Kynurenine Pathway Of Tryptophan Metabolism Research Articles

Perivascular brown adipocytes-derived kynurenic acid relaxes blood vessel via endothelium PI3K-Akt-eNOS pathway.

Several metabolites from the kynurenine pathway of tryptophan metabolism play a critical role in vascular function and vascular wall remodeling. This study aimed to test whether metabolite kynurenic acid (KYNA) from the kynurenine pathway relaxes blood vessels. We employed histological staining, in vitro cell culture, Western blotting, real-time PCR, and nitric oxide detection to validate kynurenine aminotransferase (KAT) localization in the vasculature as well as KYNA action on endothelial cells. We also detected vascular reactivity by organ chamber and monitored blood pressure by telemetry to investigate the regulation effect of KYNA on vascular tone. The results presented that perivascular adipose tissue (PVAT) from mice thoracic aorta had robust staining of anti-KAT1 and KYNA than PVAT from the abdominal aorta and mesenteric artery, which is consistent with the expression profile of brown adipocyte marker uncoupling protein 1. KYNA, metabolized from kynurenine by KAT, relaxed pre-contracted both aortic ring and mesenteric artery. In addition, KYNA derived from KAT in PVAT participates in the cross-talk between PVAT and vessel by mediating PVAT inhibition on agonist-induced thoracic aorta contraction. Furthermore, intraperitoneal injection of KYNA in mice reduced blood pressure. The vessel relaxation effect of KYNA was through the endothelium-dependent PI3K-Akt-eNOS pathway. Finally, the high-fat diet decreased KAT1 expression in perithoracic aortic fat and led to KYNA reduction in blood. Our research identified KYNA generated by KAT as a novel perivascular brown adipocyte-derived vascular relaxation factor and suggests that KYNA reduction is a critical event in vascular dysfunction under obese condition.

Tryptophan Metabolism and COVID-19-Induced Skeletal Muscle Damage: Is ACE2 a Key Regulator?

The severity of coronavirus disease 2019 (COVID-19) is characterized by systemic damage to organs, including skeletal muscle, due to excessive secretion of inflammatory cytokines. Clinical studies have suggested that the kynurenine pathway of tryptophan metabolism is selectively enhanced in patients with severe COVID-19. In addition to acting as a receptor for severe acute respiratory syndrome coronavirus 2, the causative virus of COVID-19, angiotensin converting enzyme 2 (ACE2) contributes to tryptophan absorption and inhibition of the renin-angiotensin system. In this article, we review previous studies to assess the potential for a link between tryptophan metabolism, ACE2, and skeletal muscle damage in patients with COVID-19.

Kynurenine pathway of tryptophan metabolism in patients with familial Mediterranean fever.

Familial Mediterranean fever (FMF) is an autoinflammatory syndrome characterized by recurrent episodes of fever and aseptic polyserositis. Subclinical inflammation generates a hidden threat to the development of FMF complications such as amyloidosis in attack-free intervals. The kynurenine pathway (KP) has been considered an important player in inflammation and immune response. The study was aimed to measure serum levels of KP metabolites in patients with FMF in the attack-free period. A total of 161 participants were recruited from the rheumatology department in this single-centre, case-control study. Participants meeting the eligibility criteria were divided into healthy controls (n = 80) and FMF (n = 81). The laboratory data were obtained from the electronic registration database. Serum tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxyanthranilic acid, 3-hydroxykynurenine (3HK), and quinolinic acid (QUIN) concentrations were measured with tandem mass spectrometry. Laboratory findings of FMF patients and healthy controls subjects were compared and evaluated. Serum TRP and KYNA levels were significantly decreased in both FMF groups compared to the control group, while the levels of KYN, QUIN, 3HK, the KYN/TRP ratio, and red cell distribution width were higher. TRP degradation by the KP is increased in patients with FMF. KP metabolites can be useful in demonstrating subclinical inflammation.

Probiotic Releasing Angiotensin (1-7) in a Drosophila Model of Alzheimer's Disease Produces Sex-Specific Effects on Cognitive Function.

While extensive research on the brain has failed to identify effective therapies, using probiotics to target the gut microbiome has shown therapeutic potential in Alzheimer's disease (AD). Genetically modified probiotics (GMP) are a promising strategy to deliver key therapeutic peptides with high efficacy and tissue specificity. Angiotensin (Ang)-(1-7) levels inversely correlate to AD severity, but its administration is challenging. Our group has successfully established a GMP-based method of Ang-(1-7) delivery. Since Drosophila represents an excellent model to study the effect of probiotics on complex disorders in a high throughput manner, we tested whether oral supplementation with Lactobacillus paracasei releasing Ang-(1-7) (LP-A) delays memory loss in a Drosophila AD model. Flies overexpressing the human amyloid-β protein precursor and its β-site cleaving enzyme in neurons were randomized to receive four 24-h doses of Lactobacillus paracasei alone (LP), LP-A or sucrose over 14 days. Memory was assessed via an aversive phototaxic suppression assay. Optimal dilution,1:2, was determined based on palatability. LP-A improved memory in trained AD males but worsened cognition in AD females. LP-supplementation experiments confirmed that Ang-(1-7) conferred additional cognitive benefits in males and was responsible for the deleterious cognitive effects in females. Sex-specific differences in the levels of angiotensin peptides and differential activation of the kynurenine pathway of tryptophan metabolism in response to supplementation may underlie this male-only therapeutic response. In summary, LP-A ameliorated the memory deficits of a Drosophila AD model, but effects were sex-specific. Dosage optimization may be required to address this differential response.

Association of the Kynurenine Pathway of Tryptophan Metabolism With Human Immunodeficiency Virus-Related Gut Microbiota Alterations and Visceral Adipose Tissue Accumulation.

The aim of the study was to investigate the association between human immunodeficiency virus (HIV)-related gut microbiota changes, alterations in the kynurenine (Kyn) pathway of tryptophan (Trp) metabolism, and visceral adipose tissue in the context of HIV infection. Three hundred eighty-three people with HIV (PWH) were included from the Copenhagen comorbidity in HIV infection (COCOMO) study. Gut microbiota composition was analyzed by 16S ribosomal ribonucleic acid sequencing. Plasma metabolites were analyzed by liquid chromatography-tandem mass spectrometry. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas were measured by single-slice computed tomography (CT) scan (4th lumbar vertebra). The HIV-related gut microbiota alterations were associated with lower Trp (β -.01; 95% confidence interval [CI], -0.03 to -0.00) and higher Kyn-to-Trp ratio (β 0.03; 95% CI, 0.01-0.05), which in turn was associated with higher VAT-to-SAT ratio (β 0.50; 95% CI, 0.10-0.90) and larger VAT area (β 30.85; 95% CI, 4.43-57.28). In mediation analysis, the Kyn-to-Trp ratio mediated 10% (P = .023) of the association between the VAT-to-SAT ratio and HIV-related gut microbiota. Our data suggest HIV-related gut microbiota compositional changes and gut microbial translocation as potential drivers of high Kyn-to-Trp ratio in PWH. In turn, increased activity in the Kyn pathway of Trp metabolism was associated with larger visceral adipose tissue area. Taken together, our findings suggest a possible role for this pathway in the gut-adipose tissue axis in the context of HIV infection.

Влияние гипоксии на состояние хромосомного аппарата дрозофилы в условиях накопления 3-гидроксикинуренина

M. E. Lobashev and V. B. Savvateev’s research laid the foundation for studying the relationship between neuroplasticity and reaction to extreme conditions. Common mechanisms underlying adaptive reactions and learning have been proven to exist. Hypoxia is one of the most common damaging factors in various adverse external and internal effects. Severe forms of hypoxia suppress neuroplasticity and cause learning and memory disorders. Chromatin remodelling and expression of genes involved in memory formation and learning may require double-stranded DNA breaks because they accompany intense matrix processes in neurogenesis and serve as indicators of physiological neuronal activity. Stimulation of regulatory cascades involved in learning has an impact on adaptive response formation. For instance, metabolites of the kynurenine pathway of tryptophan metabolism affect the synaptic plasticity processes that regulate memory formation and learning. This article studies the effect of hypoxia on the state of chromosomal apparatus in Drosophila cd mutant (accumulation of 3-hydroxykynurenine). We discover interlinear differences in the frequency of double-stranded DNA breaks following exposure to hypoxia in mutant cd and wild-type CS strain. Obtained data are discussed in terms of the relationship between neuroplasticity processes, circadian rhythm regulation, and mechanisms for adapting to extreme conditions.

Tryptophan, Kynurenine and Kynurenic Acid Concentrations in Milk and Serum of Dairy Cows with Prototheca Mastitis.

Simple SummaryBovine mastitis continues to be a leading cause of heavy economic losses in the dairy industry worldwide. Among a broad spectrum of infectious agents implicated in this pathology are unicellular, achlorophyllous microalgae of the genus Prototheca. The prevalence of mastitis due to Prototheca algae is currently increasing. The aim of this work was to explore a possible association of the kynurenine pathway of tryptophan metabolism with Prototheca mastitis. The authors were eager to know whether metabolites of tryptophan degradation can be used as markers of the protothecal bovine mastitis. Both tryptophan and its metabolite kynurenine occurred at a significantly lower level in the milk of cows with mastitis compared to healthy animals. Whereas the activity of indoleamine 2,3-dioxygenase, a key enzyme of tryptophan catabolism, was significantly higher in milk of mastitic cows compared to control animals. It was thus concluded that low values of tryptophan and kynurenine concentrations or elevated indoleamine 2,3-dioxygenase activity in milk samples can be used as markers of mastitis due to Prototheca spp.The aim of this work was to investigate serum and milk levels of tryptophan (TRP), kynurenine (KYN), and kynurenic acid (KYNA), as well as the activity of indoleamine 2,3-dioxygenase (IDO) in cows with mastitis due to Prototheca algae. The study was prompted by previous research showing a link between the KYN pathway of TRP metabolism and bovine mastitis of bacterial etiology. The study was carried out over a 2-year period (2018–2019) and included quarter milk and serum samples collected from six dairy herds in Poland. The samples were obtained from healthy cows and cows with Prototheca mastitis of either clinical and subclinical manifestation, as determined upon direct measurement of the somatic cell count or indirectly by performing a California Mastitis Test on suspected quarters. Both TRP and KYN concentrations were significantly lower in milk of mastitic cows compared to healthy animals (0.8 vs. 8.72 µM, p = 0.001; 0.07 vs. 0.32 µM, p = 0.001, respectively). The difference in TRP and KYN concentrations in the sera of the two animal groups was much less pronounced (25.55 vs. 27.57 µM, 3.03 vs. 3.56 nM, respectively). The concentration of KYNA was almost at the same level in milk (1.73 vs. 1.70 nM) and in serum (80.47 vs. 75.48 nM) of both mastitic and healthy cows. The data showed that the level of TRP and its metabolites in serum was conspicuously higher compared to milk in all cows under the study. The activity of IDO was significantly higher in milk of cows with Prototheca mastitis compared to healthy animals (71.4 vs. 40.86, p < 0.05), while in serum it was pretty much the same (135.94 vs. 124.98, p > 0.05). The IDO activity differed significantly between serum and milk both for mastitic (135.94 vs. 71.4, p < 0.05) and healthy cows (124.98 vs. 40.86, p < 0.001). In conclusion, low values of TRP and KYN concentrations or elevated IDO activity in milk samples might be used as markers of mastitis due to infectious causes, including Prototheca spp.

Changes in glomerular filtration rate and metabolomic differences in severely ill coronavirus disease survivors 3 months after discharge

To explore the recovery of renal function in severely ill coronavirus disease (COVID-19) survivors and determine the plasma metabolomic profile of patients with different renal outcomes 3 months after discharge, we included 89 severe COVID-19 survivors who had been discharged from Wuhan Union Hospital for 3 months. All patients had no underlying kidney disease before admission. At patient recruitment, renal function assessment, laboratory examination, chest computed tomography (CT) were performed. Liquid chromatography–mass spectrometry was used to detect metabolites in the plasma. We analyzed the longitudinally change in the estimated glomerular filtration rate (eGFR) based on serum creatinine and cystatin-c levels using the CKD-EPI equation and explored the metabolomic differences in patients with different eGFR change patterns from hospitalization to 3 months after discharge. Lung CT showed good recovery; however, the median eGFR significantly decreased at the 3-month follow-up. Among the 89 severely ill COVID-19 patients, 69 (77.5%) showed abnormal eGFR (<90 mL/min per 1.73 m2) at 3 months after discharge. Age (odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.08–1.47, p = 0.003), body mass index (OR = 1.97, 95% CI = 1.20–3.22, p = 0.007), and cystatin-c level (OR = 1.22, 95% CI = 1.07–1.39, p = 0.003) at discharge were independent risk factors for post-discharge abnormal eGFR. Plasma metabolomics at the 3-months follow-up revealed that β-pseudouridine, uridine, and 2-(dimethylamino) guanosine levels gradually increased with an abnormal degree of eGFR. Moreover, the kynurenine pathway in tryptophan metabolism, vitamin B6 metabolism, cysteine and methionine metabolism, and arginine biosynthesis were also perturbed in survivors with abnormal eGFR.

Kynurenine Pathway of Tryptophan Metabolism in Migraine and Functional Gastrointestinal Disorders

Migraine, the leading cause of disability in the population aged below 50, is associated with functional gastrointestinal (GI) disorders (FGIDs) such as functional nausea, cyclic vomiting syndrome, and irritable bowel syndrome (IBS). Conversely, changes in intestinal GI transit may cause diarrhea or constipation and are a component of the autonomic symptoms associated with pre- and post-dorsal phases of migraine attack. These mutual relationships provoke a question on a common trigger in migraine and FGIDs. The kynurenine (l-kyn) pathway (KP) is the major route for l-tryptophan (l-Trp) metabolism and transforms l-Trp into several neuroactive compounds. Changes in KP were reported in both migraine and FGIDs. Migraine was largely untreatable, but several drugs approved lately by the FDA, including monoclonal antibodies for calcitonin gene-related peptide (CGRP) and its receptor, create a hope for a breakthrough in migraine treatment. Derivatives of l-kyn were efficient in pain relief with a mechanism including CGRP inhibition. KP products are important ligands to the aryl hydrocarbon receptor (AhR), whose activation is implicated in the pathogenesis of GI and migraine. Toll-like receptors (TLRs) may play a role in migraine and IBS pathogeneses, and KP metabolites detected downstream of TLR activation may be an IBS marker. The TLR4 signaling was observed in initiating and maintaining migraine-like behavior through myeloid differentiation primary response gene 88 (MyD88) in the mouse. The aim of this review is to justify the view that KP modulation may provide common triggers for migraine and FGIDs with the involvement of TLR, AhR, and MyD88 activation.

Targeting hippocampal phospholipid and tryptophan metabolism for antidepressant-like effects of albiflorin

BackgroundCurrent antidepressant therapy remains unsatisfactory due to its delayed clinical onset of action and the heterogeneity of depression. Targeting disturbed neurometabolic pathways could provide a novel therapeutic approach for the treatment of depression. Albiflorin is a phytomedicine isolated from the root of Peony (Paeonia albiflora Pall) with excellent clinical tolerance. Until now, the antidepressant-like activities of albiflorin in different subtypes of depression and its effects on neurometabolism are unknown. PurposeThe objective of this study was to investigate the rapid antidepressant-like effects of albiflorin in three common animal models of depression and elucidate the pharmaco-metabolic mechanisms of its action using a multi-omics approach. ResultsWe found that albiflorin produces rapid antidepressant-like effects in chronic unpredictable mild stress (CUMS), olfactory bulbectomy (OBX), and lipopolysaccharide (LPS)-induced murine models of depression. Using a system-wide approach combining metabolomics, lipidomics, and transcriptomics, we showed that the therapeutic effects of albiflorin are highly associated with the rapid restoration of a set of common metabolic abnormities in the hippocampus across all three depression models, including phospholipid and tryptophan metabolism. Further mechanistic analysis revealed that albiflorin normalized the metabolic dysregulation in phospholipid metabolism by suppressing hippocampal cytosolic phospholipases A2 (cPLA2). Additionally, inhibition of cPLA2 overexpression by albiflorin corrects abnormal kynurenine pathway of tryptophan metabolism via the cPLA2-protein kinase B (Akt1)-indoleamine 2,3-dioxygenase 1(IDO1) regulatory loop and directs tryptophan catabolism towards more hippocampal serotonin biosynthesis. ConclusionOur study contributed to a better understanding of the homogeneity in the metabolic mechanisms of depression and established a proof-of-concept for rapid treatment of depression through targeting dysregulated neurometabolic pathways.

Kynurenic acid protects against mastitis in mice by ameliorating inflammatory responses and enhancing blood-milk barrier integrity

Mastitis is one of the most serious diseases in humans and animals, especially in the modern dairy industry. Seeking safe and effective mastitis prevention strategies is urgent since food safety and drug residues in milk remain an enormous concern, despite the contribution of antibiotics to control mastitis. Kynurenic acid (KYNA), derived from the kynurenine pathway of tryptophan metabolism, has been shown to exhibit anti-inflammatory and immunomodulatory effects in many diseases. Recently, it was reported that impaired KYNA levels were associated with mastitis. However, the physiological role of KYNA in mastitis has not yet been elucidated. Therefore, the aim of this study was to investigate the protective role of KYNA in pathogen-induced mastitis in mice, as well as the underlying mechanism of this effect. We first evaluated the effects of KYNA on LPS-induced mastitis in mice. Additionally, the underlying anti-inflammatory mechanism of KYNA was investigated in mammary epithelial cells (MMECs). Furthermore, we examined the effects of KYNA on S. aureus and E. coli induced mastitis in mice. Our results demonstrated that KYNA alleviated LPS-induced mastitis by reducing inflammatory responses and enhancing blood-milk barrier integrity. The fundamental mechanisms involved the inhibition of NF-κB and activation of Nrf2/Ho-1, which is probably mediated by G protein-coupled receptor 35 but not aryl hydrocarbon receptor. Notably, KYNA also protected against S. aureus and E. coli induced mastitis in mice. In conclusion, our results highlight the role of KYNA in mastitis and serve as a basis for using endogenous metabolite as a novel preventative or therapeutic strategy for disease intervention.

The Angiotensin-Converting Enzyme Inhibitor Lisinopril Mitigates Memory and Motor Deficits in a Drosophila Model of Alzheimer's Disease.

The use of angiotensin-converting enzyme inhibitors (ACEis) has been reported to reduce symptoms of cognitive decline in patients with Alzheimer’s disease (AD). Yet, the protective role of ACEis against AD symptoms is still controversial. Here, we aimed at determining whether oral treatment with the ACEi lisinopril has beneficial effects on cognitive and physical functions in a Drosophila melanogaster model of AD that overexpresses the human amyloid precursor protein and the human β-site APP-cleaving enzyme in neurons. We found a significant impairment in learning and memory as well as in climbing ability in young AD flies compared to control flies. After evaluation of the kynurenine pathway of tryptophan metabolism, we also found that AD flies displayed a >30-fold increase in the levels of the neurotoxic 3-hydroxykynurenine (3-HK) in their heads. Furthermore, compared to control flies, AD flies had significantly higher levels of the reactive oxygen species (ROS) hydrogen peroxide in their muscle-enriched thoraces. Lisinopril significantly improved deficits in learning and memory and climbing ability in AD flies. The positive impact of lisinopril on physical function might be, in part, explained by a significant reduction in ROS levels in the thoraces of the lisinopril-fed AD flies. However, lisinopril did not affect the levels of 3-HK. In conclusion, our findings provide novel and relevant insights into the therapeutic potential of ACEis in a preclinical AD model.

Methylphenidate ameliorates the homeostatic balance between levels of kynurenines in ADHD children

The kynurenine pathway of tryptophan metabolism has been involved in ADHD We quantified basal levels and daily fluctuations of tryptophan and several kynurenine metabolites, as well as their changes after treatment with methylphenidate (MPH).A total of 179 children were recruited, grouped into ADHD (n = 130) and healthy controls (CG,n = 49). Blood samples were drawn at 20:00 and 09:00 h and only in the ADHD group after 4.63±2.3 months of treatment. Nocturnal urine was collected between both draws. Factorial analysis (Stata12.0) was performed with Groups, Time, Hour of Day and Depressive Symptoms (DS) as factors.MPH significantly increased plasma Kynurenic acid (2.4 ± 1.03/2.78±1.3 ng/mL; baseline/post-treatment, morning; z = 1.96,p<0.05) and Xanthurenic acid (2.39±0.95/2.88±1.19 ng/mL; baseline/post, morning; z = 2.7,p<0.007) levels, both with higher values in the evening. In DS+ patients, MPH caused a pronounced decrease in evening Anthranilic acid [3.08±5.02/ 1.82±1.46 ng/mL, z = 2.68,p = 0.0074] until matching values to other subgroups. In urine, MPH decreased the excretion of both Nicotinamide and Quinolinic acids, but only in the DS- subgroup.The kynurenine pathway may participate in the highly clinical favorable response to MPH. The observed changes could be considered as protective (i.e. increased plasma kynurenic acid vs. decreased quinolinic acid excretion) based on the knowledge of its physiological homeostatic functions.

Alterations in the Kynurenine Pathway of Tryptophan Metabolism Are Associated With Depression in People Living With HIV.

People living with HIV have increased risk of depression compared with uninfected controls. The determinants of this association are unclear. Alterations in kynurenine (Kyn) metabolism have been associated with depression in uninfected individuals, but whether they are involved in the development of depression in the context of HIV infection is unknown. A total of 909 people living with HIV were recruited from the Copenhagen Comorbidity in HIV infection study. Information regarding demographics and depression was obtained from questionnaires. HIV-related variables and use of antidepressant medication were collected from patient records. Logistic regression models before and after adjustment for confounders were used to test our hypotheses. The prevalence of depression was 11%. Among traditional risk factors, only being unmarried was associated with greater odds of depression. Higher levels of quinolinic-to-kynurenic acid ratio (P = 0.018) and higher concentrations of quinolinic acid (P = 0.048) were found in individuals with depression than in those without. After adjusting for confounders, high levels of quinolinic-to-kynurenic acid ratio and high concentrations of quinolinic acid remained associated with depression [adjusted odds ratio 1.61 (1.01; 2.59) and adjusted odds ratio 1.68 (1.02; 2.77), respectively]. The results from this study suggest that alterations in the kynurenine pathway of tryptophan metabolism are associated with the presence of depression in the context of HIV infection.

Alcohol Consumption and Tryptophan Metabolism Among People with HIV Prior to Antiretroviral Therapy Initiation: The Uganda ARCH Cohort Study.

Alcohol is hypothesized to have effects on the kynurenine pathway of tryptophan catabolism, a potential mechanism for alcohol-induced depression and aggression. A biomarker of this pathway, the plasma kynurenine to tryptophan ratio (K/T ratio), has been associated with HIV progression, mortality and depression. Our aim was to assess whether hazardous alcohol consumption is associated higher K/T ratio among people with HIV. Participants were a subset of the Uganda Alcohol Research Collaboration on HIV/AIDS Cohort. Alcohol consumption was categorized (abstinent, moderate and hazardous alcohol use) using the Alcohol Use Disorders Identification Test-Consumption and phosphatidylethanol (PEth). K/T ratio was the primary outcome. We used linear regression adjusted for age, sex, FIB-4, hepatitis B surface antigen, log (HIV viral load) to estimate the association between alcohol consumption and K/T ratio. Compared to abstinent participants, hazardous drinkers and moderate drinkers had higher K/T ratio but these differences did not reach statistical significance. Our results suggest that hazardous alcohol consumption, in the context of untreated HIV infection, may not significantly alter kynurenine to tryptophan ratio as a measure of activity of the kynurenine pathway of tryptophan metabolism.

Azole-Based Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.

The heme enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays an essential role in immunity, neuronal function, and aging through catalysis of the rate-limiting step in the kynurenine pathway of tryptophan metabolism. Many IDO1 inhibitors with different chemotypes have been developed, mainly targeted for use in anti-cancer immunotherapy. Lead optimization of direct heme iron-binding inhibitors has proven difficult due to the remarkable selectivity and sensitivity of the heme-ligand interactions. Here, we present experimental data for a set of closely related small azole compounds with more than 4 orders of magnitude differences in their inhibitory activities, ranging from millimolar to nanomolar levels. We investigate and rationalize their activities based on structural data, molecular dynamics simulations, and density functional theory calculations. Our results not only expand the presently known four confirmed chemotypes of sub-micromolar heme binding IDO1 inhibitors by two additional scaffolds but also provide a model to predict the activities of novel scaffolds.

Natural Molecules and Neuroprotection: Kynurenic Acid, Pantethine and α-Lipoic Acid.

The incidence of neurodegenerative diseases has increased greatly worldwide due to the rise in life expectancy. In spite of notable development in the understanding of these disorders, there has been limited success in the development of neuroprotective agents that can slow the progression of the disease and prevent neuronal death. Some natural products and molecules are very promising neuroprotective agents because of their structural diversity and wide variety of biological activities. In addition to their neuroprotective effect, they are known for their antioxidant, anti-inflammatory and antiapoptotic effects and often serve as a starting point for drug discovery. In this review, the following natural molecules are discussed: firstly, kynurenic acid, the main neuroprotective agent formed via the kynurenine pathway of tryptophan metabolism, as it is known mainly for its role in glutamate excitotoxicity, secondly, the dietary supplement pantethine, that is many sided, well tolerated and safe, and the third molecule, α-lipoic acid is a universal antioxidant. As a conclusion, because of their beneficial properties, these molecules are potential candidates for neuroprotective therapies suitable in managing neurodegenerative diseases.

Влияние нарушения синтеза кинуренинов на память у дрозофилы

Such issues as life expectancy and medical care for the elderly are gaining momentum all over the world, including Russia. With an increase in life expectancy, neurodegenerative diseases (NDD) are on the rise in developed countries. One of the reasons for neurodegenerative changes in the brain is a disturbance of the kynurenine tryptophan metabolism pathway (KTMP). Drosophila KTMP mutants are suitable models for the experimental study of neurokynurenines that change brain functions resulting in learning and memory impairments. There are several mutant stocks of D. melanogaster with defects in the kynurenine pathway of tryptophan metabolism, including vermilion (v1, a block at the level of the tryptophan oxygenase enzyme that stops the production of kynurenines and leads to the accumulation of tryptophan). The mutant v1 has been shown to maintain normal learning ability, both in medium- and long-term memory formation. No defects in medium-term memory formation were detected. In contrast, the mutant showed the disturbances of long-term memory. The absence of eight-day long-term memory in the KTMP-suppressed mutant v1 may be a consequence of kynurenine imbalance.

Tat-indoleamine 2,3-dioxygenase 1 elicits neuroprotective effects on ischemic injury

It is well known that oxidative stress participates in neuronal cell death caused production of reactive oxygen species (ROS). The increased ROS is a major contributor to the development of ischemic injury. Indoleamine 2,3-dioxygenase 1 (IDO-1) is involved in the kynurenine pathway in tryptophan metabolism and plays a role as an anti-oxidant. However, whether IDO-1 would inhibit hippocampal cell death is poorly known. Therefore, we explored the effects of cell permeable Tat-IDO-1 protein against oxidative stress-induced HT-22 cells and in a cerebral ischemia/reperfusion injury model. Transduced Tat-IDO-1 reduced cell death, ROS production, and DNA fragmentation and inhibited mitogen-activated protein kinases (MAPKs) activation in H2O2 exposed HT-22 cells. In the cerebral ischemia/reperfusion injury model, Tat-IDO-1 transduced into the brain and passing by means of the blood-brain barrier (BBB) significantly prevented hippocampal neuronal cell death. These results suggest that Tat-IDO-1 may present an alternative strategy to improve from the ischemic injury.

Kynurenine Pathway of Tryptophan Metabolism in Neuropsychiatric Disorders: Pathophysiologic and Therapeutic Considerations.

Under physiological conditions 95% of the ingested essential amino acid tryptophan is metabolized by the kynurenine pathway (KP) to yield the ubiquitous co-enzyme nicotinamide adenine dinucleotide, fulfilling cellular energy require-ments. Importantly, the intermediaries of KP exert crucial effects throughout the body, including the central nervous system. Besides, KP metabolites are implicated in diverse disease processes such as inflammation/immune disorders, endocrine/metabolic conditions, cancers and neuropsychiatric diseases. A burgeoning body of research indicates that the KP plays a pathogenic role in major psychiatric diseases like mood disorders and schizophrenia. Triggered by inflammatory processes, the balance between neurotoxic and neuroprotective branches of the KP is disturbed. In preclinical models these discrepancies result in behaviors reminiscent of depression and psychosis. In clinical samples, recent studies are discovering key kynurenine pathway abnormalities which incriminate it in the pathogenesis of the main psychiatric disorders. Harnessing this knowledge has the potential to find disease biomarkers helpful in identifying and prognosticating neuropsychiatric disorders. Concurrently, earnest research efforts directed towards manipulating the KP hold the promise of discovering novel pharmacological agents that have therapeutic value. In this manuscript, an in-depth appraisal of the extant literature is done to understand the working of KP as this applies to neuropsychiatric disorders. It is concluded that this pathway plays an overarching role in the development of major psychiatric disorders, the KP metabolites have the potential to serve as disease markers and new medications based on KP modulation can bring lasting cures for patients suffering from these intractable conditions.