Kynurenines and Multiple Sclerosis: The Dialogue between the Immune System and the Central Nervous System

Rajda, Cecília; Majláth, Zsófia; Pukoli, Dániel; Vécsei, László

doi:10.3390/ijms160818270

Cited by 36 publications

(55 citation statements)

References 66 publications

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“…Recently, evidence has indicated that kynurenine dysregulation is most prominent during the acute phases of MS, whereas kynurenine metabolite levels in MS patients in remission are similar to those of controls [31]. In particular, inhibition of the first enzyme that converts tryptophan to kynurenine metabolite (indoleamine 2,3-dioxygenase) seems to be associated with the reduction of disease activity [32], evidence in line with our findings documenting an increase in tryptophan level during IFN ß treatment. Nevertheless, how IFN ß dynamically influences different levels of the kynurenine pathway has not been adequately explored.…”

Section: Discussionsupporting

confidence: 90%

Assessing the Metabolomic Profile of Multiple Sclerosis Patients Treated with Interferon Beta 1a by 1H-NMR Spectroscopy

et al. 2019

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Metabolomic research has emerged as a promising approach to identify potential biomarkers in multiple sclerosis (MS). The aim of the present study was to determine the effect of interferon beta (IFN ß) on the metabolome of MS patients to explore possible biomarkers of disease activity and therapeutic response. Twenty-one MS patients starting IFN ß therapy (Rebif® 44 μg; s.c. 3 times per week) were enrolled. Blood samples were obtained at baseline and after 6, 12, and 24 months of IFN ß treatment and were analyzed by high-resolution nuclear magnetic resonance spectroscopy. Changes in metabolites were analyzed. After IFN ß exposure, patients were divided into responders and nonresponders according to the Bno evidence of disease activity^(NEDA-3) definition (absence of relapses, disability progression, and magnetic resonance imaging activity), and samples obtained at baseline were analyzed to evaluate the presence of metabolic differences predictive of IFN ß response. The results of the investigation demonstrated differential distribution of baseline samples compared to those obtained during IFN ß exposure, particularly after 24 months of treatment (R 2 X = 0.812, R 2 Y = 0.797, Q 2 = 0.613, p = 0.003). In addition, differences in the baseline metabolome between responder and nonresponder patients with respect to lactate, acetone, 3-OH-butyrate, tryptophan, citrate, lysine, and glucose levels were found (R 2 X = 0.442, R 2 Y = 0.768, Q 2 = 0.532, p = 0.01). In conclusion, a metabolomic approach appears to be a promising, noninvasive tool that could potentially contribute to predicting the efficacy of MS therapies.

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Section: Discussionsupporting

confidence: 90%

Assessing the Metabolomic Profile of Multiple Sclerosis Patients Treated with Interferon Beta 1a by 1H-NMR Spectroscopy

et al. 2019

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“…These pathological changes were also observed in animal models, such as experimental autoimmune encephalomyelitis (EAE) (Rajda et al, 2015;Vogt et al, 2009). Currently, besides inhibition of inflammation, the promotion of nerve regeneration is a principle strategy for the treatment of MS (Cristofanilli et al, 2013).…”

mentioning

confidence: 96%

You-Gui pills promote nerve regeneration by regulating netrin1, DCC and Rho family GTPases RhoA, Racl, Cdc42 in C57BL/6 mice with experimental autoimmune encephalomyelitis

Liu

Chen

et al. 2016

Journal of Ethnopharmacology

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“…The neuroinflammatory process can be significantly decreased by inhibition of IDO-1 enzyme activity, considerably reducing disease exacerbation ( 119 ). Monaco et al revealed corresponding clinical evidence of depressed TRP levels in both serum and CSF of MS patients ( 69 ).…”

Section: Kp Influence On the Immune Systemmentioning

confidence: 99%

Current Evidence for a Role of the Kynurenine Pathway of Tryptophan Metabolism in Multiple Sclerosis

Lovelace

Varney²,

Sundaram³

et al. 2016

Front. Immunol.

125

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The kynurenine pathway (KP) is the major metabolic pathway of the essential amino acid tryptophan (TRP). Stimulation by inflammatory molecules, such as interferon-γ (IFN-γ), is the trigger for induction of the KP, driving a complex cascade of production of both neuroprotective and neurotoxic metabolites, and in turn, regulation of the immune response and responses of brain cells to the KP metabolites. Consequently, substantial evidence has accumulated over the past couple of decades that dysregulation of the KP and the production of neurotoxic metabolites are associated with many neuroinflammatory and neurodegenerative diseases, including Parkinson’s disease, AIDS-related dementia, motor neurone disease, schizophrenia, Huntington’s disease, and brain cancers. In the past decade, evidence of the link between the KP and multiple sclerosis (MS) has rapidly grown and has implicated the KP in MS pathogenesis. KP enzymes, indoleamine 2,3-dioxygenase (IDO-1) and tryptophan dioxygenase (highest expression in hepatic cells), are the principal enzymes triggering activation of the KP to produce kynurenine from TRP. This is in preference to other routes such as serotonin and melatonin production. In neurological disease, degradation of the blood–brain barrier, even if transient, allows the entry of blood monocytes into the brain parenchyma. Similar to microglia and macrophages, these cells are highly responsive to IFN-γ, which upregulates the expression of enzymes, including IDO-1, producing neurotoxic KP metabolites such as quinolinic acid. These metabolites circulate systemically or are released locally in the brain and can contribute to the excitotoxic death of oligodendrocytes and neurons in neurological disease principally by virtue of their agonist activity at N-methyl-d-aspartic acid receptors. The latest evidence is presented and discussed. The enzymes that control the checkpoints in the KP represent an attractive therapeutic target, and consequently several KP inhibitors are currently in clinical trials for other neurological diseases, and hence may make suitable candidates for MS patients. Underpinning these drug discovery endeavors, in recent years, several advances have been made in how KP metabolites are assayed in various biological fluids, and tremendous advancements have been made in how specimens are imaged to determine disease progression and involvement of various cell types and molecules in MS.

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Kynurenines and Multiple Sclerosis: The Dialogue between the Immune System and the Central Nervous System

Cited by 36 publications

References 66 publications

Assessing the Metabolomic Profile of Multiple Sclerosis Patients Treated with Interferon Beta 1a by 1H-NMR Spectroscopy

Assessing the Metabolomic Profile of Multiple Sclerosis Patients Treated with Interferon Beta 1a by 1H-NMR Spectroscopy

You-Gui pills promote nerve regeneration by regulating netrin1, DCC and Rho family GTPases RhoA, Racl, Cdc42 in C57BL/6 mice with experimental autoimmune encephalomyelitis

Current Evidence for a Role of the Kynurenine Pathway of Tryptophan Metabolism in Multiple Sclerosis

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