Abstract:
: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-γ (IFN-γ), 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'.
journal_name
Neuropharmacologyjournal_title
Neuropharmacologyauthors
Lovelace MD,Varney B,Sundaram G,Lennon MJ,Lim CK,Jacobs K,Guillemin GJ,Brew BJdoi
10.1016/j.neuropharm.2016.03.024subject
Has Abstractpub_date
2017-01-01 00:00:00pages
373-388issue
Pt Beissn
0028-3908issn
1873-7064pii
S0028-3908(16)30096-Xjournal_volume
112pub_type
杂志文章,评审abstract::The effects of intravenously administered mephenesin, tolperisone, baclofen, diazepam and midazolam on reflex activity were studied in unanesthetized spinal cats. Monosynaptic, as well as polysynaptic ventral root reflexes, the dorsal root potential and the dorsal root reflex were recorded simultaneously from L6-S1 se...
journal_title:Neuropharmacology
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journal_title:Neuropharmacology
pub_type: 杂志文章
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journal_title:Neuropharmacology
pub_type: 杂志文章
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journal_title:Neuropharmacology
pub_type: 杂志文章
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journal_title:Neuropharmacology
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journal_title:Neuropharmacology
pub_type: 杂志文章
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journal_title:Neuropharmacology
pub_type: 杂志文章,评审
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更新日期:2019-08-01 00:00:00
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journal_title:Neuropharmacology
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更新日期:1996-01-01 00:00:00