Recent advances in clinical trials targeting the kynurenine pathway.

Ananda Staats Pires, Gayathri Sundaram, Benjamin Heng, Shivani Krishnamurthy, Bruce J Brew, Gilles J Guillemin

Journal: Pharmacology & therapeutics 2022;236():108055

PMID: 34929198

Full Text on Elsevier Science View on PubMed

Abstract

The kynurenine pathway (KP) is the major catabolic pathway for the essential amino acid tryptophan leading to he production of nicotinamide adenine dinucleotide. In inflammatory conditions, the activation of the KP leads to the production of several bioactive metabolites including kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, kynurenic acid and quinolinic acid. These metabolites can have redox and immune suppressive activity, be neurotoxic or neuroprotective. While the activity of the pathway is tightly regulated under normal physiological condition, it can be upregulated by immunological activation and inflammation. The dysregulation of the KP has been implicated in wide range of neurological diseases and psychiatric disorders. In this review, we discuss the mechanisms involved in KP-mediated neurotoxicity and immune suppression, and its role in diseases of our expertise including cancer, chronic pain and multiple sclerosis. We also provide updates on the clinical trials evaluating the efficacy of KP inhibitors and/or analogues in each respective disease.

Address: Macquarie Medicine School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia; Laboratório de Bioenergética e Estresse Oxidativo, Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Brazil.; Peter Duncan Neurosciences Research Unit, St Vincent's Centre for Applied Medical Research, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.; Macquarie Medicine School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia. Electronic address: [email protected].; Macquarie Medicine School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia.; Peter Duncan Neurosciences Research Unit, St Vincent's Centre for Applied Medical Research, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: [email protected].; Macquarie Medicine School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia. Electronic address: [email protected].

DOI: 10.1016/j.pharmthera.2021.108055

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MeSH Terms: Humans, Kynurenine, Male, Nervous System Diseases, Quinolinic Acid, Tryptophan