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

Sundaram G, Brew BJ, Jones SP, Adams S, Lim CK, Guillemin GJ - J Neuroinflammation (2014)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St Vincent's Centre for Applied Medical Research, Sydney, Australia. g.sundaram@amr.org.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.

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Neutralization of endogenous quinolinic acid (QUIN) with an anti-QUIN monoclonal antibody (mAb). (a) The schematic diagram represents the effect of QUIN mAb on IFN-γ-treated BV2 supernatant in N19 and N20.1 oligodendroglial cell lines. (b) represents the levels of lactate dehydrogenase (LDH) released by oligodendroglial cell lines N19 and N20.1, respectively after 72 hours incubation with IFN-γ-treated BV2 and varying concentrations of QUIN mAb. The study was performed in triplicate and the error bars indicate SE. ***P < 0.001.
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Fig4: Neutralization of endogenous quinolinic acid (QUIN) with an anti-QUIN monoclonal antibody (mAb). (a) The schematic diagram represents the effect of QUIN mAb on IFN-γ-treated BV2 supernatant in N19 and N20.1 oligodendroglial cell lines. (b) represents the levels of lactate dehydrogenase (LDH) released by oligodendroglial cell lines N19 and N20.1, respectively after 72 hours incubation with IFN-γ-treated BV2 and varying concentrations of QUIN mAb. The study was performed in triplicate and the error bars indicate SE. ***P < 0.001.

Mentions: In addition, we also demonstrated that this strategy worked on endogenous QUIN present in supernatants of IFN-γ-treated BV2 microglial cells containing 0.99 ± 0.1 μM of QUIN (data not shown). The glioprotection observed with the QUIN mAb treatment was found to be statistically different (P < 0.001) in all the treatment groups when compared to control cells for both the cell types (Figure 4). Among the treatment groups for both cell lines, anti-QUIN mAb at 1/100 (7 ng/μL) or higher concentration showed full protective effect from QUIN-induced cell death.Figure 4


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

Sundaram G, Brew BJ, Jones SP, Adams S, Lim CK, Guillemin GJ - J Neuroinflammation (2014)

Neutralization of endogenous quinolinic acid (QUIN) with an anti-QUIN monoclonal antibody (mAb). (a) The schematic diagram represents the effect of QUIN mAb on IFN-γ-treated BV2 supernatant in N19 and N20.1 oligodendroglial cell lines. (b) represents the levels of lactate dehydrogenase (LDH) released by oligodendroglial cell lines N19 and N20.1, respectively after 72 hours incubation with IFN-γ-treated BV2 and varying concentrations of QUIN mAb. The study was performed in triplicate and the error bars indicate SE. ***P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4302518&req=5

Fig4: Neutralization of endogenous quinolinic acid (QUIN) with an anti-QUIN monoclonal antibody (mAb). (a) The schematic diagram represents the effect of QUIN mAb on IFN-γ-treated BV2 supernatant in N19 and N20.1 oligodendroglial cell lines. (b) represents the levels of lactate dehydrogenase (LDH) released by oligodendroglial cell lines N19 and N20.1, respectively after 72 hours incubation with IFN-γ-treated BV2 and varying concentrations of QUIN mAb. The study was performed in triplicate and the error bars indicate SE. ***P < 0.001.
Mentions: In addition, we also demonstrated that this strategy worked on endogenous QUIN present in supernatants of IFN-γ-treated BV2 microglial cells containing 0.99 ± 0.1 μM of QUIN (data not shown). The glioprotection observed with the QUIN mAb treatment was found to be statistically different (P < 0.001) in all the treatment groups when compared to control cells for both the cell types (Figure 4). Among the treatment groups for both cell lines, anti-QUIN mAb at 1/100 (7 ng/μL) or higher concentration showed full protective effect from QUIN-induced cell death.Figure 4

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St Vincent's Centre for Applied Medical Research, Sydney, Australia. g.sundaram@amr.org.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.

Show MeSH
Related in: MedlinePlus