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.
| Language | English |
|---|---|
| Article number | 204 |
| Pages | 1-11 |
| Number of pages | 11 |
| Journal | Journal of Neuroinflammation |
| Volume | 11 |
| DOIs | |
| Publication status | Published - 13 Dec 2014 |
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Bibliographical note
This version is archived for private and non-commercial use under the terms of this BioMed Central open access license ("license") (see http://www.biomedcentral.com/about/license). The work is protected by copyright and/or other applicable law. Any use of the work other than as authorized under this license is prohibited. For further rights please check the terms of the license, or contact the publisher.Cite this
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Quinolinic acid toxicity on oligodendroglial cells : Relevance for multiple sclerosis and therapeutic strategies. / Sundaram, Gayathri; Brew, Bruce J.; Jones, Simon P.; Adams, Seray; Lim, Chai K.; Guillemin, Gilles J.
In: Journal of Neuroinflammation, Vol. 11, 204, 13.12.2014, p. 1-11.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Quinolinic acid toxicity on oligodendroglial cells
T2 - Journal of Neuroinflammation
AU - Sundaram, Gayathri
AU - Brew, Bruce J.
AU - Jones, Simon P.
AU - Adams, Seray
AU - Lim, Chai K.
AU - Guillemin, Gilles J.
N1 - This version is archived for private and non-commercial use under the terms of this BioMed Central open access license ("license") (see http://www.biomedcentral.com/about/license). The work is protected by copyright and/or other applicable law. Any use of the work other than as authorized under this license is prohibited. For further rights please check the terms of the license, or contact the publisher.
PY - 2014/12/13
Y1 - 2014/12/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84924853615&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/arc/FT120100397
UR - http://purl.org/au-research/grants/nhmrc/1009914
UR - http://purl.org/au-research/grants/nhmrc/1031080
U2 - 10.1186/s12974-014-0204-5
DO - 10.1186/s12974-014-0204-5
M3 - Article
VL - 11
SP - 1
EP - 11
JO - Journal of Neuroinflammation
JF - Journal of Neuroinflammation
SN - 1742-2094
M1 - 204
ER -