title: Prostaglandin D2 toxicity in primary neurons is mediated through its bioactive cyclopentenone metabolites.
abstract: Prostaglandin D2 (PGD2) is the most abundant prostaglandin in brain but its effect on neuronal cell death is complex and not completely understood. PGD2 may modulate neuronal cell death via activation of DP receptors or its metabolism to the cyclopentenone prostaglandins (CyPGs) PGJ2, Δ(12)-PGJ2 and 15-deoxy-Δ(12,14)-PGJ2, inducing cell death independently of prostaglandin receptors. This study aims to elucidate the effect of PGD2 on neuronal cell death and its underlying mechanisms. PGD2 dose-dependently induced cell death in rat primary neuron-enriched cultures in concentrations of ≥10μM, and this effect was not reversed by treatment with either DP1 or DP2 receptor antagonists. Antioxidants N-acetylcysteine (NAC) and glutathione which contain sulfhydryl groups that can bind to CyPGs, but not ascorbate or tocopherol, attenuated PGD2-induced cell death. Conversion of PGD2 to CyPGs was detected in neuronal culture medium; treatment with these CyPG metabolites alone exhibited effects similar to those of PGD2, including apoptotic neuronal cell death and accumulation of ubiquitinated proteins. Disruption of lipocalin-type prostaglandin D synthase (L-PGDS) protected neurons against hypoxia. These results support the hypothesis that PGD2 elicits its cytotoxic effects through its bioactive CyPG metabolites rather than DP receptor activation in primary neuronal culture.
authors: Geriatric Research Education and Clinical Center, V.A. Pittsburgh Healthcare System, 7180 Highland Drive, Pittsburgh, PA 15206, USA; Department of Neurology, University of Pittsburgh School of Medicine, 811 Kaufmann Medical Building, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA.
authors: Hao
authors: H
authors: Liu
authors: Wenjin
authors: W
authors: Li
authors: Marie E
authors: ME
authors: Rose
authors: Jordan L
authors: JL
authors: Pascoe
authors: Tricia M
authors: TM
authors: Miller
authors: Muzamil
authors: M
authors: Ahmad
authors: Samuel M
authors: SM
authors: Poloyac
authors: Robert W
authors: RW
authors: Hickey
authors: Steven H
authors: SH
authors: Graham
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003517:Cyclopentanes / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D000860:Hypoxia / Q000517:prevention & control; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011982:Receptors, Prostaglandin / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: C477819:15-deoxyprostaglandin J2; D002227:Carbazoles; D003517:Cyclopentanes; D054834:Lipocalins; D011982:Receptors, Prostaglandin; D013449:Sulfonamides; C037112:9-deoxy-delta-9-prostaglandin D2; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; C063119:ramatroban; C013905:cyclopentenone; D015230:Prostaglandin D2
keywords: Cell death; Cyclopentenone prostaglandins; DP receptors; Primary neuron; Prostaglandin D(2); Ubiquitinated protein
references: Br J Pharmacol. 2001 Oct;134(3):673-81
references: 11588123
references: J Biol Chem. 2012 Mar 16;287(12):9414-28
references: 22275363
references: Int J Biochem Cell Biol. 2003 May;35(5):547-52
references: 12672447
references: Neurobiol Dis. 2011 Feb;41(2):318-28
references: 20933087
references: Eur J Neurosci. 2007 Jul;26(1):73-8
references: 17573924
references: Proc Natl Acad Sci U S A. 2002 May 28;99(11):7367-72
references: 12032289
references: Br J Pharmacol. 1999 May;127(1):204-10
references: 10369474
references: J Biol Chem. 2002 Mar 22;277(12):10459-66
references: 11786541
references: Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9070-4
references: 8415655
references: Exp Cell Res. 2010 Nov 15;316(19):3140-9
references: 20797396
references: J Neurosci. 2007 Apr 18;27(16):4303-12
references: 17442814
references: Biochem J. 2012 Mar 15;442(3):453-64
references: 22364280
references: Exp Cell Res. 2003 Nov 15;291(1):212-27
references: 14597421
references: Biochim Biophys Acta. 2005 Apr 15;1743(3):291-304
references: 15843042
references: Cell Death Differ. 2010 Aug;17(8):1325-34
references: 20150912
references: Eur J Pharmacol. 1999 Jul 14;377(1):101-15
references: 10448933
references: J Biol Chem. 2006 Jul 28;281(30):21377-21386
references: 16737963
references: Mol Cell Neurosci. 2005 Jun;29(2):222-31
references: 15911346
references: Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10954-9
references: 9724811
references: Neurochem Res. 2008 Mar;33(3):490-9
references: 17763946
references: J Neuroinflammation. 2007 Jul 16;4:18
references: 17634127
references: Eur J Biochem. 2000 Aug;267(16):4912-6
references: 10931173
references: Glia. 2013 Jun;61(6):943-56
references: 23505121
references: Age (Dordr). 2010 Sep;32(3):271-82
references: 20640551
references: Neuroreport. 1995 Jan 26;6(2):245-8
references: 7756602
references: J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Dec 1;877(31):3991-4000
references: 19892608
references: PLoS One. 2011 Mar 18;6(3):e17552
references: 21445266
references: Am J Physiol Endocrinol Metab. 2007 Apr;292(4):E1052-61
references: 17148750
references: Gen Pharmacol. 1985;16(3):163-75
references: 2991073
references: J Neurochem. 1993 Nov;61(5):1677-84
references: 8228987
references: Neurosci Lett. 2007 Jun 29;421(3):253-8
references: 17574754
references: Neuroscience. 2012 Aug 30;218:295-304
references: 22609937
references: Prostaglandins. 1980 Feb;19(2):249-58
references: 6892961
references: Chem Res Toxicol. 2007 Oct;20(10):1528-35
references: 17854155
references: J Neuroinflammation. 2009 Jul 25;6:18
references: 19630993
references: ScientificWorldJournal. 2007 Sep 01;7:1329-47
references: 17767353
references: J Pharmacol Sci. 2010;113(1):89-93
references: 20424389
references: Biochem Biophys Res Commun. 2004 Jul 9;319(4):1171-80
references: 15194490
references: J Neurosci. 1997 Apr 15;17(8):2746-55
references: 9092596
references: J Neurosci. 2006 Apr 19;26(16):4383-93
references: 16624958
references: Neurotox Res. 2013 Aug;24(2):191-204
references: 23355003
references: J Neurochem. 2005 Feb;92(3):477-86
references: 15659218
references: Free Radic Biol Med. 2011 Sep 1;51(5):1000-13
references: 21664268
references: Biochim Biophys Acta. 2000 Oct 18;1482(1-2):259-71
references: 11058767
references: Ann Neurol. 1988 Dec;24(6):699-707
references: 3061362