Quinolinic acid toxicity on oligodendroglial cells: relevance for multiple sclerosis and therapeutic strategies
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...
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| Veröffentlicht in: | Journal of neuroinflammation 2014-12, Vol.11 (1), p.204-204, Article 204 |
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| creator | Sundaram, Gayathri Brew, Bruce J Jones, Simon P Adams, Seray Lim, Chai K Guillemin, Gilles J |
| description | 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. |
| doi_str_mv | 10.1186/s12974-014-0204-5 |
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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.</description><identifier>ISSN: 1742-2094</identifier><identifier>EISSN: 1742-2094</identifier><identifier>DOI: 10.1186/s12974-014-0204-5</identifier><identifier>PMID: 25498310</identifier><language>eng</language><publisher>England: BioMed Central Ltd</publisher><subject>Acids ; Animals ; Antibodies, Monoclonal - administration & dosage ; Apoptosis ; Brain research ; Cell Line ; Cell Line, Transformed ; Encephalomyelitis, Autoimmune, Experimental - drug therapy ; Encephalomyelitis, Autoimmune, Experimental - metabolism ; Enzymes ; Experiments ; Gene expression ; Health aspects ; Kynurenine - antagonists & inhibitors ; Kynurenine - metabolism ; Medical research ; Medicine, Experimental ; Metabolism ; Metabolites ; Mice ; Multiple sclerosis ; Multiple Sclerosis - drug therapy ; Multiple Sclerosis - metabolism ; Neurodegeneration ; Neurosciences ; Neurotoxicity ; Oligodendroglia - drug effects ; Oligodendroglia - metabolism ; Physiological aspects ; Quinolinic Acid - metabolism ; Quinolinic Acid - therapeutic use ; Quinolinic Acid - toxicity ; Risk factors ; Studies ; Toxicity</subject><ispartof>Journal of neuroinflammation, 2014-12, Vol.11 (1), p.204-204, Article 204</ispartof><rights>COPYRIGHT 2014 BioMed Central Ltd.</rights><rights>2014 Sundaram et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.</rights><rights>Sundaram et al.; licensee BioMed Central. 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c527t-a4516e97a2eae9769e0657e11949b065164b23ec39343efbe96df0a7ff0615823</citedby><cites>FETCH-LOGICAL-c527t-a4516e97a2eae9769e0657e11949b065164b23ec39343efbe96df0a7ff0615823</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302518/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302518/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25498310$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sundaram, Gayathri</creatorcontrib><creatorcontrib>Brew, Bruce J</creatorcontrib><creatorcontrib>Jones, Simon P</creatorcontrib><creatorcontrib>Adams, Seray</creatorcontrib><creatorcontrib>Lim, Chai K</creatorcontrib><creatorcontrib>Guillemin, Gilles J</creatorcontrib><title>Quinolinic acid toxicity on oligodendroglial cells: relevance for multiple sclerosis and therapeutic strategies</title><title>Journal of neuroinflammation</title><addtitle>J Neuroinflammation</addtitle><description>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. 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Brew, Bruce J ; Jones, Simon P ; Adams, Seray ; Lim, Chai K ; Guillemin, Gilles J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c527t-a4516e97a2eae9769e0657e11949b065164b23ec39343efbe96df0a7ff0615823</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Acids</topic><topic>Animals</topic><topic>Antibodies, Monoclonal - administration & dosage</topic><topic>Apoptosis</topic><topic>Brain research</topic><topic>Cell Line</topic><topic>Cell Line, Transformed</topic><topic>Encephalomyelitis, Autoimmune, Experimental - drug therapy</topic><topic>Encephalomyelitis, Autoimmune, Experimental - metabolism</topic><topic>Enzymes</topic><topic>Experiments</topic><topic>Gene expression</topic><topic>Health aspects</topic><topic>Kynurenine - antagonists & inhibitors</topic><topic>Kynurenine - metabolism</topic><topic>Medical research</topic><topic>Medicine, Experimental</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>Mice</topic><topic>Multiple sclerosis</topic><topic>Multiple Sclerosis - drug therapy</topic><topic>Multiple Sclerosis - metabolism</topic><topic>Neurodegeneration</topic><topic>Neurosciences</topic><topic>Neurotoxicity</topic><topic>Oligodendroglia - drug effects</topic><topic>Oligodendroglia - metabolism</topic><topic>Physiological aspects</topic><topic>Quinolinic Acid - metabolism</topic><topic>Quinolinic Acid - therapeutic use</topic><topic>Quinolinic Acid - toxicity</topic><topic>Risk factors</topic><topic>Studies</topic><topic>Toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sundaram, Gayathri</creatorcontrib><creatorcontrib>Brew, Bruce J</creatorcontrib><creatorcontrib>Jones, Simon P</creatorcontrib><creatorcontrib>Adams, Seray</creatorcontrib><creatorcontrib>Lim, Chai K</creatorcontrib><creatorcontrib>Guillemin, Gilles J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of neuroinflammation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sundaram, Gayathri</au><au>Brew, Bruce J</au><au>Jones, Simon P</au><au>Adams, Seray</au><au>Lim, Chai K</au><au>Guillemin, Gilles J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Quinolinic acid toxicity on oligodendroglial cells: relevance for multiple sclerosis and therapeutic strategies</atitle><jtitle>Journal of neuroinflammation</jtitle><addtitle>J Neuroinflammation</addtitle><date>2014-12-13</date><risdate>2014</risdate><volume>11</volume><issue>1</issue><spage>204</spage><epage>204</epage><pages>204-204</pages><artnum>204</artnum><issn>1742-2094</issn><eissn>1742-2094</eissn><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.</abstract><cop>England</cop><pub>BioMed Central Ltd</pub><pmid>25498310</pmid><doi>10.1186/s12974-014-0204-5</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Acids Animals Antibodies, Monoclonal - administration & dosage Apoptosis Brain research Cell Line Cell Line, Transformed Encephalomyelitis, Autoimmune, Experimental - drug therapy Encephalomyelitis, Autoimmune, Experimental - metabolism Enzymes Experiments Gene expression Health aspects Kynurenine - antagonists & inhibitors Kynurenine - metabolism Medical research Medicine, Experimental Metabolism Metabolites Mice Multiple sclerosis Multiple Sclerosis - drug therapy Multiple Sclerosis - metabolism Neurodegeneration Neurosciences Neurotoxicity Oligodendroglia - drug effects Oligodendroglia - metabolism Physiological aspects Quinolinic Acid - metabolism Quinolinic Acid - therapeutic use Quinolinic Acid - toxicity Risk factors Studies Toxicity |
| title | Quinolinic acid toxicity on oligodendroglial cells: relevance for multiple sclerosis and therapeutic strategies |
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