acid (KYNA), 3-hydroxykynurenine, and quinolinic acid—are downstream products of the regulatory enzymes tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase, and kynurenine 3-monooxygenase (KMO) (Figure 1). The levels of KYNA, an endogenous antagonist of the glycine coagonist (glycineB) site of the glutamatergic N-methyl-d-aspartate receptor (NMDAR) and the α7 nicotinic acetylcholine receptor (α7nAChR),6,9,10 are elevated in the prefrontal cortex and cerebrospinal fluid of schizophrenia patients.1,11-13 This unique receptor affinity profile of KYNA is particularly interesting when viewed against accumulated evidence implicating NMDAR hypofunction in the pathophysiology of schizophrenia14-19 and α7nAChR hypofunction in schizophrenia-related cognitive deficits.20,21 In rats, endogenous KYNA controls extracellular levels of cortical acetylcholine, dopamine, and glutamate22-24 and the firing rate and burst activity of midbrain dopaminergic neurons.25 Remarkably, experimentally increased brain KYNA levels in rats induce deficits in visuospatial working memory, contextual learning, sensory gating, and prepulse inhibition of the acoustic startle reflex.26-29

It’s interestig, as kyna blocks most of the excitatory neurotransmitters. Dopamine, acetylcholine, glutamate...

In studies in which clinical trials were undertaken, it was shown that d-cycloserine, Compound (42) (Figure 8), has positive effects of enhancing cognitive functions in patients with schizophrenia or those additionally experiencing Alzheimer’s delusions, by decreasing KYNA levels in the human brain by inhibiting all of KAT-1, 2 and 3. The reported inhibitory activities of this compound against KAT-1, 2 and 3 in the human frontal cortex were 54, 66 and 72 at 64 μM, respectively [46]. From Compound (3), which was the template utilized, it was observed that instead of using the R configuration of the amino group, the S form may universally provide higher potency. Moreover, very early in the studies of these enzymes, back in 1979, the inhibitory effects of some antibacterial agents on rat KAT-1 reported the same results, where d-cycloserine (42) and novobiocin inhibited the rat KAT-1 activity [30].

I have just found that d-cycloserine(seromycin) is a KAT inhibitor (as well as some other antibiotics are). Also I have found that it’s an antibiotic, which can also be used in some psychiatric diseases.

Between 1959 and 1976, a small number of studies were done examining the effects of estradiol analogues on the activity of the kynurenine aminotransferase isozymes. One study showed that β-estradiol (81) and ethynylestradiol (82), shown in Figure 22, could inhibit the activity of male mice KATs [62].
In another study, the results demonstrated that conjugated estrogens affected the production of kynurenic and xanthurenic acid levels, two known products of KAT isozymes [63]. Moreover, estradiol disulphate (83) and diethylstilbestrol disulphate (84) (Figure 23) are able to inhibit KATs. It was proposed that these compounds are competitive and reversible inhibitors as their inhibitory effects are dependent on the concentration of the cofactor, PLP [64].

Also B-estradiol blocks the KAT.


https://www.ncbi.nlm.nih.gov/pmc/articl ... o=0.515464

[Ciprofloxacin]

https://www.ncbi.nlm.nih.gov/m/pubmed/29705534/

Increasing kynurenine brain levels reduces ethanol consumption in mice by inhibiting dopamine release in nucleus accumbens.
Giménez-Gómez P, et al. Neuropharmacology. 2018.
Show full citation
Abstract
Recent research suggests that ethanol (EtOH) consumption behaviour can be regulated by modifying the kynurenine (KYN) pathway, although the mechanisms involved have not yet been well elucidated. To further explore the implication of the kynurenine pathway in EtOH consumption we inhibited kynurenine 3-monooxygenase (KMO) activity with Ro 61-8048 (100 mg/kg, i.p.), which shifts the KYN metabolic pathway towards kynurenic acid (KYNA) production. KMO inhibition decreases voluntary binge EtOH consumption and EtOH preference in mice subjected to "drinking in the dark" (DID) and "two-bottle choice" paradigms, respectively. This effect seems to be a consequence of increased KYN concentration, since systemic KYN administration (100 mg/kg, i.p.) similarly deters binge EtOH consumption in the DID model. Despite KYN and KYNA being well-established ligands of the aryl hydrocarbon receptor (AhR), administration of AhR antagonists (TMF 5 mg/kg and CH-223191 20 mg/kg, i.p.) and of an agonist (TCDD 50 μg/kg, intragastric) demonstrates that signalling through this receptor is not involved in EtOH consumption behaviour. Ro 61-8048 did not alter plasma acetaldehyde concentration, but prevented EtOH-induced dopamine release in the nucleus accumbens shell. These results point to a critical involvement of the reward circuitry in the reduction of EtOH consumption induced by KYN and KYNA increments. PNU-120596 (3 mg/kg, i.p.), a positive allosteric modulator of α7-nicotinic acetylcholine receptors, partially prevented the Ro 61-8048-induced decrease in EtOH consumption. Overall, our results highlight the usefulness of manipulating the KYN pathway as a pharmacological tool for modifying EtOH consumption and point to a possible modulator of alcohol drinking behaviour.

[Half-alive]

Try rosmaric acid or another IDO inhibitor.

https://www.sciencedirect.com/science/a ... 5206008513

https://www.longecity.org/forum/topic/1 ... a-anxiety/

[iull1k]

That's interesting, also the fact that acetylcholine is involved is interesting too.

[Ciprofloxacin]

Try rosmaric acid or another IDO inhibitor.

https://www.sciencedirect.com/science/a ... 5206008513

https://www.longecity.org/forum/topic/1 ... a-anxiety/

Do you think is this the right enzyme we need to block? Maybe shifting the metabolism pathway to the QA again, would solve it in an easy way. Although, I don’t know yet if IDO or TDO is affected or not. a KMO inducer and a KAT inhibitor together must reverse what the fluoxetine did me, according to the paragraph I had posted above.

Also,
It seems that the activity of IDO and TDO increases while there is an inflammation. And it usually leading to higher QA levels, according to this:

During inflammatory conditions and when IDO1 is upregulated, kynurenine metabolism shifts from the predominant production of KA toward the generation of increased amounts of QA. In the first metabolic reaction of this branch, KMO metabolizes kynurenine to 3-hydroxykynurenine (3-HK, Figure ​Figure1).1). While KAT enzymes are expressed in astrocytes, KMO is predominantly expressed in microglia, the resident immune cells in the brain (22). In response to inflammatory stimuli or tissue damage, KMO expression and 3-HK production also increase, effectively shuttling kynurenine metabolism toward the production of QA (23).

[mxh]

I found out that Theanine's action I've talked about elsewhere seems to work indirectly by nicotinic acetylcholine receptors working on AMPA receptors, releasing dopamine in some places. And the AMPA receptors seem to be more directly acted on by Glycine, as mentioned here. In any case, this is something I will look into more.

[Meso]

Cipro, before you ever got PSSD, did you suffer from CFS? Any tick bites or stomach ulcer (h. pylori)?

[Ciprofloxacin]

Cipro, before you ever got PSSD, did you suffer from CFS? Any tick bites or stomach ulcer (h. pylori)?

No. I didn't have any problems like them.

[Meso]

Cipro, before you ever got PSSD, did you suffer from CFS? Any tick bites or stomach ulcer (h. pylori)?

No. I didn't have any problems like them.

Your symptoms seem to be neuro-inflammatory in nature. I have a feeling that you had a latent condition that PSSD brought to the surface. Any neurodegenerative diseases that run in your family? (i.e. Parkinson's or Alzheimer's, etc) or autoimmune conditions? (Graves' disease, Hashimoto's, etc)