Neuroactive kynurenines

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is defined as chronic inflammation in the gastrointestinal tract. Notably, more than 20% of people with IBD experience depressive symptoms. Understanding the immunological mechanism of chronic intestinal inflammation on cognitive behavior has become a key research focus. Previous studies have shown that a dysregulated immune response contributes to chronic inflammation and depressive symptoms. The tolerant phenotype exhibited by immune cells regulates the course of chronic inflammation in distinct ways...

BACKGROUND: Binge drinking is the consumption of an excessive amount of alcohol in a short period of time. This pattern of consumption is highly prevalent during the crucial developmental period of adolescence. Recently, the severity of alcohol use disorders (AUDs) has been linked with microbiome alterations suggesting a role for the gut microbiome in its development. Furthermore, a strong link has emerged too between microbiome composition and socio-emotional functioning across different disorders including AUD...

Migraine is a complex neurovascular disorder, which causes intense socioeconomic problems worldwide. The pathophysiology of disease is enigmatic; accordingly, therapy is not sufficient. In recent years, migraine research focused on tryptophan, which is metabolized via two main pathways, the serotonin and kynurenine pathways, both of which produce neuroactive molecules that influence pain processing and stress response by disturbing neural and brain hypersensitivity and by interacting with molecules that control vascular and inflammatory actions...

INTRODUCTION: Cannabis abuse during adolescence is a risk factor for cognitive impairments in psychiatric disorders later in life. To date, the possible causal relationship between cannabinoids, kynurenic acid (KYNA; i.e., a neuroactive metabolite of tryptophan degradation) and cognition has not been investigated in adolescence. Early exposure to delta 9-tetrahydrocannabinol (THC; i.e., the main psychotropic component of cannabis) causes enduring cognitive deficits, which critically involve impaired glutamatergic function in the prefrontal cortex (PFC)...

BACKGROUNDThe kynurenine pathway (KP) has been identified as a potential mediator linking acute illness to cognitive dysfunction by generating neuroactive metabolites in response to inflammation. Delirium (acute confusion) is a common complication of acute illness and is associated with increased risk of dementia and mortality. However, the molecular mechanisms underlying delirium, particularly in relation to the KP, remain elusive.METHODSWe undertook a multicenter observational study with 586 hospitalized patients (248 with delirium) and investigated associations between delirium and KP metabolites measured in cerebrospinal fluid (CSF) and serum by targeted metabolomics...

Objective: Our study aimed to investigate the associations between the serum level of kynurenine pathway (KP) metabolites and P50 auditory gating in non-smoking patients with first-episode schizophrenia (FES). Materials and methods: In this study, 82 non-smoking patients with FES and 73 healthy controls (HC). P50 auditory gating was measured using a fully functional digital 64-channel EEG system, and the components included S1 amplitude, S2 amplitude, gating ratio (S2/S1), and amplitude difference (S1-S2)...

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While mephedrone (4-methylmethcathinone), a synthetic cathinone derivative, is widely abused by adolescents and young adults, the knowledge about its long-term effects on memory processes is limited. Kynurenic acid (KYNA) is a neuroactive metabolite of the kynurenine pathway of tryptophan degradation. KYNA is considered an important endogenous modulator influencing physiological and pathological processes, including learning and memory processes. The aim of this study was to determine whether (A) binge-like mephedrone administration (10...

Although bisphenol F (BPF), the main replacement for bisphenol A, has been commonly used in polycarbonate production, its neurotoxicity and the underlying mechanisms remain poorly understood. To address this knowledge gap, this study aimed to assess the neurotoxicity caused by chronic exposure to BPF and to identify its underlying mechanisms. We exposed adult zebrafish chronically to BPF at environmentally relevant concentrations (0.001, 0.01, and 0.1 mg/L) for 4 weeks. The results revealed that with BPF crossing the blood-brain barrier and bioaccumulating in brain tissues, chronic exposure to BPF resulted in anxiety-like behaviors and disruptions in learning and memory function in adult zebrafish...

The pivotal tryptophan (TRP) metabolite kynurenine is converted to several neuroactive compounds, including kynurenic acid (KYNA), which is elevated in the brain and cerebrospinal fluid of people with schizophrenia (SZ) and may contribute to cognitive abnormalities in patients. A small proportion of TRP is metabolized to serotonin and further to 5-hydroxyindoleacetic acid (5-HIAA). Notably, KP metabolism is readily affected by immune stimulation. Here, we assessed the acute effects of an oral TRP challenge (6 g) on peripheral concentrations of kynurenine, KYNA and 5-HIAA, as well as the cytokines interferon-γ, TNF-α and interleukin-6, in 22 participants with SZ and 16 healthy controls (HCs) using a double-blind, placebo-controlled, crossover design...

OBJECTIVE: Tryptophan is an essential amino acid wholly derived from diet. While the majority of tryptophan is degraded through the kynurenine pathway into neuroactive metabolites like quinolinic acid and kynurenic acid, a small proportion of ingested tryptophan is metabolized into the neurotransmitter serotonin. The current cross-sectional study in Japan examined the association between tryptophan intake and depressive symptoms during pregnancy. METHODS: Study subjects were 1744 pregnant women...

Kynurenic acid (KynA) and quinolinic acid (QA) are neuroactive kynurenine pathway (KP) metabolites that have neuroprotective and neurotoxic properties, respectively. At least partly as a result of immune activation, the ratio of KynA to QA in the blood is reduced in major depressive disorder (MDD) and has been reported to be positively correlated with gray matter volume in depression. This study examined whether the inflammatory mediator, C-reactive protein (CRP) and the putative neuroprotective index, KynA/QA, were associated with white matter integrity in MDD, and secondly, whether any such associations were independent of each other or whether the effect of CRP was mediated by KynA/QA...

Kynurenines have immunomodulatory and neuroactive properties and can influence the central nervous system. Previous studies showed the involvement of the kynurenines in the pathogenesis and progression of neurodegenerative disease. In neurodegenerative disorders, including tauopathies, the tryptophan metabolism is shifted toward neurotoxic agents and the reduction of neuroprotectant products. Astrocyte-derived kynurenic acid serves as a neuroprotectant. However, systemic administration of kynurenic acid is not effective because of low permeability across the blood-brain barrier (BBB)...

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, complex, and highly debilitating long-term illness. People with ME/CFS are typically unable to carry out their routine activities. Key hallmarks of the disease are neurological and gastrointestinal impairments accompanied by pervasive malaise that is exacerbated after physical and/or mental activity. Currently, there is no validated cure of biomarker signature for this illness. Impaired tryptophan (TRYP) metabolism is thought to play significant role in the pathobiology of ME/CFS...

Depression during and after pregnancy affects up to 20% of pregnant women, but the biological underpinnings remain incompletely understood. As pregnancy progresses, the immune system changes to facilitate fetal development, leading to distinct fluctuations in the production of pro-inflammatory factors and neuroactive tryptophan metabolites throughout the peripartum period. Therefore, it is possible that depression in pregnancy could constitute a specific type of inflammation-induced depression. Both inflammatory factors and kynurenine metabolites impact neuroinflammation and glutamatergic neurotransmission and can therefore affect mood and behavior...

Evidence, largely obtained from peripheral studies, suggests that alterations in the kynurenine pathway contribute to the aetiology of depression and disorders involving psychosis. Stimulation of the kynurenine pathway leads to the formation of neuroactive metabolites, including kynurenic acid (predominantly in astrocytes) and quinolinic acid (predominantly in microglia), which are antagonists and agonists of the glutamate NMDA receptor, respectively. In this study, we measured gene expression via qRT-PCR of the main kynurenine pathway enzymes in the anterior cingulate cortex (ACC) in people with major depressive disorder and matched controls...

BACKGROUND: Imbalance in tryptophan (TRP) metabolism and its neuroactive metabolites, serotonin and kynurenine (KYN), is a known pathogenic mechanism underlying neurocognitive impairment. Gut microbiota plays an important role in TRP metabolism, and the production of these neuroactive molecules affects neurocognitive function. Although both HIV infection and normal aging independently induce gut dysbiosis and influence TRP metabolism, their interactive effects on compositional/functional changes in gut microbiota and consequent alterations in TRP metabolites remain largely undetermined...

sKynurenine (KYN) is synthesized from an essential amino acid, tryptophan by tryptophan 2,3-dioxygenase or indoleamine 2,3-dioxygenase via N-formyl- KYN in vivo. Subsequently, KYN acts as a precursor of some neuroactive metabolites such as kynurenic acid, quinolinic acid, and an important enzyme co-factor, nicotine adenine dinucleotide. These metabolites of tryptophan are a part of the "kynurenine pathway." In addition, KYN functions as an endogenous ligand for the aryl hydrocarbon receptor, which acts as a transcription factor...

Background Brain injury and neurological deficit are consequences of cardiac arrest (CA), leading to high morbidity and mortality. Peripheral activation of the kynurenine pathway (KP), the main catabolic route of tryptophan metabolized at first into kynurenine, predicts poor neurological outcome in patients resuscitated after out-of-hospital CA. Here, we investigated KP activation in hippocampus and plasma of rats resuscitated from CA, evaluating the effect of KP modulation in preventing CA-induced neurological deficit...

Alterations in the activity of tryptophan 2,3-dioxygenase (TDO) cause imbalances in the levels of serotonin and other neuroactive metabolites which can contribute to motor, psychiatric, gastrointestinal, and other dysfunctions often seen in Parkinson's disease (PD). TDO is a key enzyme of tryptophan metabolism at the entry of the kynurenine pathway (KP) which moderates production of neuroactive compounds primarily outside the central nervous system (CNS). Recent data from experimental models indicate that TDO modulation could have beneficial effects on PD symptoms not targeted by traditional dopamine substitution therapies...