Kynurenines in the Pathogenesis of Multiple Sclerosis: Therapeutic Perspectives

Over the past years, an increasing amount of evidence has emerged in support of the kynurenine pathway’s (KP) pivotal role in the pathogenesis of several neurodegenerative, psychiatric, vascular and autoimmune diseases. Different neuroactive metabolites of the KP are known to exert opposite effects on neurons, some being neuroprotective (e.g., picolinic acid, kynurenic acid, and the cofactor nicotinamide adenine dinucleotide), while others are toxic to neurons (e.g., 3-hydroxykynurenine, quinolinic acid). Not only the alterations in the levels of the metabolites but also disturbances in their ratio (quinolinic acid/kynurenic acid) have been reported in several diseases. In addition to the metabolites, the enzymes participating in the KP have been unearthed to be involved in modulation of the immune system, the energetic upkeep of neurons and have been shown to influence redox processes and inflammatory cascades, revealing a sophisticated, intertwined system. This review considers various methods through which enzymes and metabolites of the kynurenine pathway influence the immune system, the roles they play in the pathogenesis of neuroinflammatory diseases based on current evidence with a focus on their involvement in multiple sclerosis, as well as therapeutic approaches.

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Clinical relevance of depressed kynurenine pathway in episodic migraine patients: potential prognostic markers in the peripheral plasma during the interictal period

The Journal of Headache and Pain ◽

10.1186/s10194-021-01239-1 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Bernadett Tuka ◽

Aliz Nyári ◽

Edina Katalin Cseh ◽

Tamás Körtési ◽

Dániel Veréb ◽

...

Keyword(s):

Anthranilic Acid ◽

Clinical Relevance ◽

Kynurenic Acid ◽

Picolinic Acid ◽

Plasma Concentrations ◽

Episodic Migraine ◽

Kynurenine Pathway ◽

Xanthurenic Acid ◽

Control Subjects ◽

Healthy Control

Abstract Background Altered glutamatergic neurotransmission and neuropeptide levels play a central role in migraine pathomechanism. Previously, we confirmed that kynurenic acid, an endogenous glutamatergic antagonist, was able to decrease the expression of pituitary adenylate cyclase-activating polypeptide 1–38, a neuropeptide with known migraine-inducing properties. Hence, our aim was to reveal the role of the peripheral kynurenine pathway (KP) in episodic migraineurs. We focused on the complete tryptophan (Trp) catabolism, which comprises the serotonin and melatonin routes in addition to kynurenine metabolites. We investigated the relationship between metabolic alterations and clinical characteristics of migraine patients. Methods Female migraine patients aged between 25 and 50 years (n = 50) and healthy control subjects (n = 34) participated in this study. Blood samples were collected from the cubital veins of subjects (during both the interictal/ictal periods in migraineurs, n = 47/12, respectively). 12 metabolites of Trp pathway were determined by neurochemical measurements (UHPLC-MS/MS). Results Plasma concentrations of the most Trp metabolites were remarkably decreased in the interictal period of migraineurs compared to healthy control subjects, especially in the migraine without aura (MWoA) subgroup: Trp (p < 0.025), L-kynurenine (p < 0.001), kynurenic acid (p < 0.016), anthranilic acid (p < 0.007), picolinic acid (p < 0.03), 5-hydroxy-indoleaceticacid (p < 0.025) and melatonin (p < 0.023). Several metabolites showed a tendency to elevate during the ictal phase, but this was significant only in the cases of anthranilic acid, 5-hydroxy-indoleaceticacid and melatonin in MWoA patients. In the same subgroup, higher interictal kynurenic acid levels were identified in patients whose headache was severe and not related to their menstruation cycle. Negative linear correlation was detected between the interictal levels of xanthurenic acid/melatonin and attack frequency. Positive associations were found between the ictal 3-hydroxykynurenine levels and the beginning of attacks, just as between ictal picolinic acid levels and last attack before ictal sampling. Conclusions Our results suggest that there is a widespread metabolic imbalance in migraineurs, which manifests in a completely depressed peripheral Trp catabolism during the interictal period. It might act as trigger for the migraine attack, contributing to glutamate excess induced neurotoxicity and generalised hyperexcitability. This data can draw attention to the clinical relevance of KP in migraine.

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Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1604453113 ◽

2016 ◽

Vol 113 (19) ◽

pp. 5435-5440 ◽

Cited By ~ 61

Author(s):

Carlo Breda ◽

Korrapati V. Sathyasaikumar ◽

Shama Sograte Idrissi ◽

Francesca M. Notarangelo ◽

Jasper G. Estranero ◽

...

Keyword(s):

Quinolinic Acid ◽

Neurodegenerative Disorders ◽

Kynurenic Acid ◽

Therapeutic Potential ◽

Fruit Fly ◽

Kynurenine Pathway ◽

Locomotor Performance ◽

Potential Treatment ◽

Regulatory Enzymes ◽

Therapeutic Benefits

Metabolites of the kynurenine pathway (KP) of tryptophan (TRP) degradation have been closely linked to the pathogenesis of several neurodegenerative disorders. Recent work has highlighted the therapeutic potential of inhibiting two critical regulatory enzymes in this pathway—kynurenine-3-monooxygenase (KMO) and tryptophan-2,3-dioxygenase (TDO). Much evidence indicates that the efficacy of KMO inhibition arises from normalizing an imbalance between neurotoxic [3-hydroxykynurenine (3-HK); quinolinic acid (QUIN)] and neuroprotective [kynurenic acid (KYNA)] KP metabolites. However, it is not clear if TDO inhibition is protective via a similar mechanism or if this is instead due to increased levels of TRP—the substrate of TDO. Here, we find that increased levels of KYNA relative to 3-HK are likely central to the protection conferred by TDO inhibition in a fruit fly model of Huntington’s disease and that TRP treatment strongly reduces neurodegeneration by shifting KP flux toward KYNA synthesis. In fly models of Alzheimer’s and Parkinson’s disease, we provide genetic evidence that inhibition of TDO or KMO improves locomotor performance and ameliorates shortened life span, as well as reducing neurodegeneration in Alzheimer's model flies. Critically, we find that treatment with a chemical TDO inhibitor is robustly protective in these models. Consequently, our work strongly supports targeting of the KP as a potential treatment strategy for several major neurodegenerative disorders and suggests that alterations in the levels of neuroactive KP metabolites could underlie several therapeutic benefits.

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Imbalanced Kynurenine Pathway in Schizophrenia

International Journal of Tryptophan Research ◽

10.4137/ijtr.s16800 ◽

2014 ◽

Vol 7 ◽

pp. IJTR.S16800 ◽

Cited By ~ 60

Author(s):

Magdalena E. Kegel ◽

Maria Bhat ◽

Elisabeth Skogh ◽

Martin Samuelsson ◽

Kristina Lundberg ◽

...

Keyword(s):

Mass Spectrometry ◽

Cerebrospinal Fluid ◽

Liquid Chromatography ◽

Quinolinic Acid ◽

Kynurenic Acid ◽

Kynurenine Pathway ◽

The Other ◽

Healthy Controls ◽

Liquid Chromatography Mass Spectrometry ◽

Csf Levels

Several studies suggest a role for kynurenic acid (KYNA) in the pathophysiology of schizophrenia. It has been proposed that increased brain KYNA levels in schizophrenia result from a pathological shift in the kynurenine pathway toward enhanced KYNA formation, away from the other branch of the pathway leading to quinolinic acid (QUIN). Here we investigate the levels of QUIN in cerebrospinal fluid (CSF) of patients with schizophrenia and healthy controls, and relate those to CSF levels of KYNA and other kynurenine metabolites from the same individuals. CSF QUIN levels from stable outpatients treated with olanzapine (n = 22) and those of controls (n = 26) were analyzed using liquid chromatography-mass spectrometry. No difference in CSF QUIN levels between patients and controls was observed (20.6 ± 1.5 nM vs. 18.2 ± 1.1 nM, P = 0.36). CSF QUIN was positively correlated to CSF kynurenine and CSF KYNA in patients but not in controls. The CSF QUIN/KYNA ratio was lower in patients than in controls ( P = 0.027). In summary, the present study offers support for an over-activated and imbalanced kynurenine pathway, favoring the production of KYNA over QUIN in patients with schizophrenia.

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The Associations Between Cognitive Prognosis and Kynurenines Are Modified by the Apolipoprotein ε4 Allele Variant in Patients With Dementia

International Journal of Tryptophan Research ◽

10.1177/1178646919885637 ◽

2019 ◽

Vol 12 ◽

pp. 117864691988563

Author(s):

Arne Olav Ervik ◽

Stein-Erik Hafstad Solvang ◽

Jan Erik Nordrehaug ◽

Per Magne Ueland ◽

Øivind Midttun ◽

...

Keyword(s):

Cognitive Decline ◽

Apolipoprotein E ◽

Quinolinic Acid ◽

Kynurenic Acid ◽

Picolinic Acid ◽

Apoe Genotype ◽

Synaptic Function ◽

P Value ◽

Gene Variant ◽

Serum Concentrations

Background: The apolipoprotein E ε4 gene variant (APOEε4) confers considerable risk for dementia and affects neuroinflammation, brain metabolism, and synaptic function. The kynurenine pathway (KP) gives rise to neuroactive metabolites, which have inflammatory, redox, and excitotoxic effects in the brain. Aim: To assess whether the presence of at least one APOEε4 allele modifies the association between kynurenines and the cognitive prognosis. Methods: A total of 152 patients with sera for metabolite measurements and APOE genotype were included from the Dementia Study of Western Norway. The participants had mild Alzheimer disease and Lewy body dementia. Apolipoprotein E ε4 gene variant allele status was classified as one or more ε4 versus any other. Mini-Mental State Examination (MMSE) was measured at baseline and for 5 consecutive years. Mann-Whitney U tests and linear mixed-effects models were used for statistical analysis. Results: There were no significant differences in serum concentrations of tryptophan and kynurenine according to the presence or absence of APOEε4. High serum concentrations of kynurenic acid, quinolinic acid, and picolinic acid, and a higher kynurenine-to-tryptophan ratio, were all associated with more cognitive decline in patients without APOEε4 compared to those with the APOEε4 allele ( P-value of the interactions < .05). Conclusions: Kynurenic acid, quinolinic acid, picolinic acid, and the kynurenine-to-tryptophan ratio were associated with a significant increase in cognitive decline when the APOEε4 variant was absent, whereas there was a relatively less decline when the APOEε4 variant was present.

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Understanding the Roles of the Kynurenine Pathway in Multiple Sclerosis Progression

International Journal of Tryptophan Research ◽

10.4137/ijtr.s4294 ◽

2010 ◽

Vol 3 ◽

pp. IJTR.S4294 ◽

Cited By ~ 26

Author(s):

Chai K. Lim ◽

Bruce J. Brew ◽

Gayathri Sundaram ◽

Gilles J. Guillemin

Keyword(s):

Multiple Sclerosis ◽

Nicotinamide Adenine Dinucleotide ◽

Brain Tumours ◽

Therapeutic Strategy ◽

Inflammatory Diseases ◽

Kynurenine Pathway ◽

Aids Dementia Complex ◽

Regulatory Mechanisms ◽

Aids Dementia ◽

Lateral Sclerosis

The kynurenine pathway (KP) is a major degradative pathway of tryptophan ultimately leading to the production of nicotinamide adenine dinucleotide (NAD+) and is also one of the major regulatory mechanisms of the immune response. The KP is known to be involved in several neuroinflammatory disorders including Alzheimer's disease, amyotrophic lateral sclerosis, AIDS dementia complex, Parkinson's disease, schizophrenia, Huntington's disease and brain tumours. However, the KP remains a relatively new topic for the field of multiple sclerosis (MS). Over the last 2–3 years, some evidence has progressively emerged suggesting that the KP is likely to be involved in the pathogenesis of autoimmune diseases especially MS. Some KP modulators are already in clinical trials for other inflammatory diseases and would potentially provide a new and important therapeutic strategy for MS patients. This review summarizes the known relationships between the KP and MS.

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Effects of Tranilast on the Urinary Excretion of Kynurenic and Quinolinic Acid under Conditions of L Tryptophan Loading

International Journal of Tryptophan Research ◽

10.4137/ijtr.s12797 ◽

2013 ◽

Vol 6 ◽

pp. IJTR.S12797 ◽

Cited By ~ 1

Author(s):

Rowland R. Noakes

Keyword(s):

Urinary Excretion ◽

Quinolinic Acid ◽

Kynurenic Acid ◽

Competitive Inhibitor ◽

Kynurenine Pathway ◽

Tryptophan Metabolism ◽

Autoimmune Response ◽

Current Therapy ◽

Indoleamine 2 ◽

Hydroxyanthranilic Acid

The pathogenesis of morphea and other cutaneous sclerosing disorders remain poorly understood. Although they are considered to be autoimmune disorders, abnormal tryptophan metabolism may be involved. Current therapy is directed to supressing the autoimmune response. Demonstration of a therapeutic response to manipulation of the kynurenine pathway would both support a role for abnormal tryptophan metabolism and offer additional targets for therapy. Tranilast is a 3-hydroxyanthranilic acid derivative known to target the kynurenine pathway. The aim of this study was to see if tranilast lowered the urinary excretion of the kynurenine metabolites kynurenic and quinolinic acid under condition of L tryptophan loading in a volunteer. Mean baseline value for kynurenic acid and quinolinic acid were 1.1 and 2.1 mmol/mol creatinine, respectively. This rose to 5.6 and 3.8 mmol/mol creatinine respectively under conditions of L tryptophan loading 2 grams daily. Adding 1 g of tranilast daily lowered the values to 2.0 and 2.9 mmol/mol creatinine, respectively. These data suggest that tranilast acts as a competitive inhibitor of either indoleamine 2, 3-dioxygenase (IDO), tryptophan 2, 3 di-oxygenase (TDO) or both. As it involved only 1 subject, the results may not be representative of the larger population and must be considered preliminary.

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Plasma neurofilament light chain and amyloid-β are associated with the kynurenine pathway metabolites in preclinical Alzheimer’s disease

Journal of Neuroinflammation ◽

10.1186/s12974-019-1567-4 ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 14

Author(s):

Pratishtha Chatterjee ◽

Henrik Zetterberg ◽

Kathryn Goozee ◽

Chai K. Lim ◽

Kelly R. Jacobs ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Light Chain ◽

Quinolinic Acid ◽

Anthranilic Acid ◽

Kynurenic Acid ◽

Amyloid Β ◽

Kynurenine Pathway ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Elderly Individuals

Abstract Background Blood markers indicative of neurodegeneration (neurofilament light chain; NFL), Alzheimer’s disease amyloid pathology (amyloid-β; Aβ), and neuroinflammation (kynurenine pathway; KP metabolites) have been investigated independently in neurodegenerative diseases. However, the association of these markers of neurodegeneration and AD pathology with neuroinflammation has not been investigated previously. Therefore, the current study examined whether NFL and Aβ correlate with KP metabolites in elderly individuals to provide insight on the association between blood indicators of neurodegeneration and neuroinflammation. Methods Correlations between KP metabolites, measured using liquid chromatography and gas chromatography coupled with mass spectrometry, and plasma NFL and Aβ concentrations, measured using single molecule array (Simoa) assays, were investigated in elderly individuals aged 65–90 years, with normal global cognition (Mini-Mental State Examination Score ≥ 26) from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort. Results A positive correlation between NFL and the kynurenine to tryptophan ratio (K/T) reflecting indoleamine 2,3-dioxygenase activity was observed (r = .451, p < .0001). Positive correlations were also observed between NFL and kynurenine (r = .364, p < .0005), kynurenic acid (r = .384, p < .0001), 3-hydroxykynurenine (r = .246, p = .014), anthranilic acid (r = .311, p = .002), and quinolinic acid (r = .296, p = .003). Further, significant associations were observed between plasma Aβ40 and the K/T (r = .375, p < .0005), kynurenine (r = .374, p < .0005), kynurenic acid (r = .352, p < .0005), anthranilic acid (r = .381, p < .0005), and quinolinic acid (r = .352, p < .0005). Significant associations were also observed between plasma Aβ42 and the K/T ratio (r = .215, p = .034), kynurenic acid (r = .214, p = .035), anthranilic acid (r = .278, p = .006), and quinolinic acid (r = .224, p = .027) in the cohort. On stratifying participants based on their neocortical Aβ load (NAL) status, NFL correlated with KP metabolites irrespective of NAL status; however, associations between plasma Aβ and KP metabolites were only pronounced in individuals with high NAL while associations in individuals with low NAL were nearly absent. Conclusions The current study shows that KP metabolite changes are associated with biomarker evidence of neurodegeneration. Additionally, the association between KP metabolites and plasma Aβ seems to be NAL status dependent. Finally, the current study suggests that an association between neurodegeneration and neuroinflammation manifests in the periphery, suggesting that preventing cytoskeleton cytotoxicity by KP metabolites may have therapeutic potential.

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Curcumin in Depression: Potential Mechanisms of Action and Current Evidence—A Narrative Review

Frontiers in Psychiatry ◽

10.3389/fpsyt.2020.572533 ◽

2020 ◽

Vol 11 ◽

Author(s):

Tahiana Ramaholimihaso ◽

Fayçal Bouazzaoui ◽

Arthur Kaladjian

Keyword(s):

Depressive Disorders ◽

Nitrosative Stress ◽

Endocannabinoid System ◽

Mechanisms Of Action ◽

Current Evidence ◽

Therapeutic Approaches ◽

Major Depressive ◽

Oxidative And Nitrosative Stress ◽

Promising Alternative ◽

The Past

Major depressive disorder (MDD) is one of the most prevalent and debilitating disorders. Current available treatments are somehow limited, so alternative therapeutic approaches targeting different biological pathways are being investigated to improve treatment outcomes. Curcumin is the main active component in the spice turmeric that has been used for centuries in Ayurvedic medicine to treat a variety of conditions, including anxiety and depressive disorders. In the past decades, curcumin has drawn researchers' attention and displays a broad range of properties that seem relevant to depression pathophysiology. In this review, we break down the potential mechanisms of action of curcumin with emphasis on the diverse systems that can be disrupted in MDD. Curcumin has displayed, in a number of studies, a potency in modulating neurotransmitter concentrations, inflammatory pathways, excitotoxicity, neuroplasticity, hypothalamic–pituitary–adrenal disturbances, insulin resistance, oxidative and nitrosative stress, and endocannabinoid system, all of which can be involved in MDD pathophysiology. To date, a handful of clinical trials have been published and suggest a benefit of curcumin in MDD. With evidence that is progressively growing, curcumin appears as a promising alternative option in the management of MDD.

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Immunotherapy for Prostate Cancer: Biology and Therapeutic Approaches

Journal of Clinical Oncology ◽

10.1200/jco.2010.34.5025 ◽

2011 ◽

Vol 29 (27) ◽

pp. 3677-3685 ◽

Cited By ~ 36

Author(s):

Edward Cha ◽

Lawrence Fong

Keyword(s):

Prostate Cancer ◽

Clinical Trials ◽

Immune System ◽

Cancer Biology ◽

Objective Response ◽

Progression Free Survival ◽

Therapeutic Approaches ◽

Free Survival ◽

Randomized Controlled ◽

The Past

Although prostate cancer was not historically considered to be a particularly immune-responsive cancer, recent clinical trials have demonstrated that immunotherapy for prostate cancer can lead to improvements in overall survival (OS). These studies include randomized controlled trials with sipuleucel-T and another with PROSTVAC-VF, both of which rely on stimulating the immune system to target prostate proteins. This review discusses the most promising developments over the past year in immune-based therapy for prostate cancer and the opportunities that lie ahead. Recent randomized immunotherapy trials in prostate cancer have demonstrated improvements in OS but without the concomitant improvements in progression-free survival. This uncoupling of survival from clinical response poses challenges to clinical management, because conventional measures of objective response cannot be used to identify patients benefiting from treatment. There is a significant need to identify immunologic or clinical surrogates for survival so that clinical benefit can be assessed in a timely manner. Immunotherapy is now an established treatment approach for prostate cancer, with multiple clinical trials demonstrating improvements in OS. Significant challenges to this modality remain, including determining best clinical setting for immunotherapy, identifying patients who benefit, and defining relevant clinical and immunologic end points. Nevertheless, the broader availability of novel immunotherapies will provide opportunities not only to target different components of the immune system but also to combine immunotherapies with other treatments for improved clinical efficacy.

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