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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-014-0204-5) contains supplementary material, which is available to authorized users.
Highlights
Quinolinic acid (QUIN) is a downstream metabolite produced through the kynurenine pathway (KP) of tryptophan metabolism [1,2]
KP profiling in oligodendroglial cell lines N19 and N20.1 We found that both mice oligodendrocytic cell lines N19 and N20.1 have a functional KP
By comparing the levels of mRNA expression for the KP enzymes, after normalization with the endogenous reference gene RPL13, we showed that N20.1 had a much higher level of expression for tryptophan 2 (TDO-2) (P < 0.001) than N19 (Figure 1a and e)
Summary
Quinolinic acid (QUIN) is a downstream metabolite produced through the kynurenine pathway (KP) of tryptophan metabolism [1,2]. QUIN is present in nanomolar concentrations and used as substrate by cells to synthesize the essential co-factor nicotinamide adenine dinucleotide (NAD+). During neuroinflammation, the KP can be chronically or acutely activated through the induction of one of its initial enzymes, indoleamine 2,3-dioxygenase (IDO-1). QUIN is produced in excess and can kill brain cells including neurons, astrocytes and oligodendrocytes by at least six different mechanisms [2,3]. QUIN has been implicated in several neurological diseases, including multiple sclerosis (MS) [4,5]. The involvement of the KP in neurological diseases is complex, as it revolves around the metabolic
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