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Tryptophan metabolism in glaucomatous optic neuropathy: from metabolic dysregulation to therapeutic opportunities.

BACKGROUND: Glaucoma, a leading cause of irreversible blindness, involves progressive retinal ganglion cell loss. Beyond intraocular pressur … sregulated tryptophan metabolism in glaucoma shifts the balance toward neurotoxic metabolites (e.g. quinolinic acid) and reduces protective ones (e.g. kynurenic acid, indole derivatives). These changes are linked to alterations in AhR-mediated immunomodulation, NMDAR excitotoxicity, oxidative stress, intraocular pressure and vascular regulation. Therapeutic inter …

Kynurenic acid in neurodegenerative disorders-unique neuroprotection or double-edged sword?

AIMS: The family of kynurenine pathway (KP) metabolites includes compounds produced along two arms of the path and acting in clearly opposite ways. The equilibrium between neurotoxic kynurenines, such as 3-hydroxykynurenine (3-HK) or quinolinic acid (QUIN), and neuroprotective kynurenic acid (KYNA) profoundly impacts the function and survival of neurons. This comprehensive review summarizes accumulated evidence on the role of KYNA in Alzheimer's, Parkinson's and Huntington's diseases, and discusses future directions of potential pharmacological manipulations aimed to modulate brain KYNA. DISC…

Serum Tryptophan, Tryptophan Catabolites and Brain-derived Neurotrophic Factor in Subgroups of Youngsters with Autism Spectrum Disorders.

BACKGROUND: There is evidence that changes in neuro-immune responses coupled with dysfunctions in serotonin metabolism underpin the pathophysiology of autism spectrum disorders (ASD). OBJECTIVE: This study aimed to delineate whether ASD subgroups or characteristics show aberrations in tryptophan and brain-derived neurotrophic factor (BDNF) metabolism. METHODS: 65 individuals with ASD (diagnosed according to ICD criteria) and 30 healthy control patients were included. Measured were serum levels of tryptophan, kynurenine (KYN), kynurenic acid (KA), quinolinic acid (QA), BDNF and PRO-BDNF and t…

VCE-003.2, a novel cannabigerol derivative, enhances neuronal progenitor cell survival and alleviates symptomatology in murine models of Huntington's disease.

Cannabinoids have shown to exert neuroprotective actions in animal models by acting at different targets including canonical cannabinoid rec … tagonist, without affecting neural progenitor cell proliferation. In addition, VCE-003.2 attenuated quinolinic acid (QA)-induced cell death and caspase-3 activation and also reduced mutant huntingtin aggregates in striatal cells. The neuroprotective profile of VCE-003.2 was analyzed using in vivo models of striatal neurodegeneration induced by QA and 3-nitropropi …

Tryptophan Metabolism Along the Kynurenine Pathway Downstream of Toll-like Receptor Stimulation in Peripheral Monocytes.

Tryptophan degradation along the kynurenine pathway is of central importance for the immune function. Toll-like receptors (TLRs), representi … lysed using a liquid chromatography/mass spectrometry to measure kynurenine, kynurenic acid (KYNA), quinolinic acid (QUIN) and tryptophan. Stimulation of TLR-2, TLR-3, TLR-4, TLR-7/8 and TLR-9 was found to induce the production of kynurenine, but only stimulation of TLR-3 increased levels of further downstream metabolites, such as KYNA and QUIN. Stimulation of TL …

Peripheral and central kynurenine pathway abnormalities in major depression.

Considerable data relate major depressive disorder (MDD) with aberrant immune system functioning. Pro-inflammatory cytokines facilitate meta … sturbance associated with atypical depression. Plasma levels of picolinic acid (PIC), the kynurenic/quinolinic acid ratio (KYNA/QUIN), and PIC/QUIN were lower in MDD, but QUIN levels were increased. In the CSF, we found lower PIC in MDD. Confirming previous work, MDD patients had lower hippocampal, and amygdalar volumes. Hippocampal and amygdalar volumes were cor …

Current Landscape of Hydroxamic Acid Derivatives With Antileukemia Activity.

Leukemia, as the second most prevalent hematological malignancy, could disrupt the production of healthy blood cells in the bone marrow, leading to anemia, neutropenia, and thrombocytopenia, and constitutes a significant global health burden. Chemotherapy remains a cornerstone of leukemia treatment, but drug resistance and severe adverse effects are the main culprits for its failure in treating leukemia, thereby creating an urgent imperative to develop innovative anti-leukemia agents. Hydroxamic acid derivatives, recognized as prominent histone deacetylase (HDAC) inhibitors, represent a promis

Exploring new quinoxaline, quinoline, and naphthalene carboxamides as HDAC-targeted anticancer agents: Cytotoxicity, enzymatic HDAC evaluation, and in silico studies.

Histone deacetylase inhibitors (HDACis) are important epigenetic anticancer agents, but new HDAC-targeted scaffolds are still needed to improve biological profiles. Herein, quinoxaline, quinoline, and naphthalene were selected as structurally related fused-aromatic cap groups within the HDAC inhibitor pharmacophore, allowing comparison of naphthalene and its aza-analogs in a unified carboxamide series. A new series of quinoxaline, quinoline, and naphthalene carboxamides was synthesized through amidation of amino acid methyl esters, followed by hydrolysis, hydrazinolysis, and hydroxamate format

Further analysis of acute antinociceptive and anti-inflammatory actions of 4-phenylselenyl-7-chloroquinoline in mice.

A new quinoline containing selenium, 4-phenylselenyl-7-chloroquinoline (4-PSQ), was described and synthetized by our research group. Recently, we demonstrated the potential antinociceptive and anti-inflammatory of 4-PSQ. For this reason, the first objective of this study was to expand our previous findings by investigating the contribution of glutamatergic, serotonergic, and nitrergic systems to the acute antinociceptive action of this compound. Pretreatment with 4-PSQ (0.01-25 mg/kg, p.o.) reduced the nociception induced by glutamate. MK-801 (an uncompetitive antagonist of the N-Methyl-d-aspa

The kynurenine pathway and markers of neurodegeneration and cerebral small vessel disease: The Maastricht Study.

BACKGROUND: The kynurenine pathway, the main metabolic pathway of tryptophan degradation, has been mostly studied in neurodegenerative disor … ted analyses indicated that higher levels of 3-hydroxyanthranilic acid, kynurenine, kynurenic acid, quinolinic acid, and neopterin were associated with lower CSF volume. For the latter four, associations were non-linear and restricted to participants with already below average concentrations. Higher levels of tryptophan and anthranilic acid were associated with h …

Essential role of excessive tryptophan and its neurometabolites in fatigue.

PURPOSE: Serotonin, a neurotransmitter synthesized from tryptophan, has been proposed to play a key role in central fatigue. In this study, we examined whether tryptophan itself and/or its two metabolites, kyneurenic acid (KYNA) and quinolinic acid (QUIN), are involved in central fatigue. MATERIALS AND METHODS: Experiments were conducted using Sprague-Dawley rats (SDR) and Nagase analbuminemic rats (NAR). Central fatigue was assessed by treadmill running and a Morris water maze test. Microdialysis was used to collect samples for measurement of extracellular concentration of tryptophan, seroto…

PfCRT mutations conferring piperaquine resistance in falciparum malaria shape the kinetics of quinoline drug binding and transport.

The chloroquine resistance transporter (PfCRT) confers resistance to a wide range of quinoline and quinoline-like antimalarial drugs in Plasmodium falciparum, with local drug histories driving its evolution and, hence, the drug transport specificities. For example, the change in prescription practice from chloroquine (CQ) to piperaquine (PPQ) in Southeast Asia has resulted in PfCRT variants that carry an additional mutation, leading to PPQ resistance and, concomitantly, to CQ re-sensitization. How this additional amino acid substitution guides such opposing changes in drug susceptibility is la

Design, synthesis, and evaluation of 10-N-substituted acridones as novel chemosensitizers in Plasmodium falciparum.

A series of novel 10-N-substituted acridones, bearing alkyl side chains with tertiary amine groups at the terminal position, were designed, synthesized, and evaluated for the ability to enhance the potency of quinoline drugs against multidrug-resistant (MDR) Plasmodium falciparum malaria parasites. A number of acridone derivatives, with side chains bridged three or more carbon atoms apart between the ring nitrogen and terminal nitrogen, demonstrated chloroquine (CQ)-chemosensitizing activity against the MDR strain of P. falciparum (Dd2). Isobologram analysis revealed that selected candidates d

The Kynurenine Pathway: Unraveling Its Role in Neurological Disorders via Mammalian Cellular Models.

The kynurenine pathway (KP) constitutes the primary route of tryptophan catabolism, generating a spectrum of neuroactive metabolites that pr … c enzymatic profiles. Across the described cellular systems, a recurring mechanistic theme emerges: quinolinic acid-driven mitochondrial dysfunction, oxidative stress, and NAD+ depletion converge in neurodegenerative conditions such as Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Conversely, kynurenic acid exhibits disorder-depend …

Establishing biosynthetic pathways for the production of nicotinic acid and trigonelline in Escherichia coli.

Microbial cell factories offer a sustainable platform for the production of natural products, but their development is often constrained by … tly reducing energy and cofactor requirements. We optimized the supply of key precursors, including quinolinic acid (QA) and 5-phosphoribosyl-1-pyrophosphate (PRPP), and eliminated competing metabolic routes, resulting in a NA titer of 1.19 g/L in a 3-L fermenter, representing a 200-fold improvement over the original strain. We also extended the pathway to produc …

Kynurenine pathway modulates dynamic network instability and depression severity in major depressive disorder.

OBJECTIVE: This study investigates changes in dynamic functional connectivity (dFC) within the default mode, salience, and central executive networks in adults with Major Depressive Disorder (MDD). Additionally, it seeks to explore the associations between these alterations and kynurenine pathway metabolites, as well as their impact on depression severity. METHODS: Resting-state functional magnetic resonance imaging was used to assess dFC in 53 MDD patients and 58 matched healthy controls. Plasma levels of kynurenine (KYN), kynurenic acid, and quinolinic acid were measured. Analyses were cond…

Кинуреньенс и митохондриальные расстройства в многоразовом склерозе.

Множественный склероз (MS) — хроническое аутоиммунное заболевание, характеризующееся воспалением, обезвоживанием и нейродегенерацией в центральной нервной системе. Патогенез MS связан с иммунной атаки на миелин и нейроны, сопровождаемой дисфункцией мозга в крови и хроническим воспалением CNS. Центральное значение для патологии MS имеет дисрегулирование кинуреньинового пути, который метаболизирует триптофан в нейроактивные соединения. Активация Kynurenin Translation (KP) под воздействием подстрекательских цитокинов приводит к образованию как нейрозащитных (например, кинуриновой кислоты, КИНА),

Совпадение в аннотации оригинала
Multiple sclerosis (MS) is a chronic autoimmune disease characterised by inflammation, demyelination, and neurodegeneration within the centr … leads to the production of both neuroprotective (e.g., kynurenic acid, KYNA) and neurotoxic (e.g., quinolinic acid, QUIN) metabolites. Imbalance between these metabolites, particularly increased QUIN production, exacerbates glutamate excitotoxicity, oxidative stress, and mitochondrial dysfunction, contributing to neuronal and oligodendrocyte damage. Mitochondria …

Thrombin-induced kynurenine 3-monooxygenase causes variations in the kynurenine pathway, leading to neurological deficits in a murine intracerebral hemorrhage model.

The purpose of the present study is to investigate changes in the kynurenine pathway after intracerebral hemorrhage (ICH) and its effects on ICH-induced injury. The exposure of a primary rat microglial culture to thrombin increased the mRNA level of kynurenine 3-monooxygenase (KMO), and this increase was attenuated by a p38 MAPK inhibitor. Thrombin also increased the protein level of KMO. In the cultured medium, the ratio of quinolinic acid (QUIN), an N-methyl-d-aspartate receptor (NMDAR) agonist, to kynurenic acid (KYNA), its antagonist, increased. The increase in the QUIN/KYNA ratio was bloc…

The Biology and Biochemistry of Kynurenic Acid, a Potential Nutraceutical with Multiple Biological Effects.

Kynurenic acid (KYNA) is an antioxidant degradation product of tryptophan that has been shown to have a variety of cytoprotective, neuroprot … NA but also to that of many other co-metabolites (including some such as 3-hydroxy-L-kynurenine and quinolinic acid that may be toxic). With the exception of chestnut honey, KYNA exists at relatively low levels in natural foodstuffs. However, its bioavailability is reasonable, and as the terminal element of an irreversible reaction of most tryptophan degradation …

Kynurenine 3-Monooxygenase Activity in Human Primary Neurons and Effect on Cellular Bioenergetics Identifies New Neurotoxic Mechanisms.

Upregulation of the kynurenine pathway (KP) of tryptophan metabolism is commonly observed in neurodegenerative disease. When activated, L-kynurenine (KYN) increases in the periphery and central nervous system where it is further metabolised to other neuroactive metabolites including 3-hydroxykynurenine (3-HK), kynurenic acid (KYNA) and quinolinic acid (QUIN). Particularly biologically relevant metabolites are 3-HK and QUIN, formed downstream of the enzyme kynurenine 3-monooxygenase (KMO) which plays a pivotal role in maintaining KP homeostasis. Indeed, excessive production of 3-HK and QUIN has…