Kynurenic Acid Levels Research Articles

Prenatal THC exposure raises kynurenic acid levels in the prefrontal cortex of adult rats

Cannabis remains one of the most widely used illicit drugs during pregnancy. The main psychoactive component of marijuana (Δ9-tetrahydrocannabinol, THC) is correlated with untoward physiological effects in the offspring. Neurobehavioral and cognitive impairments have been reported in longitudinal studies on children and adolescents prenatally exposed to marijuana, and a link to psychiatric disorders has been proposed. Interestingly, the deleterious effects of prenatal cannabis use are similar to those observed in adult rats prenatally exposed to (L)-kynurenine, the direct bioprecursor of the neuroactive metabolite kynurenic acid (KYNA). We therefore investigated whether alterations in KYNA levels in the rat brain might play a role in the long-term consequences of prenatal cannabinoid exposure. Pregnant Wistar rats were treated daily with THC [5 mg/kg, p.o.] from gestational day (GD)5 through GD20. Using in vivo microdialysis in the medial prefrontal cortex, adult animals were then used to determine the extracellular levels of KYNA and glutamate. Compared to controls, extracellular basal KYNA levels were higher, and basal glutamate levels were lower, in prenatally THC-exposed rats. These rats also showed abnormal short-term memory. Following an additional acute challenge with a low dose of kynurenine (5 mg/kg i.p.) in adulthood, the increase in extracellular KYNA levels in the mPFC was more pronounced in in prenatally THC-exposed rats. These effects could be causally related to the cognitive dysfunction seen in prenatally THC-exposed rats. In the translational realm, these experiments raise the prospect of prevention of KYNA neosynthesis as a promising novel approach to combat some of the detrimental long-term effects of prenatal cannabis use.

Are Kynurenines Accomplices or Principal Villains in Dementia? Maintenance of Kynurenine Metabolism.

Worldwide, 50 million people suffer from dementia, a group of symptoms affecting cognitive and social functions, progressing severely enough to interfere with daily life. Alzheimer’s disease (AD) accounts for most of the dementia cases. Pathological and clinical findings have led to proposing several hypotheses of AD pathogenesis, finding a presence of positive feedback loops and additionally observing the disturbance of a branch of tryptophan metabolism, the kynurenine (KYN) pathway. Either causative or resultant of dementia, elevated levels of neurotoxic KYN metabolites are observed, potentially upregulating multiple feedback loops of AD pathogenesis. Memantine is an N-methyl-D-aspartate glutamatergic receptor (NMDAR) antagonist, which belongs to one of only two classes of medications approved for clinical use, but other NMDAR modulators have been explored so far in vain. An endogenous KYN pathway metabolite, kynurenic acid (KYNA), likewise inhibits the excitotoxic NMDAR. Besides its anti-excitotoxicity, KYNA is a multitarget compound that triggers anti-inflammatory and antioxidant activities. Modifying the KYNA level is a potential multitarget strategy to normalize the disturbed KYN pathway and thus to alleviate juxtaposing AD pathogeneses. In this review, the maintenance of KYN metabolism by modifying the level of KYNA is proposed and discussed in search for a novel lead compound against the progression of dementia.

An integrated meta-analysis of peripheral blood metabolites and biological functions in major depressive disorder

Major depressive disorder (MDD) is a serious mental illness, characterized by high morbidity, which has increased in recent decades. However, the molecular mechanisms underlying MDD remain unclear. Previous studies have identified altered metabolic profiles in peripheral tissues associated with MDD. Using curated metabolic characterization data from a large sample of MDD patients, we meta-analyzed the results of metabolites in peripheral blood. Pathway and network analyses were then performed to elucidate the biological themes within these altered metabolites. We identified 23 differentially expressed metabolites between MDD patients and controls from 46 studies. MDD patients were characterized by higher levels of asymmetric dimethylarginine, tyramine, 2-hydroxybutyric acid, phosphatidylcholine (32:1), and taurochenodesoxycholic acid and lower levels of l-acetylcarnitine, creatinine, l-asparagine, l-glutamine, linoleic acid, pyruvic acid, palmitoleic acid, l-serine, oleic acid, myo-inositol, dodecanoic acid, l-methionine, hypoxanthine, palmitic acid, l-tryptophan, kynurenic acid, taurine, and 25-hydroxyvitamin D compared with controls. l-tryptophan and kynurenic acid were consistently downregulated in MDD patients, regardless of antidepressant exposure. Depression rating scores were negatively associated with decreased levels of l-tryptophan. Pathway and network analyses revealed altered amino acid metabolism and lipid metabolism, especially for the tryptophan–kynurenine pathway and fatty acid metabolism, in the peripheral system of MDD patients. Taken together, our integrated results revealed that metabolic changes in the peripheral blood were associated with MDD, particularly decreased l-tryptophan and kynurenic acid levels, and alterations in the tryptophan–kynurenine and fatty acid metabolism pathways. Our findings may facilitate biomarker development and the elucidation of the molecular mechanisms that underly MDD.

Immune and Neuroendocrine Trait and State Markers in Psychotic Illness: Decreased Kynurenines Marking Psychotic Exacerbations.

Objective: Different patterns of immune system upregulation are present in the acute vs. post-treatment states of psychotic illness. We explored the existence of state and trait markers in the peripheral immune system and two immune-associated neuroendocrine pathways (IDO and GTP-CH1 pathway) in a longitudinal sample of psychosis patients. We also evaluated the association of these markers with neuropsychiatric symptomatology.Method: Plasma concentrations of peripheral blood markers were measured in a transdiagnostic group of 49 inpatients with acute psychosis and 52 matched healthy control subjects. Samples were obtained in patients within 48 h after hospital admission for an acute psychotic episode (before initiation of antipsychotics), after 1–2 weeks and again after 8 weeks of treatment. Kynurenine, kynurenic acid (KA), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), phenylalanine, tyrosine, nitrite, and neopterin were measured using HPLC and LC-MS/MS analysis. Concentrations of CRP, CCL2 (MCP1) and cytokines were determined with multiplex immunoassay. PANSS interviews and cognitive tests were performed at baseline and follow-up. Mixed model analyses were used to identify trait and state markers.Results: Patients had significantly higher plasma concentrations of CRP, CCL2, IL1RA, and lower concentrations of KA and KA/Kyn at all time points (F7.5–17.5, all p < 0.001). Increased concentrations of IL6, IL8, IL1RA, TNFα, and CCL2 and decreased QA and 3-HK (F8.7–21.0, all p < 0.005) were found in the acute psychotic state and normalized after treatment. Low nitrite concentrations at admission rose sharply after initiation of antipsychotic medication (F42.4, p < 0.001). PANSS positive scale scores during the acute episode correlated with pro-inflammatory immune markers (r ≥ |0.5|), while negative scale scores correlated inversely with IDO pathway markers (r ≥ |0.4|). Normalization of KA and 3-HK levels between admission and follow-up corresponded to a larger improvement of negative symptoms (r = 0.5, p < 0.030) A reverse association was found between relative improvement of SDST scores and decreasing KA levels (r = 0.5, p < 0.010).Conclusion: The acute psychotic state is marked by state-specific increases of immune markers and decreases in peripheral IDO pathway markers. Increased CRP, CCL2, and IL1RA, and decreased KA and KA/Kyn are trait markers of psychotic illness.

Predictors of response to repeated ketamine infusions in depression with suicidal ideation: An ROC curve analysis

BackgroundKetamine has rapid-acting antidepressant and antisuicidal properties, while a proportion of patients do not adequately achieve a complete response to ketamine. Our aim was to explore the applicability of using clinical factors and serum tryptophan (TRP) metabolites to predict the response to six doses of ketamine for depression with suicidal ideation. MethodsSeventy-three depressed patients with suicidal ideation received a thrice-weekly infusion regimen of subanaesthetic doses of ketamine. Clinical symptoms were assessed by the Montgomery-Asberg Depression Rating Scale (MADRS), Beck's Scale for Suicide Ideation (SSI) and Patient Health Questionnaire-9 (PHQ-9), and serum levels of TRP, kynurenine (KYN) and kynurenic acid (KYNA) were detected by liquid chromatography-tandem mass spectrometry at baseline and day 1 (1 day after the first infusion). The potential predictors of response was evaluated using receiver operating characteristic (ROC) curve analyses. ResultsThe area under the curve (AUC = 0.959) implied a good accuracy of the combination of early clinical response and day 1 KYN and KYNA levels as a predictor of acute antidepressant response. The combination of early clinical response and day 1 KYNA levels showed moderate discrimination of acute antisuicidal response with an AUC of 0.825 and short-term antidepressant response with an AUC of 0.813. LimitationsThe patients continued receiving previous medications during ketamine treatment, which may have impacted the TRP metabolites. ConclusionThe combination of early clinical response and TRP metabolites at the early stage of repeated ketamine treatment could be considered an eligible predictor for acute- and short-term response for treating depression with suicidal ideation.

Increased Plasma Kynurenic Acid Levels are Associated with Impaired Attention/Vigilance and Social Cognition in Patients with Schizophrenia.

ObjectivePreclinical studies have reported that abnormal kynurenic acid (KYNA) may play a role in cognitive deficits. Schizophrenia (SCZ) is characterized by a wide range of cognitive deficits that may evolve from abnormal KYNA. This study aimed to explore the relationship between KYNA and cognitive impairment in SCZ, which has not yet been reported.MethodsWe recruited 30 SCZ patients and 34 healthy controls, measured clinical symptoms by using the Positive and Negative Syndrome Scale and performed cognitive tests using the MATRICS Consensus Cognitive Battery (MCCB). Plasma levels of tryptophan, kynurenine, and KYNA were determined by high-performance liquid chromatography–tandem mass spectrometry.ResultsWe found that plasma KYNA levels were significantly higher in patients than in healthy controls (p=0.009). The cognitive performance of patients in the total MCCB scores and the scores of all subscales were significantly lower than those in healthy controls (all P < 0.01). Correlation analysis showed that KYNA levels were negatively correlated with attention/vigilance (r=–0.457, p=0.019) and social cognition (r=–0.481, p=0.013) only in SCZ patients.ConclusionOur results indicate that elevated plasma KYNA levels may serve as a biomarker of cognitive impairment in SCZ patients.

Effects of Sleep Deprivation on the Tryptophan Metabolism.

Sleep has a regulatory role in maintaining metabolic homeostasis and cellular functions. Inadequate sleep time and sleep disorders have become more prevalent in the modern lifestyle. Fragmentation of sleep pattern alters critical intracellular second messengers and neurotransmitters which have key functions in brain development and behavioral functions. Tryptophan metabolism has also been found to get altered in SD and it is linked to various neurodegenerative diseases. The kynurenine pathway is a major regulator of the immune response. Adequate sleep alleviates neuroinflammation and facilitates the cellular clearance of metabolic toxins produced within the brain, while sleep deprivation activates the enzymatic degradation of tryptophan via the kynurenine pathway, which results in an increased accumulation of neurotoxic metabolites. SD causes increased production and accumulation of kynurenic acid in various regions of the brain. Higher levels of kynurenic acid have been found to trigger apoptosis, leads to cognitive decline, and inhibit neurogenesis. This review aims to link the impact of sleep deprivation on tryptophan metabolism and associated complication in the brain.

Possible Use of Blood Tryptophan Metabolites as Biomarkers for Coronary Heart Disease in Sudden Unexpected Death.

Coronary heart disease (CHD) is the major cause of death in sudden unexpected death (SUD) cases. Tryptophan (TRP) and its metabolites are correlated with the CHD patient but less studies in the SUD. The aim of this study was to evaluate the relationship of TRP and its metabolites with the CHD in the SUD cases. Blood samples and heart tissues were collected from CHD subjects (n = 31) and the control group (n = 72). Levels of kynurenine (KYN), kynurenic acid (KYA), xanthurenic acid (XAN), 3-hydroxyanthranillic acid (HAA), quinolinic acid (QA), picolinic acid (PA) and 5-hydroxyindoleacetic acid (HIAA) were determined by HPLC-DAD. A severity of heart occlusion was categorized into four groups, and the relationship was measured with the TRP metabolites. The HIAA and The KYN levels significantly differed (p < 0.01) between the CHD group and the control group. Lower levels of QA/XAN, PA/KA, HAA/XAN, KYN/XAN and KYN/TRP were found in the CHD group. However, PA/HAA, PA/HIAA, PA/KYN and XAN/KA values in the CHD group were higher than the control group (p < 0.05). This study revealed that the values of PA/KA and PA/HAA provided better choices for a CHD biomarker in postmortem bodies.

Acute sleep deprivation during pregnancy in rats: Rapid elevation of placental and fetal inflammation and kynurenic acid

The kynurenine pathway (KP) is the dominant pathway for tryptophan degradation in the mammalian body and emerging evidence suggests that acute episodes of sleep deprivation (SD) disrupt tryptophan metabolism via the KP. Increases in the neuroactive KP metabolite kynurenic acid (KYNA) during pregnancy may lead to a higher risk for disrupted neurodevelopment in the offspring. As pregnancy is a critical period during which several factors, including sleep disruptions, could disrupt the fetal environment, we presently explored the relationship between maternal SD and KP metabolism and immune pathways in maternal, placenta, and fetal tissues. Pregnant Wistar rat dams were sleep deprived by gentle handling for 5 h from zeitgeber time (ZT) 0 to ZT 5. Experimental cohorts included: i) controls, ii) one session of SD on embryonic day (ED) 18 or iii) three sessions of SD occurring daily on ED 16, ED 17 and ED 18. Maternal (plasma, brain), placental and fetal (plasma, brain) tissues were collected immediately after the last session of SD or after 24 h of recovery from SD. Respective controls were euthanized at ZT 5 on ED 18 or ED 19. Maternal plasma corticosterone and fetal brain KYNA were significantly elevated only after one session of SD on ED 18. Importantly, maternal plasma corticosterone levels correlated significantly with fetal brain KYNA levels. In addition, placental levels of the proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6) were increased following maternal SD, suggesting a relationship between placental immune response to SD and fetal brain KYNA accumulation. Collectively, our results demonstrate that sleep loss during the last week of gestation can adversely impact maternal stress, placental immune function, and fetal brain KYNA levels. We introduce KYNA as a novel molecular target influenced by sleep loss during pregnancy.

P.133 Changes in kynurenic acid levels following psychostimulant drug administration in rats

P.133 Changes in kynurenic acid levels following psychostimulant drug administration in rats

Losartan Reverses Hippocampal Increase of Kynurenic Acid in Type 1 Diabetic Rats: A Novel Procognitive Aspect of Sartan Action.

Patients with diabetes mellitus (DM) type 1 and 2 are at a higher risk of cognitive decline and dementia; however, the underlying pathology is poorly understood. Kynurenic acid (KYNA), endogenous kynurenine metabolite, displays pleiotropic effects, including a blockade of glutamatergic and cholinergic receptors. Apart from well-known glial origin, kynurenic acid is robustly synthesized in the endothelium and its serum levels correlate with homocysteine, a risk factor for cognitive decline. Studies in an experimental DM model suggest that a selective, hippocampal increase of the kynurenic acid level may be an important factor contributing to diabetes-related cognitive impairment. The aim of this study was to assess the effects of chronic, four-week administration of losartan, angiotensin receptor blocker (ARB), on the brain KYNA in diabetic rats. Chromatographic and rt-PCR techniques were used to measure the level of KYNA and the expression of genes encoding kynurenine aminotransferases, KYNA biosynthetic enzymes, in the hippocampi of rats with streptozotocin-induced DM, treated with losartan. The effect of losartan on KYNA synthesis de novo was also evaluated in vitro, in brain cortical slices. The hippocampal increase of KYNA content occurred in diabetic rats treated and nontreated with insulin. Losartan did not affect KYNA levels when administered per se to naïve or diabetic animals but normalized KYNA content in diabetic rats receiving concomitantly insulin. The expression of CCBL1 (kat 1), AADAT (kat 2), and KAT3 (kat 3) genes did not differ between analyzed groups. Low concentrations of losartan did not affect KYNA production in vitro. The neuroprotective effect of ARBs in diabetic individuals may be, at least partially, linked to modulation of KYNA metabolism. The ability of ARB to modulate synthesis of KYNA in diabetic brain does not seem to result from changed expression of genes encoding KATs. We propose possible involvement of angiotensin AT4 receptors in the observed action of losartan.

Resistance Exercise Reduces Kynurenine Pathway Metabolites in Breast Cancer Patients Undergoing Radiotherapy.

Purpose: Evidence from preclinical studies and trials in healthy volunteers suggests that exercise may modulate the levels of tryptophan (TRP) metabolites along the kynurenine (KYN) pathway. As KYN and downstream KYN metabolites are known to promote cancer progression by inhibiting anti-tumor immune responses and by promoting the motility of cancer cells, we investigated if resistance exercise can also control the levels of KYN pathway metabolites in breast cancer patients undergoing radiotherapy (NCT01468766).Patients and Methods: Chemotherapy-naïve breast cancer patients (n = 96) were either randomized to an exercise/intervention group (IG) or a control group (CG). The IG participated in a 12-week supervised progressive resistance exercise program twice a week, whereas the CG received a supervised relaxation program. Serum levels of TRP and KYN as well as urine levels of kynurenic acid (KYNA) and neurotoxic quinolinic acid (QUINA) were assessed before (t0), after radiotherapy, and mid-term of the exercise intervention (t1) and after the exercise intervention (t2). Additionally, 24 healthy women (HIG) participated in the exercise program to investigate potential differences in its effects on KYN metabolites in comparison to the breast cancer patients.Results: At baseline (t0) the breast cancer patients showed a significantly elevated serum KYN/TRP ratio and urine QUINA/KYNA ratio, as well as increased urine QUINA levels in comparison to the healthy women. In response to exercise the healthy women and the breast cancer patients differed significantly in the levels of urine QUINA and the QUINA/KYNA ratio. Most importantly, serum KYN levels and the KYN/TRP ratio were significantly reduced in exercising patients (IG) compared to non-exercising patients (CG) both at t1 and t2.Conclusion: Resistance exercise may represent a potent non-pharmacological avenue to counteract an activation of the KYN pathway in breast cancer patients undergoing radiotherapy.

Exhaustion of CD4+ T-cells mediated by the Kynurenine Pathway in Melanoma

Kynurenine pathway (KP) activation by the enzymatic activity of indoleamine 2,3-dioxygenase1 (IDO1) and kynurenine (KYN) production represents an attractive target for reducing tumour progression and improving anti-tumour immunity in multiple cancers. However, immunomodulatory properties of other KP metabolites such as 3-hydroxy kynurenine (3-HK) and kynurenic acid (KYNA) are poorly understood. The association of the kynurenine metabolic pathway with T-cell status in the tumour microenvironment were characterized, using gene expression data of 368 cutaneous skin melanoma (SKCM) patients from the TCGA cohort. Based on the identified correlations, we characterized the production of KYN, 3-HK, and KYNA in vitro using melanoma-derived cell lines and primary CD4+ CD25− T-cells. Activation of the CD4+ T-cells produced IFNγ, which yielded increased levels of KYN and KYNA. Concurrently, kynurenine 3-monooxygenase (KMO) expression and proliferation of CD4+ T-cells were reduced, whereas exhaustion markers such as PD-L1, AHR, FOXP3, and CTLA4 were increased. Additionally, an analysis of the correlation network reconstructed using TCGA-SKCM emphasized KMO and KYNU with high variability among BRAF wild-type compared with V600E, which underscored their role in distinct CD4+ T-cell behavior in tumour immunity. Our results suggest that, in addition to IDO1, there is an alternative immune regulatory mechanism associated with the lower KMO expression and the higher KYNA production, which contributes to dysfunctional effector CD4+ T-cell response.

The Effect of Therapeutic Horticulture on Depression and Kynurenine Pathways

The article presents the results of a study conducted to assess change in depression severity, and modification in the kynurenine pathway at participants. Presently, depression is one of the most regularly encountered mental illnesses. Research based on experimental studies indicated the beneficial effects of activities conducted in nature are reducing self-reported anger, fatigue, anxiety, stress and depression. The present study was conducted by measuring depression on both the subjective (Beck Depression Inventory) and the objective (spectrophotometric analysis) levels, to obtain more relevant information regarding the real change in depression levels, during the therapeutic horticulture intervention. Consequently, depression is assessed with the BDI doubled the data by assessing the levels of kynurenine and kynurenic acid obtained from biological samples. Results indicate that the levels of depression measured with the BDI have significantly decreased after the Therapeutic Horticulture Sesions. An even better result regards the fact that the significance of this change was not only statistical, but also clinical. Analysing the kynurerine and kynurenic acid concentrations, differences were observed amongst subject during the research study.

2041-P: Genetic Intervention in Kynurenine Pathway Alters Glucose Metabolism in Mice

Most of tryptophan is metabolized to kynurenine (KYN) to synthesize NAD+, while a subsidiary pathway changes KYN to kynurenic acid (KYNA) by kynurenine aminoltransferases (KATs). We previously reported genetic association of a mutation in the gene encoding KAT-1, an isoform of KATs, with hypertension, adiposity and glucose intolerance in rats. Although it is widely known that KYNA negatively regulates central nervous system by antagonizing neuro-receptors, its physiological role in glucose metabolism remains unclear. To explore such role, first, we have established KAT-1 knockout mice that showed decreased levels of KAT activity in liver and brain (p&amp;lt;0.01) and KYNA levels decreased significantly in brain and blood (p&amp;lt;0.05) and tending to decrease in liver. The KAT-1 knockout mice also showed significantly deteriorated glucose tolerance (p&amp;lt;0.05 at 60min after glucose i.p.) and insulin sensitivity (p&amp;lt;0.05 at 45, 60, 75 and 90min after insulin i.p.) as compared with wild littermates. Next, to establish mice with endogenously increased levels of KYNA, the hepatic gene encoding kynurenine mono-oxygenase (KMO), a rate-limiting enzyme for conversion of KYN to NAD+, was knocked down by shRNA adenovirus. The hepatic KMO knockdown in normal mice markedly increased endogenous KYNA levels in liver, blood and several other tissues, whereas the levels of 3-hydroxykynurenine, a downstream product of KMO, were decreased in liver (p&amp;lt;0.001). Finally, the hepatic KMO knockdown in diet-induced obese mice significantly ameliorated glucose intolerance and improved insulin sensitivity and pyruvate tolerance independently of food intake or body weight. Among the enzymes related to glucose metabolism, both the gene expression (p&amp;lt;0.01) and the enzymatic activity (p&amp;lt;0.05) of glucokinase were increased in the liver of the KMO knockdown group as compared with controls. These results indicated that alterations in KYNA pathway influence glucose metabolism in vivo. Disclosure T. Yamamoto: None. T. Gotoda: None.

Assessment of Prenatal Kynurenine Metabolism Using Tissue Slices: Focus on the Neosynthesis of Kynurenic Acid in Mice

Several lines of evidence support the hypothesis that abnormally elevated brain levels of kynurenic acid (KYNA), a metabolite of the kynurenine pathway (KP) of tryptophan degradation, play a pathophysiologically significant role in schizophrenia and other major neurodevelopmental disorders. Studies in experimental animal models suggest that KP impairments in these diseases may originate already in utero since prenatal administration of KYNA’s bioprecursor, kynurenine, leads to biochemical and structural abnormalities as well as distinct cognitive impairments in adulthood. As KP metabolism during pregnancy is still insufficiently understood, we designed this study to examine the de novo synthesis of KYNA and 3-hydroxykynurenine (3-HK), an alternative biologically active product of kynurenine degradation, in tissue slices obtained from pregnant mice on gestational day (GD) 18. Fetal brain and liver, placenta, and maternal brain and liver were collected, and the tissues were incubated in vitroin the absence or presence of micromolar concentrations of kynurenine. KYNA and 3-HK were measured in the extracellular milieu. Basal and newly produced KYNA was detected in all cases. As KYNA formation exceeded 3-HK production by 2–3 orders of magnitude in the placenta and maternal brain, and as very little 3-HK neosynthesis was detectable in fetal brain tissue, detailed follow-up experiments focused on KYNA only. The fetal brain produced 3–4 times more KYNA than the maternal brain and placenta, though less than the maternal and fetal liver. No significant differences were observed when using tissues obtained on GD 14 and GD 18. Pharmacological inhibition of KYNA’s main biosynthetic enzymes, kynurenine aminotransferase (KAT) I and KAT II, revealed qualitative and quantitative differences between the tissues, with a preferential role of KAT I in the fetal and maternal brain and of KAT II in the fetal and maternal liver. Findings using tissue slices from KAT II knockout mice confirmed these conclusions. Together, these results clarify the dynamics of KP metabolism during pregnancy and provide the basis for the conceptualization of interventions aimed at manipulating cerebral KP function in the prenatal period.

Changes in tryptophan metabolism during pregnancy and postpartum periods: Potential involvement in postpartum depressive symptoms

BackgroundMany women experience depressive symptoms during pregnancy and postpartum periods. These depressive symptoms are often accompanied by other inflammatory morbidities present during pregnancy. Tryptophan (TRP) metabolism has attracted considerable attention due to its influence on the onset of depression via induction of inflammation. We examined the changes in plasma levels of TRP metabolites in pregnant women with depressive symptoms during pregnancy and/or the postpartum period. MethodsIn line with a previous analysis using the Edinburgh Postnatal Depression Scale (EPDS), participants were divided into a non-depressive (ND) group, a postpartum depressive (PD) group, a temporary gestational depressive (TG) group, and a continuous depressive (CD) group. Blood samples were collected before and 1 month after delivery. The concentrations of plasma TRP metabolites were measured using high-performance liquid chromatography (HPLC). ResultsThere are differences in plasma levels of TRP metabolites during pregnancy and postpartum periods between the ND group and the PD group, but not the TG or CD group. In the PD group, plasma levels of kynurenine (KYN) and kynurenic acid (KA), and KYN/TRP and KA/KYN ratio during the pregnancy period were higher and 3-hydroxyanthranilic acid (3HAA) during the postpartum period was lower than those in the ND group. LimitationsHistories regarding mood disorders before pregnancy were not assessed. ConclusionsThe higher plasma levels of KYN and KA, and KYN/TRP and KA/KYN ratio during pregnancy period and lower plasma level of 3HAA during the postpartum period could be useful predictive and diagnostic markers of postpartum depressive symptoms.

Changes in tryptophan and kynurenine pathway metabolites in the blood of children treated with ketogenic diet for refractory epilepsy

PurposeThere is growing evidence to support the role of the kynurenine pathway in the anticonvulsant efficacy of ketogenic diets (KDs) in refractory epilepsy. The aim of the present study was to measure blood levels of tryptophan (TRP) and its kynurenine derivatives and correlate them with seizure reduction after starting the KD in children with refractory epilepsy. MethodsSixteen children (9 F/7 M; 7.1 ± 5.1 years) with refractory epilepsy were treated with the KDs. Clinical efficacy and metabolic ketosis were monitored throughout the study; blood levels of TRP, kynurenine (KYN), kynurenic acid (KYNA), and 3-OH-kynurenine (3-OH-KYN) were measured at 3, 6, and 12 months on the diet and compared to the pre-KD levels. ResultsOut of 16 children, 14 attained a ≥50% reduction (responders) in seizure frequency 3 months after starting the KD. In the 14 responders, TRP levels decreased numerically (18–25%) but not significantly (P = 0.077) compared to the pre-KD control values. KYN levels decreased significantly (30–57%; P = 0.001) compared to the pre-KD control levels while KYNA levels significantly increased (38–96%; P < 0.001). KYNA/KYN ratios significantly increased (100–323%; P = 0.003) while 3-OH-KYN levels (P = 0.680) and KYN/TRP ratios (P = 0.385) remained unchanged. Higher concentrations of KYNA and lower concentrations of KYN (P < 0.05) were found in patients who attained a higher reduction in seizure frequencies on the KD. ConclusionsWe report a pattern of changes in the blood level of kynurenines in patients with refractory epilepsy who started the KD. The results of this study further support the role of specific kynurenines (e.g. KYNA) in the efficacy of the KD in refractory epilepsy.

Increased Levels of Kynurenic Acid in the Cerebrospinal Fluid in Patients with Hydrocephalus.

Normal pressure hydrocephalus (NPH) is a potentially reversible neurological syndrome commonly characterized by gait disturbance, urinary incontinence, and dementia. Hydrocephalus e-vacuo (He-v) is also characterized by the occurrence of dementia but does not show gait disturbance or urinary incontinence and has no evident cerebrospinal fluid (CSF) pressure elevation. Kynurenic acid (KYNA), an endogenous metabolite of the L-kynurenine (L-KYN) pathway of L-tryptophan (L-TRP) degradation, is an antagonist of glutamate N-methyl-D-aspartic acid and alpha-7 nicotinic cholinergic receptors that have been linked to dementia. We investigated KYNA, L-KYN, and L-TRP levels in human CSF and serum during the aging process in 30 healthy control individuals. In addition, clinical parameters and L-TRP metabolites in CSF and serum were evaluated in four patients with NPH and five with He-v. KYNA, L-KYN, and L-TRP levels in CSF and serum were determined using highperformance liquid chromatography. Healthy controls showed a significant decrease in serum albumin with age. Compared with their corresponding controls and unlike patients with He-v, patients with NPH (age ≤ 50 years) had significant increases in CSF protein (241%, p < 0.001), CSF albumin (246%, p < 0.001), CSF IgG (328%, p < 0.001), and CSF:serum IgG (321%, p < 0.001) and CSF:serum albumin (257%, p < 0.001) ratios. Controls had significant increases in KYNA, L-KYN, and L-TRP levels in the CSF with advancing age but not in the serum. Compared with the corresponding controls, KYNA levels were significantly increased in the CSF of patients with NPH (141%, p < 0.05) and He-v (225%; p < 0.01). Additionally, the serum levels of KYNA were increased in patients with NPH and He-v to 161% and 156% of controls, respectively (both p < 0.01). The serum levels of L-KYN and L-TRP were significantly reduced in patients with He-v but not in patients with NPH. C-reactive protein, as a marker of inflammation, was significantly increased in the serum of patients with He-v but not in patients with NPH, compared with the corresponding controls. The aging process is related to elevated CSF levels of KYNA, L-KYN, and L-TRP levels. There are significant differences in clinical parameters between the two forms of hydrocephalus and these differences might have diagnostic utility. The occurrence of dementia in patients with either form of hydrocephalus might be at least partly related to elevated KYNA levels in the CNS and/or periphery.

Kynurenic acid as the neglected ingredient of commercial baby formulas

The global increase in resorting to artificial nutritional formulas replacing breastfeeding has been identified among the complex causes of the obesity epidemic in infants and children. One of the factors recently recognized to influence metabolism and weight gain is kynurenic acid (KYNA), an agonist of G protein-coupled receptor (GPR35). Therefore the aim of the study was to determine the concentration of KYNA in artificial nutritional formulas in comparison with its level in human breast milk and to evaluate developmental changes in rats exposed to KYNA enriched diet during the time of breastfeeding. KYNA levels were measured in milk samples from 25 heathy breast-feeding women during the first six months after labor and were compared with 21 time-adjusted nutritional formulas. Animal experiments were performed on male Wistar rats. KYNA was administered in drinking water. The content of KYNA in human milk increases more than 13 times during the time of breastfeeding while its level is significantly lower in artificial formulas. KYNA was detected in breast milk of rats and it was found that the supplementation of rat maternal diet with KYNA in drinking water results in its increase in maternal milk. By means of the immunoblotting technique, GPR35 was evidenced in the mucosa of the jejunum of 1-day-old rats and distinct morphological changes in the jejunum of 21-day-old rats fed by mothers exposed to water supplemented with KYNA were found. A significant reduction of body weight gain of rats postnatally exposed to KYNA supplementation without changes in total body surface and bone mineral density was observed. The rat offspring fed with breast milk with artificially enhanced KYNA content demonstrated a lower mass gain during the first 21 days of life, which indicates that KYNA may act as an anti-obesogen. Further studies are, therefore, warranted to investigate the mechanisms regulating KYNA secretion via breast milk, as well as the influence of breast milk KYNA on mass gain. In the context of lifelong obesity observed worldwide in children fed artificially, our results imply that insufficient amount of KYNA in baby formulas could be considered as one of the factors associated with increased mass gain.