Tryptophan-kynurenine Metabolism Pathway Research Articles

Tryptophan-kynurenine metabolic pathway and daytime dysfunction in women with HIV.

Sleep disturbances are prevalent in women with HIV (WWH). Tryptophan-kynurenine (T-K) pathway metabolites are associated with alterations in actigraphy derived sleep measures in WWH, although may not always correlate with functional impairment. We investigated the relationship between T-K pathway metabolites and self-reported daytime dysfunction in WWH and women without HIV (WWoH). 141 WWH on stable antiretroviral therapy and 140 demographically similar WWoH enrolled in the IDOze Study had targeted plasma T-K metabolites measured using liquid chromatography-tandem mass spectrometry. We utilized the daytime dysfunction component of the Pittsburgh Sleep Quality Index (PSQI) to assess functional impairment across HIV-serostatus. Lower levels of 5-hydroxytryptophan and serotonin were associated with greater daytime dysfunction in all women. In WWH, daytime dysfunction was associated with increased kynurenic acid (R = 0.26, p < 0.05), and kynurenic acid-tryptophan (KA-T) ratio (R = 0.28, p < 0.01). WWH with daytime dysfunction had a 0.7 log fold increase in kynurenic acid compared to WWH without daytime dysfunction. Kynurenic acid levels and the KA-T ratio were associated with daytime dysfunction in WWH but not in WWoH. Longitudinal studies are needed to establish a causal relationship and directionality between T-K metabolic changes and sleep impairment in WWH.

IDO-1 impairs antitumor immunity of natural killer cells in triple-negative breast cancer via up-regulation of HLA-G

BackgroundTriple-negative breast cancers (TNBC) are highly aggressive malignancies with poor prognosis. As an essential enzyme in the tryptophan–kynurenine metabolic pathway, indoleamine 2,3 dioxygenase-1 (IDO-1) has been reported to facilitate immune escape of various tumors. However, the mechanism underlying the immunosuppressive role of IDO-1 in TNBC remains largely uncharacterized.MethodsWe examined the IDO-1 expression in 93 clinical TNBC tissues and paired adjacent normal tissues, and analyzed the regulation role of environmental cytokines like IFN-γ in IDO-1 expression. The effect of IDO-1 expression in TNBC cells on the function of NK cells were then evaluated and the underlying mechanisms were exploited.ResultsIDO-1 expressed in 50 of 93 (54.1%) TNBC patients. TNBC patients with high IDO-1 expression tended to have more infiltrated immune cells including NK cells, which are less active than patients with low IDO-1 expression. NK cells could produce IFN-γ, which induced IDO-1 expression in TNBC cells, whereas IDO-1 impaired the cytotoxicity of co-cultured NK cells by upregulation of HLA-G. Blockade of HLA-G improved the antitumor activity of NK cells to TNBC in vivo.ConclusionTNBC cells induce dysfunction of NK cells through an IFN-γ/IDO-1/HLA-G pathway, which provide novel insights into the mechanisms of TNBC progression and demonstrate the applicability of IDO-1 and HLA-G targeting in the treatment of TNBC.

Triphenyl phosphate disturbs placental tryptophan metabolism and induces neurobehavior abnormal in male offspring

Epidemiological studies have shown that prenatal triphenyl phosphate (TPhP) exposure is related to abnormal neurobehavior in children. However, the neurodevelopmental toxicity of TPhP in mammals is limited. To study the neurodevelopmental toxicity of TPhP in mammals and investigate the underlying mechanism, we used a mouse intrauterine TPhP exposure model. We measured the inflammatory factors (IL-6, TNFα) and NFκB levels, and tryptophan metabolism in placentae, detected the fetal brain transcriptome, hippocampal neuron development and neurobehavioral in the male offspring. The results showed that the protein level of IL-6, TNFα and NFκB in the placenta of the TPhP treatment group (1, 5 mg/kg) were significantly increased. Change of the protein level of these pro-inflammatory factors in maternal serum or fetal brain was not observed. Expression of genes along tryptophan-serotonin metabolism pathway were significantly decreased. While, the concentration of 5-HT levels in the placenta or fetal brain were significantly increased. Consistent with the increased 5-HT, the Nissl body was reduced in the hippocampus of treatment group. The expression of serotonergic neuron gene markers including Tph2, Htr1A, Htr2A, Pet1 and Lmx1b in the hippocampus of treatment group was significantly decreased. The neurobehavioral test showed that TPhP decreased center time that represent anxiety-like behavior, and reduced learning and memory in male offspring. Meanwhile, expression of genes along tryptophan-kynurenine metabolism pathway were significantly increased. The result of the transcriptome analysis of fetal brain showed that the differentially expressed genes are mainly involved in the transcription regulation of DNA as a template in the nucleus, and the enriched pathways are mainly signal pathways regulated by axon guidance and neurotrophic factors, dopaminergic and cholinergic synapses, suggest that not only serotonergic neuronal was affected. Overall, this study demonstrates that TPhP has the potential to induce placental inflammatory response in the placenta, disturb placental tryptophan metabolism, compromise the neuronal development and synaptic transmission, and cause abnormal neurobehavior in male offspring.

Metabolic Dysfunctions of Intestinal Fatty Acids and Tryptophan Reveal Immuno-Inflammatory Response Activation in IgA Nephropathy.

BackgroundImmunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis. Although an important link between intestinal metabolites and immune activity is widely established, the metabolic profile of IgAN is still poorly understood, which severely limits the mechanistic studies and therapy of IgAN.MethodsThe diversity of intestinal flora and relative abundance of metabolites in IgAN patients and healthy subjects were measured by 16s ribosomal RNA gene sequencing combined with liquid chromatography tandem-mass spectrometry. The levels of serum Gd-IgA1, IL-6, IL-10, IL-22, and TNF-a were tested by ELISA. We employed the tryptophan-targeted UHPLC-MRM-MS approach to assess the content of tryptophan metabolites quantitatively.ResultsIntestinal fatty acid levels, mainly unsaturated fatty acids, were observed to be dramatically decreased in IgAN patients. Disorders in linoleic acid and arachidonic acid metabolism, metabolic imbalances of anti-/pro- inflammatory fatty acid metabolites, and intestinal AhR signaling deficiency might reflect the damage of the intestinal mucosal barrier in IgAN patients. In addition, we found that high levels of Gd-IgA1, IL-22, and TNF-α were associated with the activity of the tryptophan-kynurenine metabolic pathway, as well as lower levels of 3-indolepropionic acid. 3-indolepropionic acid, kynurenine, and indoleacrylic acid had synergistic effects on regulating immuno-inflammatory responses in IgAN patients.ConclusionsThe metabolic characteristic of fatty acids and tryptophan in the intestinal system is disturbed in IgAN patients, leading to active immune-inflammatory reactions.

Co-Players in Chronic Pain: Neuroinflammation and the Tryptophan-Kynurenine Metabolic Pathway.

Chronic pain is an unpleasant sensory and emotional experience that persists or recurs more than three months and may extend beyond the expected time of healing. Recently, nociplastic pain has been introduced as a descriptor of the mechanism of pain, which is due to the disturbance of neural processing without actual or potential tissue damage, appearing to replace a concept of psychogenic pain. An interdisciplinary task force of the International Association for the Study of Pain (IASP) compiled a systematic classification of clinical conditions associated with chronic pain, which was published in 2018 and will officially come into effect in 2022 in the 11th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-11) by the World Health Organization. ICD-11 offers the option for recording the presence of psychological or social factors in chronic pain; however, cognitive, emotional, and social dimensions in the pathogenesis of chronic pain are missing. Earlier pain disorder was defined as a condition with chronic pain associated with psychological factors, but it was replaced with somatic symptom disorder with predominant pain in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) in 2013. Recently clinical nosology is trending toward highlighting neurological pathology of chronic pain, discounting psychological or social factors in the pathogenesis of pain. This review article discusses components of the pain pathway, the component-based mechanisms of pain, central and peripheral sensitization, roles of chronic inflammation, and the involvement of tryptophan-kynurenine pathway metabolites, exploring the participation of psychosocial and behavioral factors in central sensitization of diseases progressing into the development of chronic pain, comorbid diseases that commonly present a symptom of chronic pain, and psychiatric disorders that manifest chronic pain without obvious actual or potential tissue damage.

Immune Influencers in Action: Metabolites and Enzymes of the Tryptophan-Kynurenine Metabolic Pathway.

The tryptophan (TRP)-kynurenine (KYN) metabolic pathway is a main player of TRP metabolism through which more than 95% of TRP is catabolized. The pathway is activated by acute and chronic immune responses leading to a wide range of illnesses including cancer, immune diseases, neurodegenerative diseases and psychiatric disorders. The presence of positive feedback loops facilitates amplifying the immune responses vice versa. The TRP-KYN pathway synthesizes multifarious metabolites including oxidants, antioxidants, neurotoxins, neuroprotectants and immunomodulators. The immunomodulators are known to facilitate the immune system towards a tolerogenic state, resulting in chronic low-grade inflammation (LGI) that is commonly present in obesity, poor nutrition, exposer to chemicals or allergens, prodromal stage of various illnesses and chronic diseases. KYN, kynurenic acid, xanthurenic acid and cinnabarinic acid are aryl hydrocarbon receptor ligands that serve as immunomodulators. Furthermore, TRP-KYN pathway enzymes are known to be activated by the stress hormone cortisol and inflammatory cytokines, and genotypic variants were observed to contribute to inflammation and thus various diseases. The tryptophan 2,3-dioxygenase, the indoleamine 2,3-dioxygenases and the kynurenine-3-monooxygenase are main enzymes in the pathway. This review article discusses the TRP-KYN pathway with special emphasis on its interaction with the immune system and the tolerogenic shift towards chronic LGI and overviews the major symptoms, pro- and anti-inflammatory cytokines and toxic and protective KYNs to explore the linkage between chronic LGI, KYNs, and major psychiatric disorders, including depressive disorder, bipolar disorder, substance use disorder, post-traumatic stress disorder, schizophrenia and autism spectrum disorder.

Postpartum corticosterone and fluoxetine shift the tryptophan-kynurenine pathway in dams

Perinatal depression (PND) affects 15% of mothers. Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line of treatment for PND but are not always efficacious. Previously, we found significant reductions in plasma tryptophan concentrations and higher hippocampal proinflammatory cytokine, IL-1β levels, due to maternal SSRI treatment. Both inflammation and tryptophan-kynurenine metabolic pathway (TKP) are associated with SSRI efficacy in individuals with major depressive disorder (MDD). TKP is divided into neuroprotective and neurotoxic pathways. Higher metabolite concentrations of the neurotoxic pathway are associated with depression onset and implicated in SSRI efficacy. Metabolites in TKP were investigated in a rodent model of de novo postpartum depression (PPD) given treatment with the SSRI, fluoxetine (FLX). Dams were administered corticosterone (CORT) (40 mg/kg, s.c.), and treated with the SSRI, fluoxetine (FLX) (10 mg/kg, s.c.), during the postpartum for 22 days after parturition. Plasma TKP metabolite concentrations were quantified on the last day of treatment. Maternal postpartum CORT increased neurotoxic metabolites and co-enzyme/cofactors in dams (3-hydroxykynurenine, 3-hydroxyanthranilic acid, vitamin B2, flavin adenine dinucleotide). The combination of both CORT and FLX shifted the neuroprotective-to-neurotoxic ratio towards neurotoxicity. Postpartum FLX decreased plasma xanthurenic acid concentrations. Together, our data indicate higher neurotoxic TKP expression due to maternal postpartum CORT treatment, similar to clinical presentation of MDD. Moreover, maternal FLX treatment showed limited efficacy to influence TKP metabolites, which may correspond to its limited efficacy to treat depressive-like endophenotypes in the postpartum. Overall suggesting changes in TKP may be used as a biomarker of de novo PPD and antidepressant efficacy and targeting this pathway may serve as a potential therapeutic target.

What tomorrow will bring: Expectations for the next day predicting the cortisol awakening response in young adults

Perinatal depression (PND) affects 15% of mothers. Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line of treatment for PND but are not always efficacious. Previously, we found significant reductions in plasma tryptophan concentrations and higher hippocampal proinflammatory cytokine, IL-1β levels, due to maternal SSRI treatment. Both inflammation and tryptophan-kynurenine metabolic pathway (TKP) are associated with SSRI efficacy in individuals with major depressive disorder (MDD). TKP is divided into neuroprotective and neurotoxic pathways. Higher metabolite concentrations of the neurotoxic pathway are associated with depression onset and implicated in SSRI efficacy. Metabolites in TKP were investigated in a rodent model of de novo postpartum depression (PPD) given treatment with the SSRI, fluoxetine (FLX). Dams were administered corticosterone (CORT) (40 mg/kg, s.c.), and treated with the SSRI, fluoxetine (FLX) (10 mg/kg, s.c.), during the postpartum for 22 days after parturition. Plasma TKP metabolite concentrations were quantified on the last day of treatment. Maternal postpartum CORT increased neurotoxic metabolites and co-enzyme/cofactors in dams (3-hydroxykynurenine, 3-hydroxyanthranilic acid, vitamin B2, flavin adenine dinucleotide). The combination of both CORT and FLX shifted the neuroprotective-to-neurotoxic ratio towards neurotoxicity. Postpartum FLX decreased plasma xanthurenic acid concentrations. Together, our data indicate higher neurotoxic TKP expression due to maternal postpartum CORT treatment, similar to clinical presentation of MDD. Moreover, maternal FLX treatment showed limited efficacy to influence TKP metabolites, which may correspond to its limited efficacy to treat depressive-like endophenotypes in the postpartum. Overall suggesting changes in TKP may be used as a biomarker of de novo PPD and antidepressant efficacy and targeting this pathway may serve as a potential therapeutic target.

Structure based mimicking of Phthalic acid esters (PAEs) and inhibition of hACMSD, an important enzyme of the tryptophan kynurenine metabolism pathway

Human α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (hACMSD) is a zinc containing amidohydrolase which is a vital enzyme of the kynurenine pathway in tryptophan metabolism. It prevents the accumulation of quinolinic acid (QA) and helps in the maintenance of basal Trp-niacin ratio. To assess the structure based inhibitory action of PAEs such as DMP, DEP, DBP, DIBP, DEHP and their metabolites, these were docked into the active site cavity of hACMSD. Docking results show that the binding affinities of PAEs lie in the comparable range (−4.9 kca/mol–7.48kcal/mol) with Dipicolinic acid (−6.21kcal/mol), a substrate analogue of hACMSD. PAEs interact with the key residues such as Arg47 and Trp191 and lie within the 4Å vicinity of zinc metal at the active site of hACMSD. Dynamics and stability of the PAEs-hACMSD complexes were determined by performing molecular dynamics simulations using GROMACS 5.14. Binding free energy calculations of the PAEs-hACMSD complexes were estimated by using MMPBSA method. The results emphasize that PAEs can structurally mimic the binding pattern of tryptophan metabolites to hACMSD, which further leads to inhibition of its activity and accumulation of the quinolate in the kynurenine pathway of tryptophan metabolism.

Comprehensive analysis of the tryptophan metabolome in urine of patients with acute intermittent porphyria.

Acute intermittent porphyria (AIP) is a rare metabolic disorder due to a deficiency of porphobilinogen deaminase, the third enzyme of the heme biosynthetic pathway. This low enzymatic activity may predispose to the appearance of acute neurological attacks. Seminal studies suggested that AIP was associated with changes in tryptophan homeostasis with inconclusive results. Therefore, the aim of this study was to analyze the urinary metabolome of AIP patients focusing on tryptophan metabolism using state-of-the-art technology. This was a case-control study including a group of 25 AIP patients with active biochemical disease and increased excretion of heme-precursors and 25 healthy controls. Tryptophan and related compounds and metabolites including: large neutral amino acids (LNAAs), serotonin, kynurenine, kynurenic acid and anthranilic acid were quantified in urine by liquid chromatography tandem-mass spectrometry (LC-MS/MS). Twenty-nine biological markers (including metabolic ratios and absolute concentrations) were compared between patients and controls. Significant differences were found in the tryptophan-kynurenine metabolic pathway. Compared to controls, AIP patients showed: (a) increased urinary excretion of kynurenine and anthranilic acid (P<0.005); (b): elevation of the kynurenine/tryptophan ratio (P<0.001) and (c): decrease of the kynurenic acid/kynurenine ratio (P=0.001). In contrast, no differences were found in the serotonin metabolic pathway independently of the markers and ratios used. The results of the study demonstrate that there is an imbalance in the kynurenine metabolic pathway in AIP patients, with an increase of the kynurenine/tryptophan ratio in urine and a reduction of the kynurenic acid/kynurenine ratio. The modified ratios suggest induction of indoleamine 2,3-deoxygenase and decreased activity of kynurenine aminotransferase in the liver. The results confirm that LC-MS/MS is useful for the characterization of the urinary metabolome of hepatic porphyrias.

Maternal separation induces neuroinflammation and long-lasting emotional alterations in mice

Early life experiences play a key role in brain function and behaviour. Adverse events during childhood are therefore a risk factor for psychiatric disease during adulthood, such as mood disorders. Maternal separation is a validated mouse model for maternal neglect, producing negative early life experiences that result in subsequent emotional alteration. Mood disorders have been found to be associated with neurochemical changes and neurotransmitter deficits such as reduced availability of monoamines in discrete brain areas. Emotional alterations like depression result in reduced serotonin availability and enhanced kynurenine metabolism through the action of indoleamine 2, 3-dioxygenase in response to neuroinflammatory factors. This mechanism involves regulation of the neurotransmitter system by neuroinflammatory agents, linking mood regulation to neuroinmunological reactions. In this context, the aim of this study was to investigate the effects of maternal separation with early weaning on emotional behaviour in mice. We investigated neuroinflammatory responses and the state of the tryptophan–kynurenine metabolic pathway in discrete brain areas following maternal separation. We show that adverse events during early life increase risk of long-lasting emotional alterations during adolescence and adulthood. These emotional alterations are particularly severe in females. Behavioural impairments were associated with microglia activation and disturbed tryptophan–kynurenine metabolism in brain areas related to emotional control. This finding supports the preeminent role of neuroinflammation in emotional disorders.

Leucine blocks lipopolysaccharide-induced depression-like behavior by interfering with kynurenine influx into the brain.

Inflammation activates the tryptophan-kynurenine metabolism pathway. Circulating kynurenine is transported into the brain at the vascular blood–brain barrier (BBB) by the large amino-acid transporter LAT-1, where it is further metabolized into neurotoxic metabolites responsible for depressive symptoms. LAT-1 transports tryptophan, kynurenine and the amino acid leucine. We sought to competitively inhibit kynurenine blood-to-brain transport with leucine in order to attenuate lipopolysaccharide-induced depression-like behavior in CD-1 mice. Given that the concentration of circulating kynurenine is 100 fold less than kynurenine, we hypothesized that leucine should inhibit kynurenine more than tryptophan transport. We had already demonstrated that inflammation increases luminal-to-abluminal transport of tryptophan using an in vitro model of BBB transport. Here we show that lipopolysaccharide-treated mice (0.83 mg/kg, ip) develop depression-like behavior at 24 h (reduced sucrose preference and increased forced swim test immobility; p p p p

Interdependent and independent roles of type I interferons and IL-6 in innate immune, neuroinflammatory and sickness behaviour responses to systemic poly I:C.

Type I interferons (IFN-I) are expressed in the brain during many inflammatory and neurodegenerative conditions and have multiple effects on CNS function. IFN-I is readily induced in the brain by systemic administration of the viral mimetic, poly I:C (synthetic double-stranded RNA). We hypothesised that IFN-I contributes to systemically administered poly I:C-induced sickness behaviour, metabolic and neuroinflammatory changes. IFN-I receptor 1 deficient mice (IFNAR1(-/-)) displayed significantly attenuated poly I:C-induced hypothermia, hypoactivity and weight loss compared to WT C57BL/6 mice. This amelioration of sickness was associated with equivalent IL-1β and TNF-α responses but much reduced IL-6 responses in plasma, hypothalamus and hippocampus of IFNAR1(-/-) mice. IFN-β injection induced trivial IL-6 production and limited behavioural change and the poly I:C-induced IFN-β response did not preceed, and would not appear to mediate, IL-6 induction. Rather, IFNAR1(-/-) mice lack basal IFN-I activity, have lower STAT1 levels and show significantly lower levels of several inflammatory transcripts, including stat1. Basal IFN-I activity appears to play a facilitatory role in the full expression of the IL-6 response and activation of the tryptophan-kynurenine metabolism pathway. The deficient IL-6 response in IFNAR1(-/-) mice partially explains the observed incomplete sickness behaviour response. Reconstitution of circulating IL-6 revealed that the role of IFNAR in burrowing activity is mediated via IL-6, while IFN-I and IL-6 have additive effects on hypoactivity, but the role of IFN-I in anorexia is independent of IL-6. Hence, we have demonstrated both interdependent and independent roles for IFN-I and IL-6 in systemic inflammation-induced changes in brain function.

The impact of electroconvulsive therapy on the tryptophan-kynurenine metabolic pathway.

There is still limited knowledge about the mechanism of action of electroconvulsive therapy (ECT) in the treatment of depression. Substantial evidence suggests a role for the immune-moderated tryptophan (TRP)-kynurenine (KYN) pathway in depression; i.e. a depression-associated disturbance in the balance between the TRP-KYN metabolites towards a neurotoxic process. We, therefore, aimed to investigate the impact of ECT treatment on the TRP-KYN pathway, in association with ECT-related alterations in depressive symptoms. Twenty-three patients with unipolar or bipolar depression, treated with bilateral ECT twice a week were recruited. Blood serum samples, and depression scores using the Hamilton Depression Rating Scale-17 items (HDRS) as well as the Beck Depression Inventory (BDI) were collected repeatedly during the period of ECT and until 6 weeks after the last ECT session. TRP and KYN metabolites were analyzed in serum using the High Performance Liquid Chromatography. Four patients could not complete the study; thereby yielding data of 19 patients. Analyses were performed using multilevel linear regression analysis. There was an increase in kynurenic acid (KYNA) (B=0.04, p=0.001), KYN/TRP ratio (B=0.14, p=0.001), KYNA/KYN ratio (B=0.07, p<0.0001), and KYNA/3-hydroxykynurenine ratio (B=0.01, p=0.008) over time during the study period. KYN (B=-0.02, p=0.003) and KYN/TRP (B=-0.19, p=0.003) were negatively associated with total HDRS over time. Baseline TRP metabolite concentrations did not predict time to ECT response. Our findings show that ECT influences the TRP-KYN pathway, with a shift in TRP-KYN metabolites balance towards molecules with neuroprotective properties correlating with antidepressant effects of ECT; thereby providing a first line of evidence that the mechanism of action of ECT is (co)mediated by the TRP-KYN pathway.

84. Targeting the kynurenine blood-to-brain transport system to treat inflammation-induced fatigue and depression

Inflammation is associated with activation of the tryptophan-kynurenine metabolism pathway. Circulating kynurenine is transported into the brain at the vascular blood–brain barrier (BBB) by the large neutral amino-acid transporter LAT-1. LAT-1 transports tryptophan and kynurenine. To determine how LAT-1 responds to inflammation, we used mouse microvascular endothelial cells that form tight junctions in vitro and constitutively express the tryptophan degrading enzyme indoleamine 2,3-dioxygenase (IDO) and LAT-1. We first showed that addition of lipopolysaccharide and interferon-γ to the culture significantly increased endothelial cell IDO mRNA and the transport capacity of LAT-1 as measured with tryptophan from the luminal to the abluminal side of an in vitro model of the BBB. Before using leucine as a competitive inhibitor of LAT-1-mediated transport of kynurenine, we determined whether leucine can block the transport of tryptophan across BBB endothelial cells. Whereas leucine had no effect on tryptophan in the untreated BBB, it inhibited a portion of the enhanced transport of tryptophan conferred by pretreatment with lipopolysaccharide and interferon-γ. Consistent with this ability to block LPS-mediated brain uptake of tryptophan, leucine (administered 500 mg/kg IP before and 6 h after lipopolysaccharide) was also effective in abrogating lipopolysaccharide-induced decreases in locomotor activity and sucrose preference. Experiments are under way to assess the effect of leucine on kynurenine transport into the brain both in vivo and in vitro .

Hypericum Perforatum Decreased Hippocampus TNF-α and Corticosterone Levels with No Effect on Kynurenine/Tryptophan Ratio in Bilateral Ovariectomized Rats.

The present study was designed to investigate the effect Hypericum Perforatum (HP), on behavioral changes, corticosterone, TNF-α levels and tryptophan metabolism and disposition in bilateral ovariectomized rats compared to 17α -ethinylestradiol. Behavioral analysis by measuring immobility time in forced swimming test and open field test, serum and hippocampal corticosterone and TNF-α along with hippocampal kynurenine/tryptophan ratio were determined in mature ovariectomized rats treated orally either by HP at three different doses 125, 250, and 500 mg/kg/day or by 17α-ethinylestradiol 30 µg/kg/day for 30 days. Ovariectomized rats showed significant increase in immobility time in the forced swimming test. Along with elevation in serum and hippocampal TNF-α and corticosterone levels associated with significant increase in hippocampal kynurenine/tryptophan ratio. Immobility time in the forced swimming test was decreased in rats treated by different doses of HP in a dose dependent manner and 17α-ethinylestradiol with no concomitant changes in the open field test. Only Rats treated with HP exhibited significant decrease in the elevated serum and hippocampal TNF-α and corticosterone, which couldn't explain the associated insignificant effect on hippocampaus kynurenine/tryptophan ratio in comparison to ovariectomized untreated rats. It is concluded that increased tryptophan metabolism toward kynurenine secondary to elevated corticosterone and TNF-α might be one of the pathohphysiological mechanisms that could explain depression like state observed in this rat model. Further, the observed attenuating effect of HP on TNF-α and corticosterone could contribute in its antidepressant effect in this animal model by other ways than their effects on tryptophan-kynurenine metabolism pathway.

Tryptophan breakdown is increased in euthymic overweight individuals with bipolar disorder: a preliminary report

Individuals with bipolar disorder (BD) are disproportionately affected by symptoms of being overweight and metabolic syndrome when compared to the general population. The pertinence of this observation is underscored by observations that excess weight is associated with a more complex illness presentation, course, and outcome in BD. We present the first preliminary report of our BIPFAT study, which explored shared hypothesized pathophysiological pathways between being overweight and having BD. We investigated the tryptophan-kynurenine metabolism pathway as a proxy of dysregulated inflammatory homeostasis in euthymic, overweight individuals with BD (n = 78) compared to healthy controls (n = 156). Both blood kynurenine concentrations and the kynurenine to tryptophan ratio [(Kyn:Trp); an estimate of tryptophan breakdown] were significantly higher in the total sample of euthymic patients with BD, with greater increases noted in both parameters in the subsample of overweight patients with BD. When compared to controls, peripheral neopterin concentrations were significantly lower. Within the BD group, there were also significant between-group differences in neopterin concentrations, with higher levels in those who were overweight and in subjects with BD in the later stages of illness compared to earlier stages. Increased tryptophan breakdown, as well as neopterin levels in BD, may be an indirect mediator of immune-mediated inflammation. In BD, this may account for the high prevalence of medical comorbidities and increased mortality. The observation of increased kynurenine levels and Kyn:Trp, and altered circulating neopterin levels provides indirect evidence of increased activity of tryptophan-degrading indoleamine 2,3-dioxygenase in euthymic individuals with BD, underscoring the role of inflammatory mediators as a causative and/or consequent factor. More robust abnormalities in the overweight subsample underscore the additional inflammatory burden of medical comorbidity and suggest a shared pathophysiology as well as a mechanism mediating BD and cardiovascular disease.

Urinary excretion of tryptophan metabolites during phototherapy

PREVIOUS STUDIES in animals have d e m o n s t r a t e d that, under intense illumination, the transmission of light through living tissue takes place at a degree which causes the occurrence of photochemical reactions) It is known, in fact, that light exposure causes a decrease in blood riboflavin level. 2 Since this vitamin is involved in tryptophan metabolism, participating in the transformation of kynurenine into 3-hydroxykynurenine, 3,4 we have investigated the effects of light on the tryptophankynurenine metabolic pathway in a group of full-term hyperbil i rubinemic newborn infants treated with light exposure. Studies on the ur inary excre t ion of 5 -hyd roxy in dolacetic acid, which is the major metabolite of serotonin and which is derived from the t ryptophan-serotonin metabo l ic pa thway, have not demons t r a t ed any apprec iable changes dur ing the pho to the rapy of lowb i r th -we igh t infants when compared to un i r r ad ia t ed cont ro l subjec ts , imply ing that the p roduc t ion and Catabolism of se ro ton in in the two groups was the Same. 5 In addition the authors did not find any correlat ion be tween the dai ly excre t ion of 5 -hyd roxy in dolacet ic acid and bi r th weight , ges ta t ional age, or serum bilirubin concentration. 5