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Pathogenesis of Mood Disorders
Published in Dr. Ather Muneer, Mood Disorders, 2018
Among the products of the kynurenine pathway, kynurenic acid has a putative neuroprotective role by acting as an antagonist of NMDA receptors, while it also decreases glutamate levels via inhibition of α7 nicotinic receptors. 3-hydroxykynurenine is a free radical generator, and QA is an NMDA receptor agonist that also exerts neurotoxic effects via lipid peroxidation and disruption of the blood–brain barrier. The neurotoxic activity of QA has been known for more than 30 years and this metabolite should a priori be a therapeutic target by blocking its formation or antagonizing its excitotoxic effect on NMDA glutamatergic receptors. However, in the context of an inflamed brain the microglia are activated which release large quantities of glutamate, a process facilitated by the uptake of extracellular glutamine that is converted to glutamate by the enzyme glutaminase. Moreover, oxidative stress generated by 3-hydroxykynurenine and 3-hydroxyanthranilic acid further contributes to microglia priming. In the normal brain the clearance of glutamate is efficient as astrocytes uptake this substance and convert it to glutamine via glutamine synthetase which is recycled back to neurons for the continued formation of glutamate. However, in conditions of excitotoxicity the extracellular concentration of glutamate can increase up to 100 fold, overwhelming this mechanism of glutamate reprocessing. Such pathologically increased levels of glutamate result in atrophic changes in key mood regulating areas like the hippocampus and amygdala.30
Biochemical Effects in Animals
Published in Stephen P. Coburn, The Chemistry and Metabolism of 4′-Deoxypyridoxine, 2018
Druyan and Haeger-Aronsen125 administered 5 mg deoxypyridoxine per kilogram body weight per day, via an unspecified route, to rabbits receiving a presumably nutritionally complete natural diet. Excretion of kynurenine and 3-hydroxykynurenine was significantly increased before a tryptophan load. Compared with controls, deoxypyridoxine treatment decreased kynurenine excretion after a tryptophan load but did not significantly alter excretion of 3-hydroxykynurenine. Deoxypyridoxine significantly decreased delta-aminolevulinic acid excretion. Deoxypyridoxine also tended to reduce excretion of these substances in experimental porphyria. Administration of a single 25 mg dose of pyridoxine tended to reverse these effects.
Pharmacokinetics and metabolic disposition of a potent and selective kynurenine monooxygenase inhibitor, CHDI-340246, in laboratory animals
Published in Xenobiotica, 2021
Vinod Khetarpal, Todd Herbst, Diana Shefchek, Steven Ash, Michael Fitzsimmons, Mark Gohdes, Ignacio Munoz-Sanjuan, Celia Dominguez
The metabolism of kynurenine (KYN), formed as a product of tryptophan catabolism, is well known and occurs by three different pathways that are mediated by kynurenine monooxygenase (KMO), Kynureninase (KYNU) and kynurenine amino transferase (KATs) leading to the formation of 3-hydroxykynurenine (3-OH-KYN), anthranilic acid (AA), and kynurenic acid (KYNA), respectively. 3-OH-KYN and AA undergo further metabolism to form 3-hydroxy anthranilic acid (3-OH-AA) by reactions mediated by anthranilate 3-monooxygenase and KYNU, respectively. 3-OH-AA is a substrate of 3-hydroxy anthranilic acid oxidase which converts it to quinolinic acid (QA) through a semialdehyde intermediate. Several studies have implicated dysregulation of the KYN pathway (KP) metabolites in the pathophysiology of Huntington’s disease (HD) and other neurodegenerative diseases (Guidetti et al. 2000; Forrest et al. 2010; Sathyasaikumar et al. 2010), providing evidence that, among various KYN metabolites, 3-OH-KYN and QA are neurotoxic while KYN and KYNA are neuroprotective. KMO is a critical enzyme in the metabolism of KYN and its activity can determine the relative amounts of neuroprotective and neurotoxic metabolites. Therefore, KMO inhibition may have potential as a therapeutic approach for HD by shunting the pathway away from toxic metabolites (3-OH-KYN and QA) and towards the formation of protective metabolites (KYN and KYNA).
Tryptophan 2,3-dioxygenase, a novel therapeutic target for Parkinson’s disease
Published in Expert Opinion on Therapeutic Targets, 2021
Fanni Annamária Boros, László Vécsei
The first step of the KP is the conversion of Trp into N-formyl-L-kynurenine in a reaction catalyzed by indoleamine 2,3-dioxygenase 1 and 2 (IDO1 and IDO2) and tryptophan 2,3-dioxygenase (TDO) enzymes. N-formyl-L-kynurenine is then metabolized into L-kynurenine (KYN) by formamidase. KYN is situated at an important branch point of the KP, since it can be converted into i) kynurenic acid (KYNA) by kynurenine aminotransferases (KATs), ii) anthranilic acid (AA) by kynureninase (KYNU), and iii) 3-hydroxykynurenine (3-HK) via a reaction catalyzed by kynurenine 3-monooxygenase (KMO). 3HK can further be metabolized into xanthurenic acid (XA) by KATs or can form 3-hydroxyanthranilate (3-HAA), which is further converted into 2-amino-3-carboxymuconate semialdehyde (ACMS) in a reaction catalyzed by 3-hydroxyanthranilate 3,4-dioxygenase. ACMS can be further processed by aminocarboxymuconate-semialdehyde decarboxylase (ACMSD) for the synthesis of 2-aminomuconate semialdehyde, which is then further metabolized into picolinic acid (PIC). ACMS can also undergo non-enzymatic cyclization and form quinolinic acid (QUIN), which is then ultimately metabolized into nicotinamide adenine dinucleotide (NAD+), a crucial molecule for cellular energy production and metabolism.
Involvement of the microbiota-gut-brain axis in chronic restraint stress: disturbances of the kynurenine metabolic pathway in both the gut and brain
Published in Gut Microbes, 2021
Yuanyuan Deng, Manfei Zhou, Junfeng Wang, Jiaxi Yao, Jing Yu, Wenwei Liu, Linlin Wu, Jun Wang, Rong Gao
Neurochemical imbalances, especially the neurotransmitter imbalances in the tryptophan (Trp) pathway, underlie the pathophysiology of mood disorders.6 One major metabolite of Trp is serotonin (5-hydroxytryptamine, 5-HT), which modulates cognition, reward, physiological processes, etc.7,8 5-HT is mainly located in the gastrointestinal tract and brain, with a few circulating in peripheral blood.9 The pathophysiology of depression has been closely linked to low levels of 5-HT.10–12 Reciprocally, selective serotonin reuptake inhibitors (SSRIs), the commonly prescribed antidepressants in clinical treatment, target the serotoninergic system by inhibiting the uptake of 5-HT and increasing its synaptic level.13,14 Notably, disturbances in Trp metabolism can activate the kynurenine (Kyn) pathway, contributing to alterations in kynurenic acid (Kna), 3-hydroxykynurenine (3-HK) and quinolinic acid (QA),15 which are remarkably associated with psychiatric diseases such as depression.16 Figure. S1 represents the detailed Trp pathway and its major metabolites.