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J Neuroinflammation. 2014 Dec 13;11:204. doi: 10.1186/s12974-014-0204-5.

Quinolinic acid toxicity on oligodendroglial cells: relevance for multiple sclerosis and therapeutic strategies.

Sundaram G1,2, Brew BJ3,4, Jones SP5, Adams S6,7, Lim CK8,9,10, Guillemin GJ11,12,13.

Author information

1
Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St Vincent's Centre for Applied Medical Research, Sydney, Australia. g.sundaram@amr.org.au.
2
School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia. g.sundaram@amr.org.au.
3
Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St Vincent's Centre for Applied Medical Research, Sydney, Australia. bbrew@stvincents.com.au.
4
Department of Neurology, St Vincent's Hospital, Sydney, Australia. bbrew@stvincents.com.au.
5
Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St Vincent's Centre for Applied Medical Research, Sydney, Australia. s.jones@amr.org.au.
6
School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia. seray.adams@mq.edu.au.
7
Neurodegenerative diseases Research Group, Australian School of Advanced Medicine, Faculty of Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia. seray.adams@mq.edu.au.
8
Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St Vincent's Centre for Applied Medical Research, Sydney, Australia. edwin.lim@mq.edu.au.
9
School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia. edwin.lim@mq.edu.au.
10
Neurodegenerative diseases Research Group, Australian School of Advanced Medicine, Faculty of Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia. edwin.lim@mq.edu.au.
11
Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St Vincent's Centre for Applied Medical Research, Sydney, Australia. gilles.guillemin@mq.edu.au.
12
School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia. gilles.guillemin@mq.edu.au.
13
Neurodegenerative diseases Research Group, Australian School of Advanced Medicine, Faculty of Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia. gilles.guillemin@mq.edu.au.

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.

PMID:
25498310
PMCID:
PMC4302518
DOI:
10.1186/s12974-014-0204-5
[Indexed for MEDLINE]
Free PMC Article

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