Quinolinic Acid Research Articles

Activation of the kynurenine pathway identified in individuals with covert hepatic encephalopathy

Background: HE is a neuropsychiatric complication of liver disease characterized by systemic elevation in ammonia and proinflammatory cytokines. These neurotoxins cross the blood-brain barrier and cause neuroinflammation, which can activate the kynurenine pathway (KP). This results in dysregulated production of neuroactive KP metabolites, such as quinolinic acid, which is known to cause astrocyte and neuronal death. Our aim was to compare KP activity between patients with covert HE (CHE), patients without encephalopathic cirrhosis (NHE), and healthy controls (HCs). Methods: This was a single-center prospective cohort study conducted between 2018 and 2021 at St Vincent’s Hospital, Sydney. Overall, 13 patients with CHE, 10 patients with NHE, and 12 with HC were recruited. Patients with cirrhosis were diagnosed with CHE if they scored ≤−4 on the Psychometric Hepatic Encephalopathy Score. KP metabolite levels were quantified on plasma samples via HPLC and gas chromatography/mass spectrometry. One-way Kruskal-Wallis test was used to compare the expression levels of KP enzymes. Results: KP was highly activated in patients with cirrhosis, demonstrated by higher levels of activity in the rate-limiting enzymes, indoleamine 2,3-dioxygenase, and tryptophan-2,3-dioxygenase in both CHE (65.04±20.72, p=0.003) and patients with NHE (64.85±22.10, p=0.015) compared to HC (40.95±7.301). Higher quinolinic acid concentrations were demonstrated in CHE (3726 nM±3385, p<0.001) and patients with NHE (1788 nM±632.3, p=0.032) compared to HC (624 nM±457). KP activation was positively correlated with inflammatory marker C-reactive protein in patients with CHE (Rs=0.721, p≤0.01). Conclusions: KP is highly activated in patients with CHE, resulting in heightened production of neurotoxic metabolites. Dysregulation of the pathway is demonstrable in patients who do not yet show clinical signs of neurocognitive impairment. Therapeutic agents that modulate KP activity may be able to alleviate symptoms of patients with CHE.

Organophosphate Insecticide Malathion Induces Alzheimer's Disease-Like Cognitive Impairment in Mice: Evidence of the Microbiota-Gut-Brain Axis.

Evidence suggests that exposure to organophosphate pesticides increases the risk of neurodegenerative diseases, but the mechanisms remain unclear. This study investigated the effects of malathion on Alzheimer's disease (AD)-like symptoms at environmentally relevant concentrations using wild-type (WT) and APP/PS1 transgenic mouse models. Results showed that malathion exposure induced AD-like cognitive impairment, amyloid-β (Aβ) accumulation, and neuroinflammation in WT mice, with worsened symptoms in APP/PS1 mice. Mechanistic studies revealed that malathion induced AD-like gut microbiota dysbiosis (reduced Lactobacillus and Akkermansia, and increased Dubosiella), causing gut barrier impairment and tryptophan metabolism disruptions. This resulted in a significant increase in indole derivatives and activation of the colonic aryl hydrocarbon receptor (AhR), promoting the kynurenine (KYN) pathway while inhibiting the serotonin (5-HT) pathway. Increased neurotoxic KYN metabolites (3-hydroxykynurenine and quinolinic acid) triggered gut and systemic inflammation, upregulating hippocampal IL-6 and IL-1β mRNA levels and thereby causing neuroinflammation. Gut tryptophan metabolism disruptions caused hippocampal neurotransmitter imbalances, reducing the levels of 5-HT and its derivatives. These effects promoted AD progression in both WT and APP/PS1 mice. This study highlights the crucial role of the microbiota-gut-brain axis in AD-like cognitive impairment induced by malathion exposure, providing insights into the neurodegenerative disease risks posed by organophosphate pesticides.

The Connection Between the Oral Microbiota and the Kynurenine Pathway: Insights into Oral and Certain Systemic Disorders

The oral microbiome, comprising bacteria, fungi, viruses, and protozoa, is essential for maintaining both oral and systemic health. This complex ecosystem includes over 700 bacterial species, such as Streptococcus mutans, which contributes to dental caries through acid production that demineralizes tooth enamel. Fungi like Candida and pathogens such as Porphyromonas gingivalis are also significant, as they can lead to periodontal diseases through inflammation and destruction of tooth-supporting structures. Dysbiosis, or microbial imbalance, is a key factor in the development of these oral diseases. Understanding the composition and functions of the oral microbiome is vital for creating targeted therapies for these conditions. Additionally, the kynurenine pathway, which processes the amino acid tryptophan, plays a crucial role in immune regulation, neuroprotection, and inflammation. Oral bacteria can metabolize tryptophan, influencing the production of kynurenine, kynurenic acid, and quinolinic acid, thereby affecting the kynurenine system. The balance of microbial species in the oral cavity can impact tryptophan levels and its metabolites. This narrative review aims to explore the relationship between the oral microbiome, oral diseases, and the kynurenine system in relation to certain systemic diseases.

Structure-Activity Relationship of 7-Chloro-4-(Phenylselanyl) Quinoline: Novel Antinociceptive and Anti-Inflammatory Effects in Mice.

The 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) shows promise for its antinociceptive and anti-inflammatory properties. Here, we explored the structure-activity relationship of 4-PSQ and its analogues: 7-chloro-4-[(4-fluorophenyl) selanyl]quinoline (a), 7-chloro-4-{[3-trifluoromethyl)phenyl] selanyl} quinoline (b), 4-((3,5-Bis(trifluoromethyl)phenyl) selanyl-7-chloroquinoline (c), 7-chloro-4-[(2,4,6-trimethyl)selanyl]quinolinic acid (d) and 7-chloroquinoline-4-selenium acid (e) in models of acute inflammation and chemical, thermal and mechanical nociception in mice, alongside in silico analysis. Compounds a (-F), b (-CF3), c (-Bis-CF3), d (-CH3), e (-OOH), and 4-PSQ exhibited antinociceptive effects in chemical and thermal nociception models, except d (-CH3) and e (-OOH) in the hot plate test. None induced locomotor changes. In silico, only c (-Bis-CF3) showed low gastrointestinal absorption, and c (-Bis-CF3) and e (-OOH) lacked blood-brain barrier penetration, suggesting e (-OOH) lacked central antinociceptive effect. These compounds had higher COX-2 affinity than COX-1. Our findings suggest substituent insertion alters 4-PSQ's efficacy as an antinociceptive and anti-inflammatory agent.

In vitro effects of l-kynurenine and quinolinic acid on adhesion, migration and apoptosis in B16 F10 melanoma cells

IntroductionThe inhibition of melanoma adhesion through adhesion molecules, such as integrins and E-cadherin, may represent a promising strategy for managing melanoma metastasis. Compounds, namely l-kynurenine (L-kyn) and quinolinic acid (Quin), previously displayed anti-cancer effects at half-maximal inhibitory concentration (IC50) against B16 F10 melanoma cells in vitro. However, the role of these compounds in B16 F10 melanoma cell adhesion, migration and apoptosis remain unknown. MethodsPost-exposure to the compounds, flow cytometry was used to analyse the expression of very late antigen-5 (VLA-5), E-cadherin and cleaved caspase-3 in B16 F10 melanoma and RAW 264.7 murine macrophage cells. An adhesion assay was used to quantify the adhesion of both cell lines to vitronectin. A scratch migration assay was used to measure the possible inhibition of cell migration in B16 F10 cells in response to L-kyn and Quin. ResultsIn both B16 F10 and RAW 264.7 cells, neither L-kyn nor Quin induced significant effects on VLA-5 expression or cell adhesion to vitronectin. In B16 F10 cells, both L-kyn and Quin elevated E-cadherin expression and displayed a trend of suppressed migration. However, only L-kyn elevated E-cadherin in RAW 264.7 cells. L-kyn induced apoptosis by elevating cleaved caspase-3 expression in both cell lines. ConclusionL-kyn and Quin demonstrated promising antimetastatic effects in their ability to elevate E-cadherin expression and induce apoptosis in B16 F10 melanoma cells. However, these effects did not occur in response to vitronectin or VLA-5 integrin alterations. Furthermore, it cannot be excluded that L-kyn also induced apoptosis in RAW 264.7 cells. As such, these effects should be confirmed in additional control cell lines and substantiated with in vivo models.

Association of concussion history with psychiatric symptoms, limbic system structure, and kynurenine pathway metabolites in healthy, collegiate-aged athletes

Psychiatric outcomes are commonly observed in individuals with repeated concussions, though their underlying mechanism is unknown. One potential mechanism linking concussion with psychiatric symptoms is inflammation-induced activation of the kynurenine pathway, which is thought to play a role in the pathogenesis of mood disorders. Here, we investigated the association of prior concussion with multiple psychiatric-related outcomes in otherwise healthy male and female collegiate-aged athletes (N = 212) with varying histories of concussion recruited from the community. Specially, we tested the hypotheses that concussion history is associated with worse psychiatric symptoms, limbic system structural abnormalities (hippocampal volume, white matter microstructure assessed using neurite orientation dispersion and density imaging; NODDI), and elevations in kynurenine pathway (KP) metabolites (e.g., Quinolinic acid; QuinA). Given known sex-effects on concussion risk and recovery, psychiatric outcomes, and the kynurenine pathway, the moderating effect of sex was considered for all analyses. More concussions were associated with greater depression, anxiety, and anhedonia symptoms in female athletes (ps ≤ 0.005) and greater depression symptoms in male athletes (p = 0.011). More concussions were associated with smaller bilateral hippocampal tail (ps < 0.010) and left hippocampal body (p < 0.001) volumes across male and female athletes. Prior concussion was also associated with elevations in the orientation dispersion index (ODI) and lower intracellular volume fraction in several white matter tracts including the in uncinate fasciculus, cingulum-gyrus, and forceps major and minor, with evidence of female-specific associations in select regions. Regarding serum KP metabolites, more concussions were associated with elevated QuinA in females and lower tryptophan in males (ps ≤ 0.010). Finally, serum levels of QuinA were associated with elevated ODI (male and female athletes) and worse anxiety symptoms (females only), while higher ODI in female athletes and smaller hippocampal volumes in male athletes were associated with more severe anxiety and depression symptoms (ps ≤ 0.05). These data suggest that cumulative concussion is associated with psychiatric symptoms and limbic system structure in healthy athletes, with increased susceptibility to these effects in female athletes. Moreover, the associations of outcomes with serum KP metabolites highlight the KP as one potential molecular pathway underlying these observations.

A salt from biologically active compounds pyridine-2,3-dicarboxylic (quinolinic) acid and cytosine.

Biologically active compounds are highly sought-after materials for developing novel structures applicable to industry. Cytosine and pyridine-2,3-dicarboxylic acid (quinolinic acid) are notably significant environmentally. Cytosine, a pyrimidine derivative, features a six-membered ring with a ketone and an amino group, constituting a fundamental nitrogenous base found in deoxyribonucleic acid (DNA). The present synthesis yielded a salt of dipyridine-2,3-dicarboxylic acid with cytosine, wherein a proton was transferred from a carboxyl group of quinolinic acid to a ring N atom in the cytosine molecule giving the salt 6-amino-2-oxo-2,3-dihydropyrimidin-1-ium 3-carboxypyridine-2-carboxylate, C4H6N3O+·C7H4NO4-. A Hirshfeld surface analysis was conducted to examine the contribution of contacts within the salt. The structure of the salt was compared to other structures containing quinolinic acid in the Cambridge Structural Database (CSD).

Gut-Brain Axis and Neuroinflammation: The Role of Gut Permeability and the Kynurenine Pathway in Neurological Disorders.

The increasing prevalence of neurological disorders such as Alzheimer's, Parkinson's, and multiple sclerosis presents a significant global health challenge. Despite extensive research, the precise mechanisms underlying these conditions remain elusive, with current treatments primarily addressing symptoms rather than root causes. Emerging evidence suggests that gut permeability and the kynurenine pathway are involved in the pathogenesis of these neurological conditions, offering promising targets for novel therapeutic and preventive strategies. Gut permeability refers to the intestinal lining's ability to selectively allow essential nutrients into the bloodstream while blocking harmful substances. Various factors, including poor diet, stress, infections, and genetic predispositions, can compromise gut integrity, leading to increased permeability. This condition facilitates the translocation of toxins and bacteria into systemic circulation, triggering widespread inflammation that impacts neurological health via the gut-brain axis. The gut-brain axis (GBA) is a complex communication network between the gut and the central nervous system. Dysbiosis, an imbalance in the gut microbiota, can increase gut permeability and systemic inflammation, exacerbating neuroinflammation-a key factor in neurological disorders. The kynurenine pathway, the primary route for tryptophan metabolism, is significantly implicated in this process. Dysregulation of the kynurenine pathway in the context of inflammation leads to the production of neurotoxic metabolites, such as quinolinic acid, which contribute to neuronal damage and the progression of neurological disorders. This narrative review highlights the potential and progress in understanding these mechanisms. Interventions targeting the kynurenine pathway and maintaining a balanced gut microbiota through diet, probiotics, and lifestyle modifications show promise in reducing neuroinflammation and supporting brain health. In addition, pharmacological approaches aimed at modulating the kynurenine pathway directly, such as inhibitors of indoleamine 2,3-dioxygenase, offer potential avenues for new treatments. Understanding and targeting these interconnected pathways are crucial for developing effective strategies to prevent and manage neurological disorders.

Mechanism of Treadmill Exercise Combined with Rich Environmental Stimulation to Improve Depression in Post-stroke Depression Model Rats.

Post-stroke depression (PSD) is a common complication, occurring in approximately one-third of these patients. The neurological symptoms of PSD affect patients' daily life and subsequent recovery. Analyzing the pathogenesis of post-stroke depression from a psychological perspective, it was found that PSD patients often feel despair and anxiety, and it is crucial to explore non-pharmacological ways to improve post-stroke depressive symptoms. A combination of exercise and rich environmental stimulation (RES) has been found effective in improving post-stroke depressive symptoms. Therefore, this study aimed to explore the effects of exercise and rich environmental stimulation on PSD in rats and their potential underlying mechanisms and to provide a theoretical basis for managing PSD. The PSD rat model was constructed, and the depression-like behaviors of rats in each group were evaluated using the open field test (OFT), sucrose preference test (SPT), and forced swimming test (FST). Moreover, changes in the morphological behavior of rat hippocampus were observed using hematoxylin-eosin (HE) staining and Nissl staining. The expression levels of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) in hippocampus tissues were assessed using enzyme linked immunosorbent assay (ELISA), and the levels of tryptophan-related proteins were determined employing western blot analysis. Additionally, a kynurenine-3-monooxygenase (KMO) inhibitor was administered to the combined stimulation group, and the levels of tryptophan (TRP), 5-HT, kynurenine (KYN), 3-hydroxy-kynurenine (3-HK), and quinolinic acid (QA) were evaluated using liquid chromatography mass spectrometry/mass spectrometry (LC-MS/MS). Treadmill exercise combined with rich environmental stimulation significantly reduced the immobility time in the FST (p < 0.01), increased the exploratory behavior in the OFT (p < 0.05), and increased the sucrose water consumption in the SPT (p < 0.01), indicating that the depression-like behavior was improved. Treadmill exercise combined with rich environmental stimulation also improved the shape of the damaged hippocampus and increased the number of neurons in the hippocampus. Additionally, treadmill exercise combined with rich environmental stimulation significantly increased the levels of 5-HT and NE in hippocampus tissues (p < 0.01) and decreased KMO protein level (p < 0.01). In the KMO inhibitor group, the neural function was efficiently restored, the levels of 3-HK, QA, and KMO in the hippocampus were substantially reduced (p < 0.01), and the expression level of 5-HT was increased (p < 0.01). Exercise stimulation combined with enriched environmental stimuli alleviates post-stroke depression in rats, and the underlying mechanisms may be related to TRP/KYN/3-HK/QA excitotoxicity pathways and increased 5-hydroxytryptamine levels.

Quinolinic Acid Excess May Promote Kidney Fibrosis

Quinolinic Acid Excess May Promote Kidney Fibrosis

Kynurenines in heart failure with preserved ejection fraction: an influence of type 2 diabetes.

Given their association with inflammatory processes and oxidative stress, tryptophan metabolites involved in the kynurenine pathway (KP) play a role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes (T2D). The study aimed to examine the relationship between the parameters of HFpEF, as determined by transthoracic echocardiography, and metabolites of the KP. We prospectively included 120 patients with HFpEF, 60 with and 60 without T2D, and 55 controls. High‑performance liquid chromatography was used to quantify the serum metabolites of KP. Echocardiography was used to assess left ventricular systolic and diastolic function. The patients with HFpEF and T2D showed an increase in tryptophan, kynurenine, and anthranilic acid concentrations (P = 0.001, P <0.001, and P <0.001, respectively) with a concomitant decrease in 3‑hydroxykynurenine (P <0.001) and quinolinic acid (P = 0.003), as compared with those with HFpEF without T2D. Left ventricular and left atrial remodeling was more pronounced in the group with T2D, but differences between these parameters did not reach statistical significance. Left ventricular global longitudinal strain was lower in the subgroup of patients with HFpEF and T2D than in the subgroup without T2D (P = 0.003). The study showed altered tryptophan metabolism in patients with HFpEF, highlighting a possible connection. The findings suggest potential implications for targeted therapeutic strategies focusing on tryptophan metabolism and cardiac function in patients with HFpEF and T2D.

Parkinson's disease is characterized by vitamin B6-dependent inflammatory kynurenine pathway dysfunction.

Parkinson's disease (PD) is a complex multisystem disorder clinically characterized by motor, non-motor, and premotor manifestations. Pathologically, PD involves neuronal loss in the substantia nigra, striatal dopamine deficiency, and accumulation of intracellular inclusions containing aggregates of α-synuclein. Recent studies demonstrate that PD is associated with dysregulated metabolic flux through the kynurenine pathway (KP), in which tryptophan is converted to kynurenine (KYN), and KYN is subsequently metabolized to neuroactive compounds quinolinic acid (QA) and kynurenic acid (KA). This multicenter study used highly sensitive liquid chromatography-tandem mass-spectrometry to compare blood and cerebral spinal fluid (CSF) KP metabolites between 158 unimpaired older adults and 177 participants with PD. Results indicate that increased neuroexcitatory QA/KA ratio in both plasma and CSF of PD participants associated with peripheral and cerebral inflammation and vitamin B6 deficiency. Furthermore, increased QA tracked with CSF tau and severity of both motor and non-motor PD clinical dysfunction. Importantly, plasma and CSF kynurenine metabolites classified PD participants with a high degree of accuracy (AUC = 0.897). Finally, analysis of metabolite data revealed subgroups with distinct KP profiles, and these were subsequently found to display distinct PD clinical features. Together, these data further support the hypothesis that the KP serves as a site of brain and periphery crosstalk, integrating B-vitamin status, inflammation and metabolism to ultimately influence PD clinical manifestation.

Circulating tryptophan–kynurenine pathway metabolites are associated with all‐cause mortality among patients with stage I–III colorectal cancer

AbstractAlterations within the tryptophan–kynurenine metabolic pathway have been linked to the etiology of colorectal cancer (CRC), but the relevance of this pathway for prognostic outcomes in CRC patients needs further elucidation. Therefore, we investigated associations between circulating concentrations of tryptophan–kynurenine pathway metabolites and all‐cause mortality among CRC patients. This study utilizes data from 2102 stage I–III CRC patients participating in six prospective cohorts involved in the international FOCUS Consortium. Preoperative circulating concentrations of tryptophan, kynurenine, kynurenic acid (KA), 3‐hydroxykynurenine (HK), xanthurenic acid (XA), 3‐hydroxyanthranilic acid (HAA), anthranilic acid (AA), picolinic acid (PA), and quinolinic acid (QA) were measured by liquid chromatography–tandem mass spectrometry. Using Cox proportional hazards regression, we examined associations of above‐mentioned metabolites with all‐cause mortality, adjusted for potential confounders. During a median follow‐up of 3.2 years (interquartile range: 2.2–4.9), 290 patients (13.8%) deceased. Higher blood concentrations of tryptophan, XA, and PA were associated with a lower risk of all‐cause mortality (per doubling in concentrations: tryptophan: HR = 0.56; 95%CI:0.41,0.76, XA: HR = 0.74; 95%CI:0.64,0.85, PA: HR = 0.76; 95%CI:0.64,0.92), while higher concentrations of HK and QA were associated with an increased risk of death (per doubling in concentrations: HK: HR = 1.80; 95%CI:1.47,2.21, QA: HR = 1.31; 95%CI:1.05,1.63). A higher kynurenine‐to‐tryptophan ratio, a marker of cell‐mediated immune activation, was associated with an increased risk of death (per doubling: HR = 2.07; 95%CI:1.52,2.83). In conclusion, tryptophan–kynurenine pathway metabolites may be prognostic markers of survival in CRC patients.

The Kynurenine Pathway, Aryl Hydrocarbon Receptor, and Alzheimer's Disease.

Alzheimer's disease (AD) is the leading cause of dementia, mainly affecting elderly individuals. AD is characterized by β-amyloid plaques, abnormal tau tangles, neuronal loss, and metabolic disruptions. Recent studies have revealed the involvement of the kynurenine (KP) pathway and the aryl hydrocarbon receptor (AhR) in AD development. The KP pathway metabolizes tryptophan to produce neuroactive substances like kynurenine, kynurenic acid, and quinolinic acid. In AD, high levels of kynurenine and the neurotoxic quinolinic acid are associated with increased neuroinflammation and excitotoxicity; conversely, reduced levels of kynurenic acid, which acts as a glutamate receptor antagonist, compromise neuroprotection. Research has indicated elevated KP metabolites and enzymes in the hippocampus of AD patients and other tissues such as blood, cerebrospinal fluid, and urine. However, the finding that KP metabolites are AD biomarkers in blood, cerebrospinal fluid, and urine has been controversial. This controversy, stemming from the lack of consideration of the specific stage of AD, details of the patient's treatment, cognitive deficits, and psychiatric comorbidities, underscores the need for more comprehensive research. AhR, a ligand-activated transcription factor, regulates immune response, oxidative stress, and xenobiotic metabolism. Various ligands, including tryptophan metabolites, can activate it. Some studies suggest that AhR activation contributes to AD, while others propose that it provides neuroprotection. This discrepancy may be explained by the specific ligands that activate AhR, highlighting the complex relationship between the KP pathway, AhR activation, and AD, where the same pathway can produce both neuroprotective and harmful effects.

Changes in D4 and GABAA subunit α3 receptors in the thalamic reticular nucleus caused by unilateral lesion of the globus pallidus.

The thalamic reticular nucleus controls information processing in thalamocortical neurons. GABAergic neurons present in this nucleus express the α3 subunit of post‑synaptic GABAA receptors, which bind GABA from globus pallidus neurons. Pallidal neurons, in turn, have dopaminergic D4 receptors in their axon terminals. The thalamic reticular nucleus connects reciprocally with the thalamus, and it receives afferents from the brain cortex, as well as from other brain structures that have an important role in the modulation of the thalamic network. Based on the above, the purpose of this study was to assess the electrophysiological and molecular effects of unilateral lesion of the globus pallidus on the electric activity of the thalamic reticular nucleus. Two‑month‑old male rats were used. The right globus pallidus was lesioned with quinolinic acid. Seven days after the lesion, ipsilateral turning was registered, confirming the lesion. Afterward, electrophysiological evaluation of the right thalamic reticular nucleus' electrical activity was performed. Subsequently, mRNA expression for D4 receptors and subunit α3, as well as protein content were assessed in the right reticular nucleus. Pallidum lesion caused an increase in firing frequency and decreased firing bursts of reticular neurons. In addition, dopaminergic D4 mRNA, as well as protein increased. In contrast, GABAergic GABAA subunit α3 expression was suppressed, but protein content increased. These results show that the globus pallidus regulates firing in reticular neurons through D4 receptors and subunit α3 of GABAA receptor in the reticular nucleus of the thalamus.

Ameliorative effect of diclofenac in rotenone corneal kindling model of drug-resistant epilepsy: Edge of dual COX and KMO inhibition

Epilepsy affects millions of people worldwide, about one-third patients with epilepsy exhibits resistance to available antiseizures medications, known as drug-resistant epilepsy (DRE). Mitochondrial dysfunction has been implicated as a hallmark in drug-resistant epilepsy via activation of microglial kynurenine 3-monooxygenase (KMO) and cyclooxygenase (COX) enzymes, leading to neuroinflammation and oxidative stress. Diclofenac, an equipotent non selective cyclooxygenase inhibitor, has inhibitory action on KMO enzyme and has also shown anti-inflammatory and antioxidant properties in animal models of epilepsy. These properties make it a suitable candidate for amelioration of DRE. However, its potential in drug-resistant epilepsy remained unexplored till date. In this study, dose dependent effect of diclofenac (5 mg/kg, 10 mg/kg, 20 mg/kg) has been explored in rotenone corneal kindling model of mitochondrial DRE. The results of our study revealed the induction of drug resistance to antiseizure medications and induced kynurenine 3-monooxygenase activity in rotenone corneal kindled epileptic mice in comparison to naive mice. Treatment of rotenone corneal kindled epileptic mice with diclofenac resulted in a significant decrease in drug resistance to antiseizure medications as evident by a reduction in seizure score in the treatment groups as compared to control group, in post-treatment resistance validation. The kynurenine 3-monooxygenase inhibitory activity (as evidenced by decreased levels of neurotoxic quinolinic acid) and the antioxidant effect (as evident by significantly reduced oxidative stress) in the diclofenac treated groups, emerged as a major contributor for its ameliorative action. Findings of this study suggests, diclofenac can be used as an adjunct therapy in amelioration of drug-resistant epilepsy.

Association of the Serotonin and Kynurenine Pathways as Possible Therapeutic Targets to Modulate Pain in Patients with Fibromyalgia.

Fibromyalgia (FM) is a disorder characterized by widespread chronic pain, significant depression, and various neural abnormalities. Recent research suggests a reciprocal exacerbation mechanism between chronic pain and depression. In patients with FM, dysregulation of tryptophan (Trp) metabolism has been identified. Trp, an essential amino acid, serves as a precursor to serotonin (5-HT), a neuromodulator that influences mood, appetite, sleep, and pain perception through the receptors 5-HT1, 5-HT2, and 5-HT3. Additionally, Trp is involved in the kynurenine pathway, a critical route in the immune response, inflammation, and production of neuroactive substances and nicotinamide adenine dinucleotide (NAD+). The activation of this pathway by pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interferon gamma (IFN-γ), leads to the production of kynurenic acid (KYNA), which has neuroprotective properties, and quinolinic acid (QA), which is neurotoxic. These findings underscore the crucial balance between Trp metabolism, 5-HT, and kynurenine, where an imbalance can contribute to the dual burden of pain and depression in patients with FM. This review proposes a novel therapeutic approach for FM pain management, focusing on inhibiting QA synthesis while co-administering selective serotonin reuptake inhibitors to potentially increase KYNA levels, thus dampening pain perception and improving patient outcomes.

The association between HIV-1 Tat and Vif amino acid sequence variation, inflammation and Trp-Kyn metabolism: an exploratory investigation

BackgroundHIV-1 has well-established mechanisms to disrupt essential pathways in people with HIV, such as inflammation and metabolism. Moreover, diversity of the amino acid sequences in fundamental HIV-1 proteins including Tat and Vif, have been linked to dysregulating these pathways, and subsequently influencing clinical outcomes in people with HIV. However, the relationship between Tat and Vif amino acid sequence variation and specific immune markers and metabolites of the tryptophan-kynurenine (Trp-Kyn) pathway remains unclear. Therefore, this study aimed to investigate the relationship between Tat/Vif amino acid sequence diversity and Trp-Kyn metabolites (quinolinic acid (QUIN), Trp, kynurenic acid (KA), Kyn and Trp/Kyn ratio), as well as specific immune markers (sCD163, suPAR, IL-6, NGAL and hsCRP) in n = 67 South African cART-naïve people with HIV.MethodsSanger sequencing was used to determine blood-derived Tat/Vif amino acid sequence diversity. To measure Trp-Kyn metabolites, a LC–MS/MS metabolomics platform was employed using a targeted approach. To measure immune markers, Enzyme-linked immunosorbent assays and the Particle-enhanced turbidimetric assay was used.ResultsAfter adjusting for covariates, sCD163 (p = 0.042) and KA (p = 0.031) were higher in participants with Tat signatures N24 and R57, respectively, and amino acid variation at position 24 (adj R2 = 0.048, β = -0.416, p = 0.042) and 57 (adj R2 = 0.166, β = 0.535, p = 0.031) of Tat were associated with sCD163 and KA, respectively.ConclusionsThese preliminary findings suggest that amino acid variation in Tat may have an influence on underlying pathogenic HIV-1 mechanisms and therefore, this line of work merits further investigation.

Neurobiological mechanisms in the kynurenine pathway and major depressive disorder.

Major depressive disorder (MDD) is a prevalent psychiatric disorder that has damage to people's quality of life. Tryptophan is the precursor to serotonin, a critical neurotransmitter in mood modulation. In mammals, most free tryptophan is degraded by the kynurenine pathway (KP), resulting in a range of metabolites involved in inflammation, immune response, and neurotransmission. The imbalance between quinolinic acid (QA), a toxic metabolite, and kynurenic acid (KynA), a protective metabolite, is a relevant phenomenon involved in the pathophysiology of MDD. Proinflammatory cytokines increase the activity of the enzyme indoleamine 2,3-dioxygenase (IDO), leading to the degradation of tryptophan in the KP and an increase in the release of QA. IDO activates proinflammatory genes, potentiating neuroinflammation and deregulating other physiological mechanisms related to chronic stress and MDD. This review highlights the physiological mechanisms involved with stress and MDD, which are underlying an imbalance of the KP and discuss potential therapeutic targets.

Prospective Clinical Study: Full-Body Blue Irradiation in the Treatment of Atopic Dermatitis.

Ultraviolet-free (UV-free) blue light phototherapy has emerged as a promising option due to its reported efficacy and minimal adverse effects. This study aims to evaluate the effectiveness of full-body blue light irradiation in both adult and pediatric patients with atopic dermatitis (AD), assessing its impact on skin condition and mood regulation by investigating serum concentrations of serotonin and kynurenine pathway metabolites. 20 patients (age 9-45) with moderate and severe AD were included in the study. Treatment consisted of 10 irradiations with Full Body Blue device (453nm). Serum concentrations of serotonin, quinolinic acid, kynurenic acid, tryptophan, and kynurenine were measured before and after irradiations. After 10 sessions of full blue light therapy (453nm) statistically significant improvements were observed in Eczema Area Severity Index (EASI 13.16 vs. 8.65; p = 0.00016), SCORing Atopic Dermatitis (SCORAD 44.99 vs. 23.73; p < 0.00001), Visual Analogue Scale (VAS 6.53 vs. 3.95; p = 0.00251), 10-item pruritus severity scale (13.32 vs. 7.05; p < 0.00001). Moreover, statistically significant decrease in Dermatology Life Quality Index (DLQI) was noted (14.37 vs. 7.42; p = 0.00351). Additionally, increase in the serum concentration of serotonin was observed after completing 10 irradiation sessions (median 139.77mg/ml vs. 274.92mg/ml; p < 0.00001). Blue light may be a promising and safe treatment in patients with AD. It might also positively influence mood. Further investigations are needed to confirm those findings. ClinicalTrials.gov identifier, NCT06516783.