Effects of Kynurenine Pathway Metabolites on Intracellular NAD+ Synthesis and Cell Death in Human Primary Astrocytes and Neurons

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avondale-bepress-to-dspace.facultyNursing
avondale-bepress-to-dspace.licensehttp://creativecommons.org/licenses/by/3.0/
avondale-bepress.abstract<p>The kynurenine pathway (KP) is a major route of L-tryptophan catabolism resulting in the production of the essential pyridine nucleotide nicotinamide adenine dinucleotide, (NAD+). Up-regulation of the KP during infl ammation leads to the release of a number of biologically active metabolites into the brain. We hypothesised that while some of the extracellular KP metabolites may be benefi cial for intracellular NAD+ synthesis and cell survival at physiological concentrations, they may contribute to neuronal and astroglial dysfunction and cell death at pathophysiological concentrations. In this study, we found that treatment of human primary neurons and astrocytes with 3-hydroxyanthranilic acid (3-HAA), 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN), and picolinic acid (PIC) at concentrations below 100 nM significantly increased intracellular NAD+ levels compared to non-treated cells. However, a dose dependent decrease in intracellular NAD+ levels and increased extracellular LDH activity was observed in human astrocytes and neurons treated with 3-HAA, 3-HK, QUIN and PIC at concentrations >100 nM and kynurenine (KYN), at concentrations above 1 μM. Intracellular NAD+ levels were unchanged in the presence of the neuroprotectant, kynurenic acid (KYNA), and a dose dependent increase in intracellular NAD+ levels was observed for TRP up to 1 mM. While anthranilic acid (AA) increased intracellular NAD+ levels at concentration below 10 μM in astrocytes. NAD+ depletion and cell death was observed in AA treated neurons at concentrations above 500 nM. Therefore, the differing responses of astrocytes and neurons to an increase in KP metabolites should be considered when assessing KP toxicity during neuroinfl ammation.[from article]</p>
avondale-bepress.articleid1015
avondale-bepress.authorsNady Braidy
avondale-bepress.authorsRoss Grant
avondale-bepress.authorsBruce J Brew
avondale-bepress.authorsSeray Adams
avondale-bepress.authorsTharusha Jayasena
avondale-bepress.authorsGilles Guillemin
avondale-bepress.context-key2979319
avondale-bepress.coverpage-urlhttps://research.avondale.edu.au/nh_papers/16
avondale-bepress.document-typearticle
avondale-bepress.field.author_faculty_disciplineNursing
avondale-bepress.field.comments<p>Used by permission: the authors<a href="http://creativecommons.org/licenses/by/3.0/"><br /></a></p> <p><em>International Journal of Tryptophan Research</em> may be accessed <a href="http://www.la-press.com/international-journal-of-tryptophan-research-j97">here</a>.</p>
avondale-bepress.field.create_openurltrue
avondale-bepress.field.custom_citation<p>Braidy, N., Grant, R., Brew, B., Adams, S., & Jayasena, T. (2009). Effects of kynurenine pathway metabolites on intracellular NAD+ synthesis and cell death in human primary astrocytes and neurons. <em>International Journal of Tryptophan Research, 2</em>, 61-69. doi:10.4137/IJTR.S2318</p>
avondale-bepress.field.distribution_licensehttp://creativecommons.org/licenses/by/3.0/
avondale-bepress.field.doihttps://doi.org/10.4137/IJTR.S2318
avondale-bepress.field.embargo_date2012-06-11T00:00:00Z
avondale-bepress.field.issn1178-6469
avondale-bepress.field.journalInternational Journal of Tryptophan Research
avondale-bepress.field.page_numbers61-69
avondale-bepress.field.publication_date2009-01-01T00:00:00Z
avondale-bepress.field.source_publication<p>This article was originally published as:</p><p> Braidy, N., Grant, R., Brew, B., Adams, S., & Jayasena, T. (2009). Effects of kynurenine pathway metabolites on intracellular NAD+ synthesis and cell death in human primary astrocytes and neurons. <em>International Journal of Tryptophan Research, 2</em>, 61-69. Retrieved from http://insights.sagepub.com/effects-of-kynurenine-pathway-metabolites-on-intracellular-nad-synthes-article-a1389</p><p>ISSN: 1178-6869</p>
avondale-bepress.field.volume_number2
avondale-bepress.fulltext-urlhttps://research.avondale.edu.au/cgi/viewcontent.cgi?article=1015&amp;context=nh_papers&amp;unstamped=1
avondale-bepress.keywordskynurenine pathway
avondale-bepress.keywordsnicotinamide adenine dinucleotide
avondale-bepress.keywordsTryptophan catabolism
avondale-bepress.keywordstoxicity during neuroinflammation
avondale-bepress.label16
avondale-bepress.publication-date2009-01-01T00:00:00Z
avondale-bepress.publication-titleNursing and Health Papers and Journal Articles
avondale-bepress.statepublished
avondale-bepress.submission-date2012-06-11T19:29:54Z
avondale-bepress.submission-pathnh_papers/16
avondale-bepress.titleEffects of Kynurenine Pathway Metabolites on Intracellular NAD+ Synthesis and Cell Death in Human Primary Astrocytes and Neurons
avondale-bepress.typearticle
dc.contributor.authorGuillemin, Gilles
dc.contributor.authorJayasena, Tharusha
dc.contributor.authorAdams, Seray
dc.contributor.authorBrew, Bruce J.
dc.contributor.authorGrant, Ross
dc.contributor.authorBraidy, Nady
dc.date.accessioned2023-11-01T00:22:09Z
dc.date.available2023-11-01T00:22:09Z
dc.date.issued2009-01-01
dc.date.submitted2012-06-11T19:29:54Z
dc.description.abstract<p>The kynurenine pathway (KP) is a major route of L-tryptophan catabolism resulting in the production of the essential pyridine nucleotide nicotinamide adenine dinucleotide, (NAD+). Up-regulation of the KP during infl ammation leads to the release of a number of biologically active metabolites into the brain. We hypothesised that while some of the extracellular KP metabolites may be benefi cial for intracellular NAD+ synthesis and cell survival at physiological concentrations, they may contribute to neuronal and astroglial dysfunction and cell death at pathophysiological concentrations. In this study, we found that treatment of human primary neurons and astrocytes with 3-hydroxyanthranilic acid (3-HAA), 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN), and picolinic acid (PIC) at concentrations below 100 nM significantly increased intracellular NAD+ levels compared to non-treated cells. However, a dose dependent decrease in intracellular NAD+ levels and increased extracellular LDH activity was observed in human astrocytes and neurons treated with 3-HAA, 3-HK, QUIN and PIC at concentrations >100 nM and kynurenine (KYN), at concentrations above 1 μM. Intracellular NAD+ levels were unchanged in the presence of the neuroprotectant, kynurenic acid (KYNA), and a dose dependent increase in intracellular NAD+ levels was observed for TRP up to 1 mM. While anthranilic acid (AA) increased intracellular NAD+ levels at concentration below 10 μM in astrocytes. NAD+ depletion and cell death was observed in AA treated neurons at concentrations above 500 nM. Therefore, the differing responses of astrocytes and neurons to an increase in KP metabolites should be considered when assessing KP toxicity during neuroinfl ammation.[from article]</p>
dc.identifier.citation<p>Braidy, N., Grant, R., Brew, B., Adams, S., & Jayasena, T. (2009). Effects of kynurenine pathway metabolites on intracellular NAD+ synthesis and cell death in human primary astrocytes and neurons. <em>International Journal of Tryptophan Research, 2</em>, 61-69. doi:10.4137/IJTR.S2318</p>
dc.identifier.doihttps://doi.org/10.4137/IJTR.S2318
dc.identifier.issn1178-6469
dc.identifier.urihttps://research.avondale.edu.au/handle/123456789/02979319
dc.language.isoen_us
dc.provenance<p>This article was originally published as:</p><p> Braidy, N., Grant, R., Brew, B., Adams, S., & Jayasena, T. (2009). Effects of kynurenine pathway metabolites on intracellular NAD+ synthesis and cell death in human primary astrocytes and neurons. <em>International Journal of Tryptophan Research, 2</em>, 61-69. Retrieved from http://insights.sagepub.com/effects-of-kynurenine-pathway-metabolites-on-intracellular-nad-synthes-article-a1389</p><p>ISSN: 1178-6869</p>
dc.rights<p>Used by permission: the authors<a href="http://creativecommons.org/licenses/by/3.0/"><br /></a></p> <p><em>International Journal of Tryptophan Research</em> may be accessed <a href="http://www.la-press.com/international-journal-of-tryptophan-research-j97">here</a>.</p>
dc.rights.licensehttp://creativecommons.org/licenses/by/3.0/
dc.subjectkynurenine pathway
dc.subjectnicotinamide adenine dinucleotide
dc.subjectTryptophan catabolism
dc.subjecttoxicity during neuroinflammation
dc.titleEffects of Kynurenine Pathway Metabolites on Intracellular NAD+ Synthesis and Cell Death in Human Primary Astrocytes and Neurons
dc.typeJournal Article
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