Kynurenine Pathway In Patients Research Articles

Level of selected exponents of the kynurenine pathway in patients diagnosed with depression and selected cancers

Altered immune system activity is one of the common pathomechanisms of depressive disorders and cancer. The aim of this study is to evaluate level of selected elements of the kynurenine pathway in groups of depressed and oncological patients. The study included 156 individuals, aged 19–65 years (M = 43.46, SD = 13.99), divided into three groups, namely depressive disorders (DD), oncology patients (OG), and a comparison group of healthy subjects (CG). A sociodemographic questionnaire and the Hamilton Depression Rating Scale (HDRS) were used in the study to assess the intensity of depressive symptoms. Level of TDO2, L-KYN, HK, AA and QA was significantly higher in patients from OG and DD groups than in the comparison group. TDO2 level in the OG group was positively correlated with the severity of depressive symptoms. When the OG and DD groups were analyzed together, level of TDO2, 3-HKYN, AA, QA correlated positively with the severity of depressive symptoms. Thus, kynurenine pathway might play an integral role in the pathogenesis of depression.

Herpes simplex reactivation triggers symptom exacerbation in patients with major depressive disorder

BackgroundHerpes Simplex Virus (HSV) infection has been linked to depression, but the underlying mechanism remains largely unknown. We hypothesized that recurring HSV infection could exacerbate depressive symptomatology via activation of the immune response and the kynurenine pathway in patients with Major Depressive Disorder (MDD). Methods32 MDD patients and 17 psychiatrically healthy individuals with a history of HSV recurrence were enrolled into the study. Blood samples were obtained, and psychiatric symptom severity was assessed at three separate visits- asymptomatic, active infection, and follow-up. Plasma levels of tryptophan metabolite levels were measured using ultra-high performance liquid chromatography-mass spectrometry (LC-MS), and inflammation-associated proteins were measured using high sensitivity electrochemiluminescence. ResultsThere was a significant effect of infection recurrence on IFN-γ and sICAM-1 levels, the latter being influenced by MDD diagnosis. This indicates that the effect of infection on sICAM-1 levels differs between control and depressed groups, although post hoc analysis suggests that interaction effect might be subtle. Infection recurrence had a significant effect on the reactivity of psychiatric symptoms. Finally, there was a positive correlation between levels of anti-inflammatory cytokines IL-10 and IL-13 and depression severity in the cohort during infection recurrence. LimitationsRelatively small sample size, limited number of male participants, and the relatively weak inflammatory stimuli studied. ConclusionsMDD patients might react with an exacerbation of symptoms along with elevations of inflammatory markers during HSV recurrence. Further, the association with symptom severity indicates that therapeutic modulation of inflammation may be beneficial in patients with MDD, especially during active infections.

The kynurenine pathway in patients with rheumatoid arthritis during tumor necrosis factor α inhibitors treatment

ObjectivesThe importance of the kynurenine pathway in normal immune system function has led to an appreciation of its possible contribution to autoimmune disorders such as rheumatoid arthritis (RA). The aim of the study was to evaluate the effect of treatment with tumor necrosis factor α (TNF-α) inhibitors on the activity of the kynurenine pathway in patients with RA.Material and methodsThis was an investigator-initiated, prospective, observational study. The study was performed on 30 RA patients (Caucasian, 11 male, 19 female; mean age 45 ±16 years) treated with TNF-α inhibitors. All patients were assessed before and after 6 months of therapy. As a control group, age- and sex-matched, 20 healthy volunteers were recruited. Disease activity was evaluated by the Modified Disease Activity Score with 28-joint count (DAS28). Inflammatory markers were assessed routinely by the hospital central laboratory. Serum concentrations of kynu­renine, serotonin and tryptophan were measured with specific immunoassays. To estimate indoleamine 2,3-dioxygenase (IDO) activity, kynurenine-to-tryptophan ratio was calculated.ResultsThe results of our study showed changes in tryptophan metabolism in RA patients, compared with healthy controls. Surprisingly, RA patients had statistically significant decreased kynu­renine-to-tryptophan ratio (p = 0.003), which could indicate diminished IDO activation in RA. Moreover, we found no significant changes in kynurenine-to-tryptophan ratio after treated with TNF-α inhibitors (p = 0.490), despite disease remission. Additionally, tryptophan metabolism activity did not correlate with objective markers of inflammation.ConclusionsThe RA patients had altered tryptophan metabolism, compared with healthy controls. The mechanisms affecting tryptophan metabolism in RA may be complex. We believe that continuing elucidation of pathophysiological pathways relevant in RA offer substantial hope for the development of specific pharmacotherapy for treatment of RA – especially for comorbidity of RA and depression.

Alterations of the kynurenine pathway in patients with type 1 diabetes are associated with metabolic control of diabetes.

Alterations of the kynurenine pathway in patients with type 1 diabetes are associated with metabolic control of diabetes.

Evaluation of neopterin levels and kynurenine pathway in patients with acute coronary syndrome.

Coronary atherosclerosis is the leading cause of coronary artery disease. Several investigations have indicated that tear-sensitive plaques contain macrophages and T cells. Neopterin is an essential cellular immune response biomarker. The main goal of this study was to see if there were any changes in biomarkers like unconjugated pteridines, neopterin, and biopterin, as well as kynurenine pathway enzymes like indoleamine 2,3-dioxygenase (IDO), which catalyzes the rate-limiting step in tryptophan degradation, in patients with the acute coronary syndrome (ACS) caused by angiographic atherosclerosis. High-performance liquid chromatography was used to determine the amounts of neopterin, biopterin, and creatinine in urine samples, as well as tryptophan and kynurenine in serum samples. The enzyme-linked immunosorbent assay was used to assess the amounts of neopterin in serum samples. The measured parameters were evaluated between ACS patients and controls. The measured levels of neopterin, biopterin and the kynurenine to tryptophan ratio reflecting IDO activity, and the specifically known biomarkers such as cardiac troponin, creatine kinase, myoglobin, and natriuretic peptides are statistically higher in ACS patients compared to control subjects. On the other hand, the measured parameters are inadequate to classify the conventional kinds of ACS, ST-elevation- and non-ST-elevation- myocardial infarction. The study found that determining and using neopterin and IDO parameters as biomarkers in individuals with the ACS can support traditional biomarkers. However, it can be concluded that evaluating pteridine biomarkers solely have no privilege to clinical findings in ACS diagnosis and classification.

Kinureninski put katabolizma triptofana i shizofrenija

The development of new therapeutic options focused on the recovery of patients with schizophrenia is primarily conditioned by elucidating the biological underpinnings of the disorder. The kynurenine pathway of tryptophan catabolism is the focus of psychiatric research since its catabolites have neuroactive properties, and one of the most important is the effect of kynurenic acid as the only endogenous NMDA receptor antagonist. According to the kynurenine hypothesis, there is an imbalance of excitatory and neuroprotective metabolites of the kynurenine pathway in patients with schizophrenia. It is postulated that excessive production of kynurenic acid leads to excessive blockade of NMDA glutamate and alpha-7 nicotinic receptors, acting as a trigger for the development of psychotic symptoms and neurocognitive deficits. This paper aims to review the kynurenine hypothesis of schizophrenia, important findings of studies exploring metabolites of the kynurenine pathway in patients with schizophrenia, and findings from the research on the potential impact of proinflammatory cytokines on the kynurenine pathway.

Bifidobacterium longum CCFM1077 Ameliorated Neurotransmitter Disorder and Neuroinflammation Closely Linked to Regulation in the Kynurenine Pathway of Autistic-like Rats.

The kynurenine pathway (KP) is abnormal in autistic patients and model animals. According to studies on the brain–gut axis, probiotics can help ameliorate the metabolic abnormalities of the KP in patients and model animals with neurological diseases. This study was aimed at evaluating the ability of Bifidobacterium longum (B. longum) CCFM077 to enhance the gut microbiome and KP metabolism and regulate the neurotransmitter levels and neuroinflammation of autistic rats. The KP metabolism of autistic rats was significantly disordered and significantly related to the regulation of neurotransmitter (excitation and inhibition) and neuroglia states. B. longum CCFM1077 could effectively alleviate autistic-like behaviours (repetitive stereotyped behaviour, learning and memory ability, and despair mood) and regulate the KP metabolism in the periphery system (gut and blood) and brain. In particular, B. longum CCFM1077 could significant regulate the quinolinic acid (QUIN) level in the brain and markedly regulate glutamic acid (Glu) and Glu/γ-aminobutyric acid (GABA) levels in the brain while alleviating microglia activity in the cerebellum. Through a correlation analysis, the QUIN level in the brain was strongly related with autistic-like behaviours and neurotransmitter levels (GABA and Glu). The QUIN level may thus be a potential therapeutic marker for treating autism through the intestinal and neural pathways.

Association of Serum Kynurenine Levels and Neural Networks in Patients with First-Episode, Drug-Naïve Major Depression: A Source-Based Morphometry Study.

PurposeThe kynurenine (KYN) pathway can directly or indirectly influence cerebral volume and neural integrity in patients with major depression (MD). The aim of the present study was to investigate neural network systems and the KYN pathway in patients with first-episode, drug-naïve MD.Patients and MethodsTwenty right-handed drug-naïve patients, with MD diagnosed using the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, Text Revision, Research Version, were included in this study. Magnetic resonance imaging scans and scores on the Hamilton Rating Scale for Depression were assessed, and serum sampling was performed prior to the start of pharmacological treatment. Image processing and data analysis were performed according to our recently published procedure. Serum metabolomes were measured in the cation and anion modes of CE-FTMS-based metabolome analysis.ResultsWe found that serum KYN levels were positively correlated with the Z-scores of the salience network but not with those of the central executive network or default mode network. No associations were observed between serum glutamate levels and the Z-score of any of the three networks.ConclusionOur results indicate that serum KYN levels might affect the activity of the salience network in first-episode, drug-naïve patients with MD.

Resistance Exercise Modulates Kynurenine Pathway in Pancreatic Cancer Patients.

The aim of this study was to investigate the impact of Supervised and Home-based resistance exercise on the Kynurenine pathway in patients with pancreatic cancer who underwent surgery and chemotherapy. In the SUPPORT study, adult pancreatic cancer patients were randomized to intervention programs of 6-month (1) a Supervised moderate-to-high-intensity progressive resistance training or (2) unsupervised Home-based resistance training, or (3) to a standard care patient Control group. Serum levels of kynurenine, tryptophan and IL-6 were assessed for 32 participants before, after 3 months and after 6 months of exercise intervention. Group differences were investigated using analysis-of-covariance. Patients in the Supervised training group showed decreased levels of serum kynurenine and kynurenine/tryptophan ratio (p = 0.07; p = 0.01 respectively) as well as increased Tryptophan levels (p = 0.05) in comparison to Home-based and Control group over time. The Home-based exercise group had significant increased kynurenine and kynurenine/tryptophan ratio levels. IL-6 levels decreased over the first three months for both intervention groups as well as the Control group (Supervised: p < 0.01, Home-based: p < 0.010, Control group: p < 0.01). Supervised resistance exercise might positively regulate the Kynurenine pathway and downregulate the kynurenine/tryptophan (indicative of IDO/TDO enzyme) levels, hence modulating the immune system.

Characterization of kynurenine pathway in patients with diarrhea-predominant irritable bowel syndrome.

Our objectives are to demonstrate whether the kynurenine pathway is activated in diarrhea-type irritable bowel syndrome (IBS-D) patients, and whether the neurotoxic metabolite quinolinic acid (QUIN) is out of balance with the neuroprotective metabolite kynurenic acid (KYNA), and further explore whether this can lead to increased expression of N-methyl D-aspartate receptor 2B (NMDAR2B) in the enteric nervous system and in turn leads to intestinal symptoms and mood disorders. All enrolled healthy controls and patients accepted IBS Symptom Severity Scale (IBS-SSS) score, Self-rating Depression Scale (SDS) and Self-rating Anxiety Scale (SAS) anxiety and depression scores, and also underwent colonoscopy to collect ileum and colonic mucosa specimens. The expression of NMDAR2B in intestinal mucosa was detected by immunofluorescence, and fasting serum was collected to detect the tryptophan, kynurenine (KYN), KYNA and QUIN by high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Our results showed that the KYN pathway of IBS-D patients was activated. The production of QUIN and KYNA was imbalanced and resulting in an increased NMDAR2B for patients with IBS-D, which may be involved in intestinal symptoms and mood disorders of IBS-D.

Orchestration of Tryptophan-Kynurenine Pathway, Acute Decompensation, and Acute-on-Chronic Liver Failure in Cirrhosis.

Systemic inflammation (SI) is involved in the pathogenesis of acute decompensation (AD) and acute-on-chronic liver failure (ACLF) in cirrhosis. In other diseases, SI activates tryptophan (Trp) degradation through the kynurenine pathway (KP), giving rise to metabolites that contribute to multiorgan/system damage and immunosuppression. In the current study, we aimed to characterize the KP in patients with cirrhosis, in whom this pathway is poorly known. The serum levels of Trp, key KP metabolites (kynurenine and kynurenic and quinolinic acids), and cytokines (SI markers) were measured at enrollment in 40 healthy subjects, 39 patients with compensated cirrhosis, 342 with AD (no ACLF) and 180 with ACLF, and repeated in 258 patients during the 28-day follow-up. Urine KP metabolites were measured in 50 patients with ACLF. Serum KP activity was normal in compensated cirrhosis, increased in AD and further increased in ACLF, in parallel with SI; it was remarkably higher in ACLF with kidney failure than in ACLF without kidney failure in the absence of differences in urine KP activity and fractional excretion of KP metabolites. The short-term course of AD and ACLF (worsening, improvement, stable) correlated closely with follow-up changes in serum KP activity. Among patients with AD at enrollment, those with the highest baseline KP activity developed ACLF during follow-up. Among patients who had ACLF at enrollment, those with immune suppression and the highest KP activity, both at baseline, developed nosocomial infections during follow-up. Finally, higher baseline KP activity independently predicted mortality in patients with AD and ACLF. Conclusion: Features of KP activation appear in patients with AD, culminate in patients with ACLF, and may be involved in the pathogenesis of ACLF, clinical course, and mortality.

Increased expression of kynurenine aminotransferases mRNA in lymphocytes of patients with inflammatory bowel disease.

Background:Complex interaction of genetic defects with environmental factors seems to play a substantial role in the pathogenesis of inflammatory bowel disease (IBD). Accumulating data implicate a potential role of disturbed tryptophan metabolism in IBD. Kynurenic acid (KYNA), a derivative of tryptophan (TRP) along the kynurenine (KYN) pathway, displays cytoprotective and immunomodulating properties, whereas 3-OH-KYN is a cytotoxic compound, generating free radicals.Methods:The expression of lymphocytic mRNA encoding enzymes synthesizing KYNA (KAT I–III) and serum levels of TRP and its metabolites were evaluated in 55 patients with IBD, during remission or relapse [27 patients with ulcerative colitis (UC) and 28 patients with Crohn’s disease (CD)] and in 50 control individuals.Results:The increased expression of KAT1 and KAT3 mRNA characterized the entire cohorts of patients with UC and CD, as well as relapse–remission subsets. Expression of KAT2 mRNA was enhanced in patients with UC and in patients with CD in remission. In the entire cohorts of UC or CD, TRP levels were lower, whereas KYN, KYNA and 3-OH-KYN were not altered. When analysed in subsets of patients with UC and CD (active phase–remission), KYNA level was significantly lower during remission than relapse, yet not versus control. Functionally, in the whole groups of patients with UC or CD, the TRP/KYN ratio has been lower than control, whereas KYN/KYNA and KYNA/3-OH-KYN ratios were not altered. The ratio KYN/3-OH-KYN increased approximately two-fold among all patients with CD; furthermore, patients with CD with relapse, manifested a significantly higher KYNA/3-OH-KYN ratio than patients in remission.Conclusion:The presented data indicate that IBD is associated with an enhanced expression of genes encoding KYNA biosynthetic enzymes in lymphocytes; however, additional mechanisms appear to influence KYNA levels. Higher metabolic conversion of serum TRP in IBD seems to be followed by the functional shift of KYN pathway towards the arm producing KYNA during exacerbation. We propose that KYNA, possibly via interaction with aryl hydrocarbon receptor or G-protein-coupled orphan receptor 35, may serve as a counter-regulatory mechanism, decreasing cytotoxicity and inflammation in IBD. Further longitudinal studies evaluating the individual dynamics of TRP and KYN pathway in patients with IBD, as well as the nature of precise mechanisms regulating KYNA synthesis, should be helpful in better understanding the processes underlying the observed changes.

The Metabolic Factor Kynurenic Acid of Kynurenine Pathway Predicts Major Depressive Disorder.

Background: Metabolic factors in the kynurenine pathway (KP) have been widely accepted as being a major mechanism in Major Depressive Disorder (MDD). However, the effects of these metabolites on the degree and pattern of MDD are still poorly understood, partly due to the elusiveness of the level of metabolites when diagnosing depression. This study aimed to explore a novel diagnostic method analyzing peripheral blood with mass spectrometry to assess metabolites from KP in patients with MDD and Bipolar Depression (BD).Methods: Thirty-three patients with MDD, 20 patients with BD, and 23 healthy control participants were enrolled Metabolic factors of KP from plasma including tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QUIN) were analyzed by UPLC-3Q-MS, and levels compared across three groups. Correlation between HAMD scores and metabolite levels conducted. Receiver operating characteristic (ROC) curve was used to determine the diagnostic value of metabolic factors in MDD.Results: Levels of KYNA, QUIN, KYNA/QUIN, and KYNA/KYN were statistically different across the three groups (P < 0.05); HAMD scores and TRP, KYN, KYNA/QUIN levels were negatively correlated in the MDD group (r = −0.633, −0.477, −0.418, P < 0.05); Accuracy of KYNA diagnosing MDD was 82.5% with the optimal diagnostic value being 15.48 ng/ml. Diagnostic accuracy was increased to 83.6% when KYNA and QUIN levels were used in combination.Conclusion: This results indicate that metabolic factors of KP play a crucial role in the occurrence and development of MDD, supporting the metabolic imbalance hypothesis of MDD. Furthermore, our study also provides a new diagnostic method to study MDD based on plasma KYNA level, and suggests that KYNA would be a potential biomarker in diagnosing depression patients.

Folate, neopterin and kynurenine pathway in patients with statin therapy

Abstract Statins, widely used antihyperlipidemic drugs, also have immunomodulatory properties independent from their lipid lowering effect. Even with slight modulations in the immune system, pteridine levels can display changes. The effect of statins on pteridines and related pathways has been demonstrated in a limited number of studies. The aim of the study was to evaluate the possible changes in neopterin and folate levels, and tryptophan (Trp) degradation in hyperlipidemic patients. Patients who were admitted to the cardiology clinic were randomly grouped if they were having statin treatment (n=69) or not (n=36). Serum Trp and kynurenine (Kyn), erythrocyte folate, and urinary neopterin levels were measured. It was found that urinary neopterin levels were significantly higher in patients on statin treatment (p&lt;0.05) while levels of folate, Trp, Kyn, and Kyn-to-Trp ratios (Kyn/Trp) presented no significant changes (all, p&gt;0.05). The correlation of the measured parameters was also evaluated and neopterin, folate and tryptophan degradation were found to be positively correlated. According to the results, neopterin levels, folate status and Trp degradation were altered in patients with statin treatment in comparison with the patients not receiving statin therapy. In order to point out the direct effect of statins on pteridines, further studies presenting both pre- and post-statin treatment of these parameters are needed.

(13)C-tryptophan breath test detects increased catabolic turnover of tryptophan along the kynurenine pathway in patients with major depressive disorder.

Altered tryptophan–kynurenine (KYN) metabolism has been implicated in major depressive disorder (MDD). The l-[1-13C]tryptophan breath test (13C-TBT) is a noninvasive, stable-isotope tracer method in which exhaled 13CO2 is attributable to tryptophan catabolism via the KYN pathway. We included 18 patients with MDD (DSM-IV) and 24 age- and sex-matched controls. 13C-tryptophan (150 mg) was orally administered and the 13CO2/12CO2 ratio in the breath was monitored for 180 min. The cumulative recovery rate during the 180-min test (CRR0–180; %), area under the Δ13CO2-time curve (AUC; %*min), and the maximal Δ13CO2 (Cmax; %) were significantly higher in patients with MDD than in the controls (p = 0.004, p = 0.008, and p = 0.002, respectively). Plasma tryptophan concentrations correlated negatively with Cmax in both the patients and controls (p = 0.020 and p = 0.034, respectively). Our results suggest that the 13C-TBT could be a novel biomarker for detecting a subgroup of MDD with increased tryptophan–KYN metabolism.

Associations between intake of fish and n-3 long-chain polyunsaturated fatty acids and plasma metabolites related to the kynurenine pathway in patients with coronary artery disease.

Enhanced tryptophan degradation via the kynurenine pathway has been related to several pathological conditions. However, little is known about the effect of diet on individual metabolites of this pathway. We investigated cross-sectional associations between reported intake of fish and omega-3 (n-3) long-chain PUFA (LC-PUFA) and plasma metabolites related to the kynurenine pathway. Participants were 2324 individuals with coronary artery disease from the Western Norway B Vitamin Intervention Trial. Fish and n-3 LC-PUFA intakes were assessed using a food frequency questionnaire. Plasma concentrations of tryptophan, kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, xanthurenic acid, 3-hydroxyanthranilic acid, neopterin, and kynurenine-to-tryptophan ratio (KTR) were analyzed. Associations were investigated using partial Spearman's rank correlations and multiple linear regressions. Median age at inclusion was 62years (80% males), and 84% had stable angina pectoris. Intake of fatty fish and n-3 LC-PUFA was inversely associated with plasma 3-hydroxykynurenine. Consumption of total fish, lean fish, and n-3 LC-PUFA was inversely associated with plasma neopterin. Intake of total fish, fatty fish, and n-3 LC-PUFA was inversely associated with KTR. All these correlations were weak (ρ between -0.12 and -0.06, P<0.01). In 306 patients with diabetes, lean fish intake was positively associated with plasma 3-hydroxyanthranilic acid (ρ=0.22, P<0.001, P for interaction=0.01), and total fish intake was inversely associated with KTR (ρ=-0.17, P<0.01, P for interaction=0.02). Fish intake was not an important determinant of individual metabolites in the kynurenine pathway. However, some correlations were stronger in patients with diabetes. The inverse associations of fish or n-3 LC-PUFA with neopterin and KTR may suggest a slightly lower IFN-γ-mediated immune activation with a higher intake.

Kynurenine pathway metabolites in migraine.

Kynurenine pathway (KP), the quantitatively main branch of tryptophan metabolism, has long been considered a source of nicotinamide adenine dinucleotide, although several of its products, the so-called kynurenines, are endowed with the capacity to activate glutamate receptors, thus potentially influencing a large group of functions in the central nervous system (CNS). In fact, Kynurenic Acid and Quinolinic Acid are able to interact with ionotropic glutamate receptors and Cinnabarinic Acid has been reported as an orthosteric agonist of metabotropic glutamate receptors (mGlu4), and Xanthurenic Acid has been recently demonstrated to be a putative agonist of metabotropic glutamate receptors 2/3 (mGlu2/3). Moreover, 3-HK and 3-HANA have mainly been studied, since they have been shown to induce neurotoxic effects by increasing oxidative stress and the production of free radicals or through excitotoxicity. Migraine has a complex pathophysiology in which both central and peripheral components of the trigeminal pain pathway play a central role. The trigemino-vascular activation during the attack has largely been described, and recently the brainstem nuclei, called “migraine generators”, have been reported to be involved in migraine. Moreover, a series of destabilizing events within the brain trigger a cortical spreading depression (CSD), responsible for the aura phenomena and for trigeminal activation. The role of glutamate is heavily supported both in the trigemino-vascular as well as in brainstem nuclei activation, and furthermore in the CSD initiation and propagation. Some of the KP metabolites able to interact both with ionotropic and metabotropic glutamate receptors might be involved in migraine pathophysiology. Despite the large number of studies conducted on migraine etiopathology, the KP has only been recently linked to this disease. Nonetheless, some evidence suggests an intriguing role for some kynurenines, and an exploratory study on the serum kynurenine levels has been helpful to better understand possible alterations of the kynurenine pathway in patients suffering from migraine.

Does escitalopram reduce neurotoxicity in major depression?

A pro-inflammatory state and a dysregulation in the tryptophan/kynurenine pathway have been documented in depression. This study examined whether treatment with the SSRI, escitalopram (ESC), could suppress inflammation and favorably shift metabolites of the kynurenine pathway in patients with major depressive disorder (MDD) within the utilized treatment period. Twenty seven healthy control subjects were included for comparison. Thirty patients were enrolled after completing baseline assessments. They received a 12-week ESC monotherapy. Twenty subjects were completers. Clinical assessments were carried out at each visit using the HAM-D, HAM-A, CGI and BDI rating scales. Blood samples were collected at each assessment and stored until analyzed. Cytokines were analyzed with Randox multiplex assay and tryptophan and kynurenine metabolites were analyzed using HPLC/GCMS. Baseline plasma concentrations of hsCRP, TNFα, IL6 and MCP-1 were significantly higher in patients compared to healthy controls. IL10 trended toward an increase. Baseline plasma IL1β correlated significantly with IL1α, and IL4. Patients showed significant improvement in all outcome measures with a high remission rate. Significant correlations were obtained between specific symptoms and certain biomarkers at baseline but these correlations must be viewed as very preliminary. During ESC treatment concentrations of inflammatory biomarkers did not change except for TNFα that trended lower. Metabolites and ratios of the tryptophan/kynurenine pathway showed reductions of the neurotoxic metabolites, 3-hydroxykynurenine and quinolinic acid, 3-hydroxykynurenine/kynurenine, quinolinic acid/tryptophan, kynurenic acid/quinolinic acid and quinolinic acid/3-hydroxykynurenine. The results indicate that ESC may exert its antidepressant effect in part through inhibition of synthesis of certain neurotoxic kynurenine metabolites and possibly also through reduction of the inflammatory response, although there was no concordance in the time course of changes between antidepressant efficacy and reversal of the pro-inflammatory status.

Fathoming the kynurenine pathway in migraine: why understanding the enzymatic cascades is still critically important.

Kynurenine pathway, the quantitatively main branch of tryptophan metabolism, has been long been considered a source of nicotinamide adenine dinucleotide, although several of its products, the so-called kynurenines, are endowed with the capacity to activate glutamate receptors, thus potentially influencing a large group of functions in the central nervous system (CNS). Migraine, a largely unknown pathology, is strictly related to the glutamate system in the CNS pathologic terms. Despite the large number of studies conducted on migraine etio-pathology, the kynurenine pathway has been only recently linked to this disease. Nonetheless, some evidence suggests an intriguing role for some kynurenines, and an exploratory study on the serum kynurenine level might be helpful to better understand possible alterations of the kynurenine pathway in patients suffering from migraine.

Association of kynurenine aminotransferase II gene C401T polymorphism with immune response in patients with meningitis

BackgroundThe kynurenine (KYN) pathway has been shown to be altered in several diseases which compromise the central nervous system (CNS) including infectious diseases such as bacterial meningitis (BM). The aim of this study was to assess single nucleotide polymorphisms (SNPs) in four genes of KYN pathway in patients with meningitis and their correlation with markers of immune response in BM.MethodsOne hundred and one individuals were enrolled in this study to investigate SNPs in the following genes: indoleamine-2,3-dioxygenase (IDO1 gene), kynureninase (KYNU gene), kynurenine aminotransferase I (CCBL1 gene), and kynurenine aminotransferase II (AADAT gene). SNP analyses were performed by primer-introduced restriction analysis-PCR (PIRA-PCR) followed by RFLP. Cytokines were measured using multiplex bead assay while immunoglobulins (IG) by immunodiffusion plates and NF-kappaB and c-Jun by dot blot assay.ResultsThe variant allele of SNP AADAT+401C/T showed prevalent frequency in patients with BM. A significant decrease (p < 0.05) in TNF-α, IL-1β, IL-6, MIP-1αCCL3 and MIP-1β/CCL4 levels was observed in BM patients homozygous (TT) to the SNP AADAT+401C/T. Furthermore, a significant (p < 0.05) decrease in cell count was observed in cerebrospinal fluid (CSF) from patients with TT genotype. In addition, an increase in the IgG level in adults (p < 0.05) was observed. The variant allele for KYNU+715G/A was found with low frequency in the groups, and the SNPs in IDO1+434T/G, KYNU+693G/A, CCBL1+164T/C, and AADAT+650C/T had no frequency in this population.ConclusionsThis study is the first report of an association of SNP AADAT+401C/T with the host immune response to BM, suggesting that this SNP may affect the host ability in recruitment of leukocytes to the infection site. This finding may contribute to identifying potential targets for pharmacological intervention as adjuvant therapy for BM.