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Background: The increased degradation of tryptophan (Trp) along the kynurenine (Kyn) pathway due to inflammation and/or activation of the hypothalamic-pituitary–adrenal (HPA) axis has been reported among the biological factors involved in the pathophysiology of major depressive disorder (MDD) and suicide. However, the interaction among these multiple factors is not yet completely clarified. Method: We studied plasma levels of Trp, Kyn, cortisol and proinflammatory cytokines (IL-1, IL- 6, IL-12, IL-20) and calculated the ratio Kyn/Trp as an index of the breakdown of Trp into Kyn in 31 suicidal MDD patients and 67 non-suicidal MDD patients. Result: We confirmed that suicidal MDD patients have reduced plasma Trp, higher Kyn and Kyn/Trp ratio, and no difference in cortisol levels than non-suicidal MDD patients. IL-1 and IL-12 levels were significantly higher in suicidal MDD than in non-suicidal MDD (p=0.034 and p=0.023, respectively), whereas Il-6 and IL-20 levels were equal in the two groups. The Kyn/Trp ratio was positively correlated with a pro-inflammatory cytokines index (r=0.309, p=0.002) and cortisol (r=0.368, p=0.001). Notably, the variance in the Kyn/Trp ratio explained by the model including both cortisol and inflammatory parameters as dependent variables, substantially improved compared with the models in which the two parameters were considered separately. Conclusion: These findings show that both cortisol and proinflammatory cytokines are involved in the enhanced breakdown of Trp into Kyn occurring in suicidal MDD patients, thus adding new knowledge on the biological mechanisms leading to the activation of the Kyn pathway in MDD and suicide.

Objectives: Patients affected by major depression (MDD) are at high risk of suicide. The metabolism of tryptophan (Trp) along the serotonin (5-HT) and kynurenine (Kyn) pathways was found dysfunctional in MDD and in suicide. However, a clear biological framework linking dysfunctions in Trp metabolism via 5-HT and Kyn, cortisol, and the activities of tryptophan and indoleamino 2,3-dioxygenase (TDO, IDO) enzymes has not been yet clarified in MDD with or without suicidal behaviours. Methods: We analysed peripheral markers of Trp via 5-HT and Kyn pathways, Kyn/Trp ratio as a measure of TDO/IDO activities, cortisol, and psychopathology in 73 non-suicidal and 56 suicidal MDD patients, and in 40 healthy controls. Results: Plasma Trp levels were lower and the ratio Kyn/Trp higher in suicidal MDD than in non-suicidal MDD patients and controls. Trp levels and the ratio Kyn/Trp correlated with suicidal ideation, and cortisol with the Kyn/Trp ratio. Finally, Trp levels discriminated controls from non-suicidal and suicidal MDD patients, and also non-suicidal from suicidal MDD patients. Conclusions: Reduced availability of Trp for 5-HT synthesis and increased activation of the Kyn pathway and cortisol correlate with depression and suicide. Low plasma Trp levels may be a biomarker of MDD and suicide in MDD.

Aggressive behavior is one of the most challenging symptoms in psychiatry, and biological markers for aggression lack of large sample validations. Serotonin (5-HT) and other neuroactive compounds deriving from Tryptophan (Trp), including kynurenine (Kyn), have not yet been investigated in large cohorts of aggressive individuals to validate their potential as biomarkers of aggression.In 361 male inmates we measured serum levels of Trp, 5-hydroxytryptophan, 5-HT, Kyn, the ratios 5-HT/Trp * 1000 and Kyn/Trp * 1000, and performed Structured Clinical Interview for DSM-IV Axis-I and -II Disorders (SCID-I and -II), global assessment of functioning (GAF), and scales for aggressive behavior, impulsivity, adult attention-deficit/hyperactivity disorder (ADHD), and intelligent quotient (IQ).Aggressive compared to non-aggressive inmates exhibited lower Trp and Kyn serum levels but higher levels of 5-HT and 5-HT/Trp * 1000, higher levels of impulsivity and ADHD indices, lower IQ and GAF, higher prevalence of mood disorders, drug abuse/dependence, and borderline, conduct and antisocial behaviors. Interestingly, Kyn/Trp * 1000 was positively correlated to the number of severe aggressive acts (r = 0.593, P < 0.001). After adjusting for confounding factors, logistic regression analysis indicated that 5-HT/Trp * 1000, antisocial behavior, and GAF were predictors of aggressive behavior. The model combining these three predictors had an area under the ROC curve of 0.851 (95% CI 0.806-0.895).This study indicates that while circulating Trp is reduced in aggressive individuals, the combination of biological (5-HT/Trp ratio) and psychopathological (antisocial behavior and GAF) markers discriminates between aggressive and non-aggressive behavior suggesting the potential of a multi-marker approach in psychiatry given the heterogenic nature of mental diseases.

In order to investigate the role of tryptophan and its metabolites in biogenesis of melanins, a study on the enzymatic reaction of 3-hydroxykynurenine with tyrosinase and peroxidase was performed. The reaction at different pH values was monitored by sampling at different times, with ultrafiltration used before analysis by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). The data obtained in this way showed that oligomerization processes take place with both enzymes, but with different behaviour, also depending on pH. 3-Hydroxykynurenine in the presence of tyrosinase at pH 6.0 leads to formation of xanthommatin, and at pH 8.0 hydroxanthommatin is formed in the first step of the reaction followed by formation of black-brown pigments. In contrast, the formation of oligomerization products by peroxidase action is observed in high yields under both acidic and basic conditions; however, at pH 6.0, a more extensive oligomerization process is observed. Thus peroxidase is able to activate oligomerization analogous to that observed in the case of tyrosinase without depending on the variation of pH. Due to the early formation of decarboxylated hydroxykynurenine, hydroxanthommatin and decarboxylated hydroxanthommatin, the enzymatic reaction leads to mixed oligomers, which can be considered as precursors of new pathways in pigment production.

The currently recommended therapy for chronic hepatitis C (HCV) is a combination of pegylated interferon-alpha (PEG-IFN alpha) and ribavirin. Psychiatric disorders, including depression, are frequent in HCV patients under therapy. We investigated the effect of the antiviral treatment on tryptophan (Trp) metabolism along both serotonin pathway (via 5-hydroxytryptophan, 5-HTP) and kynurenine (Kyn) pathway and on the onset of depressive symptoms in patients with HCV. The key enzyme of the Kyn pathway is indoleamine 2,3-dioxygenase (IDO), an intracellular haem protein enzyme expressed in several tissues. It was also investigated the influence of the therapy with PEG-IFN-alpha-2a or PEG-IFN-alpha-2b plus oral ribavirin and possible differences between genders. Free and total Trp, 5-hydroxytryptophan (5-HTP) and Kyn serum concentrations and the presence of depressive symptoms [Beck Depression Inventory (BDI) scores] were evaluated in 45 patients with HCV infection treated with PEG-IFN alpha-2a or -2b at four different times: baseline (before treatment), 1 and 6 months during therapy, and 3 months after the end of therapy. The concentration of serum total TRP (free + protein bound) as well as that of 5-HTP significantly decreased after 1 and 6 months of therapy, and then returned to baseline values 3 months after the end of therapy, while the levels of free TRP did not vary significantly during and after the therapy. On the contrary, the time course of Kyn markedly arose during treatment, paralleled by a significant increase of [Kyn/Trp] × 10 3 ratio, an index used to measure IDO activity. No significant difference was detected between males and females neither between PEG-IFN-alpha-2a or -2b treatment. The BDI scores significantly increased during therapy, and returned to baseline values 3 months after the end of therapy. Our results support the hypothesis that the increased IDO-mediated tryptophan metabolism along the Kyn pathway, leading to plasma Trp depletion and a decline of serotonin pathway, concurs to the development of depressive symptoms observed in HCV patients undergoing IFN-alpha therapy. © 2010 Elsevier Masson SAS. All rights reserved.

Since alterations of tryptophan metabolism have been reported in diabetes and atherosclerosis, it was thought of interest to investigate any role of cloricromene through the influence on the oxidative metabolism of the amino acid by using diabetic/hyperlipidemic rabbits. Male 4-month-old New Zealand white rabbits, fed a diet enriched with 1% cholesterol and 10% corn oil, were made diabetic with alloxan. During the hyperlipidemic diet, a group of rabbits was treated with cloricromene (10 mg/kg/day subcutaneously plus 1.5 mg/kg/day intravenously, for 5 weeks). The other group received saline. Normometabolic New Zealand rabbits fed standard diet, treated or not with cloricromene, were used as control. The specific activities of liver tryptophan 2,3-dioxygenase and small intestine indole 2,3-dioxygenase were not significantly changed by the drug treatment. Also the specific activities of other enzymes of the kynurenine pathway in the liver and kidneys, specifically kynurenine 3-monooxygenase, kynureninase and kynurenine-oxoglutarate transaminase, did not show any significant difference in both tissues between the two groups of rabbits. On the contrary, 3-hydroxyanthranilate 3,4-dioxygenase activity in the liver of diabetic/hyperlipidemic rabbits and control rabbits treated with cloricromene showed a slight increase in comparison with untreated animals. Conversely, the specific activity of the enzyme in kidneys was not affected by the drug treatment in diabetic/hyperlipidemic animals but was reduced in controls. Aminocarboxymuconate-semialdehyde decarboxylase specific activity remained unchanged in the liver following cloricromene treatment, instead the specific activity of the enzyme in the kidneys of the diabetic/hyperlipidemic rabbits was significantly increased by the drug, with a value more than double in comparison to untreated animals. The activity of the scavenger enzyme Cu/Zn superoxide dismutase (Cu/Zn SOD) in the small intestine was also determined and found significantly increased of about twice as much in the group of diabetic/hyperlipidemic rabbits treated with cloricromene. In conclusion, in diabetic/hyperlipidemic rabbits, cloricromene appeared to influence the enzymes involved in the last steps of tryptophan oxidative metabolism through the kynurenine pathway. This, together with the antioxidant action through the activation of Cu/Zn SOD, might deserve further investigation for evaluating any link between the observed experimental findings at the level of the kynurenine pathway and the clinical effect of the drug.

Background Quinolinic acid and other kynurenine metabolites of the oxidative metabolism of tryptophan play an important role in several pathophysiological conditions. We aimed to study the effect of age on the enzyme activities of tryptophan metabolism along the kynurenine pathway. Methods Enzyme activity was investigated in liver, kidneys and small intestine obtained from Sprague–Dawley rats of various ages (1 week, 2–3, 12 and 18 months). Results We found age-related differences in the liver tryptophan 2,3-dioxygenase, small intestine indole 2,3-dioxygenase, liver and kidney kynurenine 3-monooxygenase activities, which decreased significantly with age. Also liver kynureninase activity declined with age, while the activity in kidneys did not show an evident age-related pattern from 2–3 months to 18 months of age. Liver kynurenine oxoglutarate transaminase was quite similar through all considered age groups, while the activity in kidneys was significantly lower in newborn rats and progressively increased up to 12 months, then significantly decreased at 18 months of age. Liver and kidney 3-hydroxyanthranilate 3,4-dioxygenase progressively and significantly increased from newborns to 12 months of age; in the group of rats aged 18 months, the enzyme activity tended to diminish, although not significantly. The liver aminocarboxymuconate-semialdehyde decarboxylase activity increased up to 12 months of age, then tended to decrease at 18 months, while in the kidneys, in which the activity was higher than in the liver at all the considered ages, the activity remained constantly elevated from 2–3 months to 18 months of age. Conclusions A progressive decline in the enzyme activities involved in tryptophan metabolism along the kynurenine pathway in rat tissues was found with age, except for aminocarboxymuconate-semialdehyde decarboxylase, which, on the contrary, was increased after 2–3 months to the other older groups of age. The altered metabolism of tryptophan with ageing can lead to a decreased biosynthesis of nicotinic acid, tryptophan being the major source of body stores of NAD coenzymes, which are involved in almost all biogenetic and biosynthetic pathways of the organism.

Background The activity of nicotinic acid in hypercholesterolemia has been poorly understood. In man, nicotinic acid derives for the most part from tryptophan along the tryptophan–nicotinic acid pathway, also called the kynurenine pathway, kynurenine being the key metabolite in this process. In the present paper, we investigated if, in animals with hypercolesterolemia, degradation of tryptophan to nicotinic acid along the kynurenine pathway was perturbated. Methods Liver, kidney and intestine enzyme activities of the tryptophan–nicotinic acid pathway in normolipidemic, diet-induced hyperlipidemic New Zealand and heritable hypercholesterolemic Watanabe (WHHL) rabbits were determined. Results Liver tryptophan 2,3-dioxygenase (TDO) activity was present only as a holoenzyme and was higher in the controls than in the hyperlipidemic and Watanabe rabbits, but no difference was present between the group fed an atherogenic hyperlipidic diet and the WHHL rabbits. Small intestine indole 2,3-dioxygenase (IDO) did not vary significantly among the three groups but was higher in comparison with liver TDO activity. In liver, kynurenine 3-monooxygenase and kynurenine-oxoglutarate transaminase activities did not show any significant difference among the three groups of rabbits. Kynureninase and 3-hydroxyanthranilate 3,4-dioxygenase activities per g of fresh tissue decreased significantly in the group of hyperlipidemic and in WHHL rabbits. In the kidneys, kynurenine 3-monooxygenase and kynureninase activity did not change significantly in the three groups of rabbits; kynurenine-oxoglutarate transaminase activity per g of fresh tissue decreased in both hyperlipidemic groups, but no significant difference was observed between hyperlipidemic and Watanabe rabbits. 3-Hydroxyanthranilate 3,4-dioxygenase activity in kidney was decreased markedly in hyperlipidemic and Watanabe rabbits, but there was no difference between the two hypercholesterolemic groups. Aminocarboxymuconate-semialdehyde decarboxylase activity did not change. Thus 3-hydroxyanthranilate 3,4-dioxygenase may be an important regulatory mechanism in the control of the flow of tryptophan along the kynurenine pathway to NAD in hypercholesterolemic rabbits. Conclusions This study first demonstrates that in rabbits, hypercholesterolemia, both diet- or genetically induced, can influence the enzyme activities of the tryptophan–nicotinic acid pathway leading to a decreased formation of nicotinic acid, and thus NAD.

Bipolar (BD) and major depression (MDD) disorders are severe mental illnesses characterised by altered levels of immune/inflammatory markers and disrupted white matter (WM) microstructure. A pro-inflammatory state was suggested to activate indoleamine 2,3-dioxygenase which, in turn, increases the amount of tryptophan (Trp) converted into kynurenine (Kyn). We investigated whether plasma levels of Trp, Kyn and Kyn/Trp ratio are associated with peripheral levels of immune/inflammatory markers and whether they are related to WM integrity in 100 MDD and 66 BD patients. Patients also underwent MRI, and fractional anisotropy (FA) was estimated as a measure of WM microstructure. BD patients showed higher Kyn levels and Kyn/Trp ratio than MDD patients, and lower FA in several WM tracts, including the corpus callosum and the inferior fronto-occipital fasciculus (IFO). Lower Trp levels associated with a more severe depressive symptomatology irrespective of diagnosis and with lower FA in the corpus callosum (CC) and external capsule (EC). We found an association of immune/inflammatory markers with Kyn/Trp ratio selectively in BD patients: IL-1β and TNF-α showed a positive relationship and IL-2 and IL-9 a negative relationship; in addition, higher IL-4 correlated with lower Kyn levels; higher Kyn/Trp ratio and IL-1β correlated with lower FA in the CC and IFO. Notably, the detrimental effect of IL-1β on the IFO was moderated by the Kyn/Trp ratio. These data suggest that in BD, cytokines and the conversion of Trp into Kyn may affect WM microstructure and support the idea that distinct mechanisms underlie the pathophysiology of BD and MDD.