Cargando…

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

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 metabol...

Descripción completa

Detalles Bibliográficos
Autores principales: Lovelace, Michael D., Varney, Bianca, Sundaram, Gayathri, Franco, Nunzio F., Ng, Mei Li, Pai, Saparna, Lim, Chai K., Guillemin, Gilles J., Brew, Bruce J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4972824/
https://www.ncbi.nlm.nih.gov/pubmed/27540379
http://dx.doi.org/10.3389/fimmu.2016.00246
_version_ 1782446297748340736
author Lovelace, Michael D.
Varney, Bianca
Sundaram, Gayathri
Franco, Nunzio F.
Ng, Mei Li
Pai, Saparna
Lim, Chai K.
Guillemin, Gilles J.
Brew, Bruce J.
author_facet Lovelace, Michael D.
Varney, Bianca
Sundaram, Gayathri
Franco, Nunzio F.
Ng, Mei Li
Pai, Saparna
Lim, Chai K.
Guillemin, Gilles J.
Brew, Bruce J.
author_sort Lovelace, Michael D.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4972824
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-49728242016-08-18 Current Evidence for a Role of the Kynurenine Pathway of Tryptophan Metabolism in Multiple Sclerosis Lovelace, Michael D. Varney, Bianca Sundaram, Gayathri Franco, Nunzio F. Ng, Mei Li Pai, Saparna Lim, Chai K. Guillemin, Gilles J. Brew, Bruce J. Front Immunol Immunology 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. Frontiers Media S.A. 2016-08-04 /pmc/articles/PMC4972824/ /pubmed/27540379 http://dx.doi.org/10.3389/fimmu.2016.00246 Text en Copyright © 2016 Lovelace, Varney, Sundaram, Franco, Ng, Pai, Lim, Guillemin and Brew. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Lovelace, Michael D.
Varney, Bianca
Sundaram, Gayathri
Franco, Nunzio F.
Ng, Mei Li
Pai, Saparna
Lim, Chai K.
Guillemin, Gilles J.
Brew, Bruce J.
Current Evidence for a Role of the Kynurenine Pathway of Tryptophan Metabolism in Multiple Sclerosis
title Current Evidence for a Role of the Kynurenine Pathway of Tryptophan Metabolism in Multiple Sclerosis
title_full Current Evidence for a Role of the Kynurenine Pathway of Tryptophan Metabolism in Multiple Sclerosis
title_fullStr Current Evidence for a Role of the Kynurenine Pathway of Tryptophan Metabolism in Multiple Sclerosis
title_full_unstemmed Current Evidence for a Role of the Kynurenine Pathway of Tryptophan Metabolism in Multiple Sclerosis
title_short Current Evidence for a Role of the Kynurenine Pathway of Tryptophan Metabolism in Multiple Sclerosis
title_sort current evidence for a role of the kynurenine pathway of tryptophan metabolism in multiple sclerosis
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4972824/
https://www.ncbi.nlm.nih.gov/pubmed/27540379
http://dx.doi.org/10.3389/fimmu.2016.00246
work_keys_str_mv AT lovelacemichaeld currentevidenceforaroleofthekynureninepathwayoftryptophanmetabolisminmultiplesclerosis
AT varneybianca currentevidenceforaroleofthekynureninepathwayoftryptophanmetabolisminmultiplesclerosis
AT sundaramgayathri currentevidenceforaroleofthekynureninepathwayoftryptophanmetabolisminmultiplesclerosis
AT franconunziof currentevidenceforaroleofthekynureninepathwayoftryptophanmetabolisminmultiplesclerosis
AT ngmeili currentevidenceforaroleofthekynureninepathwayoftryptophanmetabolisminmultiplesclerosis
AT paisaparna currentevidenceforaroleofthekynureninepathwayoftryptophanmetabolisminmultiplesclerosis
AT limchaik currentevidenceforaroleofthekynureninepathwayoftryptophanmetabolisminmultiplesclerosis
AT guillemingillesj currentevidenceforaroleofthekynureninepathwayoftryptophanmetabolisminmultiplesclerosis
AT brewbrucej currentevidenceforaroleofthekynureninepathwayoftryptophanmetabolisminmultiplesclerosis