title: Quinolinic acid toxicity on oligodendroglial cells: relevance for multiple sclerosis and therapeutic strategies.
abstract: The excitotoxin quinolinic acid, a by-product of the kynurenine pathway, is known to be involved in several neurological diseases including multiple sclerosis (MS). Quinolinic acid levels are elevated in experimental autoimmune encephalomyelitis rodents, the widely used animal model of MS. Our group has also found pathophysiological concentrations of quinolinic acid in MS patients. This led us to investigate the effect of quinolinic acid on oligodendrocytes; the main cell type targeted by the autoimmune response in MS. We have examined the kynurenine pathway (KP) profile of two oligodendrocyte cell lines and show that these cells have a limited threshold to catabolize exogenous quinolinic acid. We further propose and demonstrate two strategies to limit quinolinic acid gliotoxicity: 1) by neutralizing quinolinic acid's effects with anti-quinolinic acid monoclonal antibodies and 2) directly inhibiting quinolinic acid production from activated monocytic cells using specific KP enzyme inhibitors. The outcome of this study provides a new insight into therapeutic strategies for limiting quinolinic acid-induced neurodegeneration, especially in neurological disorders that target oligodendrocytes, such as MS.
authors.affiliation: Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St Vincent's Centre for Applied Medical Research, Sydney, Australia. g.sundaram@amr.org.au.|School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia. g.sundaram@amr.org.au.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Sundaram
authors.affiliation: Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St Vincent's Centre for Applied Medical Research, Sydney, Australia. bbrew@stvincents.com.au.|Department of Neurology, St Vincent's Hospital, Sydney, Australia. bbrew@stvincents.com.au.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Brew
authors.affiliation: Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St Vincent's Centre for Applied Medical Research, Sydney, Australia. s.jones@amr.org.au.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Jones
authors.affiliation: School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia. seray.adams@mq.edu.au.|Neurodegenerative diseases Research Group, Australian School of Advanced Medicine, Faculty of Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia. seray.adams@mq.edu.au.
authors.forename: Seray
authors.initials: S
authors.lastname: Adams
authors.affiliation: Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St Vincent's Centre for Applied Medical Research, Sydney, Australia. edwin.lim@mq.edu.au.|School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia. edwin.lim@mq.edu.au.|Neurodegenerative diseases Research Group, Australian School of Advanced Medicine, Faculty of Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia. edwin.lim@mq.edu.au.
authors.forename: Chai K
authors.initials: CK
authors.lastname: Lim
authors.affiliation: Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St Vincent's Centre for Applied Medical Research, Sydney, Australia. gilles.guillemin@mq.edu.au.|School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia. gilles.guillemin@mq.edu.au.|Neurodegenerative diseases Research Group, Australian School of Advanced Medicine, Faculty of Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia. gilles.guillemin@mq.edu.au.
authors.forename: Gilles J
authors.initials: GJ
authors.lastname: Guillemin
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D002460:Cell Line; D002461:Cell Line, Transformed; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000378:metabolism; D007737:Kynurenine / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000378:metabolism*; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism*; D017378:Quinolinic Acid / Q000378:metabolism* / Q000627:therapeutic use / Q000633:toxicity*
chemical_list: D000911:Antibodies, Monoclonal; D007737:Kynurenine; D017378:Quinolinic Acid