PMID- 26995730 OWN - NLM STAT- MEDLINE DCOM- 20170605 LR - 20220408 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 112 IP - Pt B DP - 2017 Jan TI - Recent evidence for an expanded role of the kynurenine pathway of tryptophan metabolism in neurological diseases. PG - 373-388 LID - S0028-3908(16)30096-X [pii] LID - 10.1016/j.neuropharm.2016.03.024 [doi] AB - The kynurenine pathway (KP) of tryptophan metabolism has emerged in recent years as a key regulator of the production of both neuroprotective (e.g. kynurenic and picolinic acid, and the essential cofactor NAD+) and neurotoxic metabolites (e.g. quinolinic acid, 3-hydroxykynurenine). The balance between the production of the two types of metabolites is controlled by key rate-limiting enzymes such as indoleamine-2,3-dioxygenase (IDO-1), and in turn, molecular signals such as interferon-gamma (IFN-gamma), which activate the KP metabolism of tryptophan by this enzyme, as opposed to alternative pathways for serotonin and melatonin production. Dysregulated KP metabolism has been strongly associated with neurological diseases in recent years, and is the subject of increasing efforts to understand how the metabolites are causative of disease pathology. Concurrent with these endeavours are drug development initiatives to use inhibitors to block certain enzymes in the pathway, resulting in reduced levels of neurotoxic metabolites (e.g. quinolinic acid, an excitotoxin and N-Methyl-d-Aspartate (NMDA) receptor agonist), while in turn enhancing the bioavailability of the neuroprotective metabolites such as kynurenic acid. Neurodegenerative diseases often have a substantial autoimmune or inflammatory component; hence a greater understanding of how KP metabolites influence the inflammatory cascade is required. Additionally, challenges exist in diseases like multiple sclerosis (MS) and motor neurone disease (MND), which do not have reliable biomarkers. Clinical diagnosis can often be prolonged in order to exclude other diseases, and often diagnosis occurs at an advanced state of disease pathology, which does not allow a lengthy time for patient assessment and intervention therapies. This review considers the current evidence for involvement of the KP in several neurological diseases, in biomarkers of disease and also the parallels that exist in KP metabolism with what is known in other diseases such as HIV, Alzheimer's disease/dementia, infection, immune privilege and cardiovascular disease. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'. CI - Copyright A(c) 2016. Published by Elsevier Ltd. FAU - Lovelace, Michael D AU - Lovelace MD AD - Peter Duncan Neurosciences Research Unit, St Vincent's Centre for Applied Medical Research, 405 Liverpool Street, Darlinghurst, Sydney, NSW, 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, Australia. FAU - Varney, Bianca AU - Varney B AD - Peter Duncan Neurosciences Research Unit, St Vincent's Centre for Applied Medical Research, 405 Liverpool Street, Darlinghurst, Sydney, NSW, 2010, Australia. FAU - Sundaram, Gayathri AU - Sundaram G AD - Peter Duncan Neurosciences Research Unit, St Vincent's Centre for Applied Medical Research, 405 Liverpool Street, Darlinghurst, Sydney, NSW, 2010, Australia. FAU - Lennon, Matthew J AU - Lennon MJ AD - Peter Duncan Neurosciences Research Unit, St Vincent's Centre for Applied Medical Research, 405 Liverpool Street, Darlinghurst, Sydney, NSW, 2010, Australia. FAU - Lim, Chai K AU - Lim CK AD - Neuroinflammation Group, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia. FAU - Jacobs, Kelly AU - Jacobs K AD - Neuroinflammation Group, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia. FAU - Guillemin, Gilles J AU - Guillemin GJ AD - Neuroinflammation Group, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia. FAU - Brew, Bruce J AU - Brew BJ AD - Peter Duncan Neurosciences Research Unit, St Vincent's Centre for Applied Medical Research, 405 Liverpool Street, Darlinghurst, Sydney, NSW, 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, Australia; Department of Neurology, St Vincent's Hospital, Level 4 Xavier Building, Victoria Street, Darlinghurst, Sydney, NSW, 2010, Australia. Electronic address: b.brew@unsw.edu.au. LA - eng PT - Journal Article PT - Review DEP - 20160316 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 343-65-7 (Kynurenine) RN - 8DUH1N11BX (Tryptophan) SB - IM MH - Animals MH - Humans MH - Kynurenine/*metabolism MH - Metabolic Networks and Pathways/*physiology MH - Nervous System Diseases/*metabolism MH - Tryptophan/*metabolism OTO - NOTNLM OT - HIV-acquired neurodeficit disorder OT - Kynurenine pathway OT - Neurodegenerative disease OT - Neuroinflammation EDAT- 2016/03/21 06:00 MHDA- 2017/06/06 06:00 CRDT- 2016/03/21 06:00 PHST- 2015/11/20 00:00 [received] PHST- 2016/03/10 00:00 [revised] PHST- 2016/03/12 00:00 [accepted] PHST- 2016/03/21 06:00 [pubmed] PHST- 2017/06/06 06:00 [medline] PHST- 2016/03/21 06:00 [entrez] AID - S0028-3908(16)30096-X [pii] AID - 10.1016/j.neuropharm.2016.03.024 [doi] PST - ppublish SO - Neuropharmacology. 2017 Jan;112(Pt B):373-388. doi: 10.1016/j.neuropharm.2016.03.024. Epub 2016 Mar 16.