title: Prostaglandin E2 type 1 receptors contribute to neuronal apoptosis after transient forebrain ischemia.
abstract: Cyclooxygenase-2-derived prostaglandin E2 (PGE2) contributes to excitotoxic and ischemic neuronal cell death by engaging neuronal PGE2 type 1 receptors (EP1R). Our previous studies have shown that EP1R signaling resulted in disturbances of intracellular Ca(2+) homeostasis and suppression of the pro-survival protein kinase AKT. The aim of this study was to investigate whether these pathophysiological mechanism have a role in the neuronal cell death after transient forebrain ischemia. Mice were subjected to ischemia/reperfusion by bilateral common carotid artery occlusion. Hippocampal cornu ammonis area 1 (CA1) neuronal cell death was determined 5 days after reperfusion. Animals treated with the EP1R antagonist SC51089 or EP1R-deficient mice (EP1(-/-)) showed significantly less neuronal injury as compared to vehicle-treated wild-type controls. Benefits of EP1R blockage were still evident 14 days after injury. Better neuronal survival was correlated with reduced neuronal caspase-3 activity and decreased nuclear translocation of the apoptosis-inducing factor . Neuroprotection could be reverted by intracerebroventricular administration of the phosphoinositide 3-kinase inhibitor LY294002 and was not further increased by the calcineurin inhibitor FK506. These data implicate EP1R in postischemic neuronal apoptosis possibly by facilitating AKT inhibition.
authors: Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10065, USA.
authors: Munehisa
authors: M
authors: Shimamura
authors: Ping
authors: P
authors: Zhou
authors: Barbara
authors: B
authors: Casolla
authors: Liping
authors: L
authors: Qian
authors: Carmen
authors: C
authors: Capone
authors: Hitomi
authors: H
authors: Kurinami
authors: Costantino
authors: C
authors: Iadecola
authors: Josef
authors: J
authors: Anrather
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D056547:CA1 Region, Hippocampal / Q000473:pathology; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D053148:Caspase 3 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D006834:Hydrazines / Q000494:pharmacology; D007150:Immunohistochemistry; D002546:Ischemic Attack, Transient / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000502:physiology*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010077:Oxazepines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D021381:Protein Transport; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D051033:Apoptosis Inducing Factor; D065095:Calcineurin Inhibitors; D006834:Hydrazines; D010077:Oxazepines; D000081082:Phosphoinositide-3 Kinase Inhibitors; C545636:Ptger1 protein, mouse; D058306:Receptors, Prostaglandin E, EP1 Subtype; C086836:SC 51089; D051058:Oncogene Protein v-akt; D019703:Calcineurin; D053148:Caspase 3; D015232:Dinoprostone
references: Annu Rev Pharmacol Toxicol. 2007;47:117-41
references: 16879082
references: J Cereb Blood Flow Metab. 2005 Jun;25(6):713-21
references: 15703698
references: Science. 1999 Apr 9;284(5412):339-43
references: 10195903
references: J Cereb Blood Flow Metab. 1988 Dec;8(6):790-8
references: 3142890
references: Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10954-9
references: 9724811
references: Arch Biochem Biophys. 1995 Dec 1;324(1):26-34
references: 7503555
references: J Neurosci Methods. 2007 Oct 15;166(1):73-80
references: 17692388
references: J Cereb Blood Flow Metab. 2001 Feb;21(2):99-109
references: 11176275
references: Mol Pharmacol. 2005 Feb;67(2):349-55
references: 15548766
references: Neuropathology. 2000 Sep;20 Suppl:S95-7
references: 11037198
references: Endocrinology. 1996 Jun;137(6):2572-9
references: 8641211
references: J Biol Chem. 1993 Sep 25;268(27):20175-8
references: 7690750
references: Neurobiol Aging. 2012 Sep;33(9):2215-9
references: 22015313
references: Neuropharmacology. 2005 Mar;48(3):391-7
references: 15721171
references: J Biol Chem. 1997 Nov 28;272(48):30491-7
references: 9374542
references: Nature. 1999 Oct 14;401(6754):703-8
references: 10537109
references: J Neurochem. 2003 Aug;86(3):545-55
references: 12859668
references: J Cereb Blood Flow Metab. 2009 Jan;29(1):66-72
references: 18648380
references: Prog Neurobiol. 2007 Feb;81(3):179-96
references: 17267093
references: Toxicol Sci. 2006 Jan;89(1):265-70
references: 16237196
references: Curr Med Chem. 2008;15(19):1863-9
references: 18691044
references: Neuroscience. 2007 Nov 30;150(1):50-7
references: 17936515
references: Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13313-8
references: 9789085
references: J Biol Chem. 1994 Feb 18;269(7):5241-8
references: 8106507
references: J Cereb Blood Flow Metab. 2005 Mar;25(3):348-57
references: 15660100
references: Neuron. 2010 Jul 29;67(2):181-98
references: 20670828
references: Nat Med. 2006 Feb;12(2):225-9
references: 16432513
references: Neurobiol Dis. 2008 Mar;29(3):543-51
references: 18178094
references: PLoS One. 2011;6(10):e25916
references: 22022466
references: J Neurotrauma. 2000 Oct;17(10):811-29
references: 11063050
references: J Invest Surg. 2007 May-Jun;20(3):195-203
references: 17613695
references: J Cell Biochem. 2007 Dec 1;102(5):1160-70
references: 17471535
references: J Neurosci. 2007 Aug 29;27(35):9278-93
references: 17728442
references: J Cereb Blood Flow Metab. 2001 Dec;21(12):1436-41
references: 11740205
references: Brain Res. 2008 Oct 9;1234:148-57
references: 18703031
references: Nature. 1999 Feb 4;397(6718):441-6
references: 9989411
references: Biochim Biophys Acta. 1995 May 11;1244(1):41-8
references: 7766667
references: Exp Neurol. 2006 Feb;197(2):353-62
references: 16297913
references: J Neurol Sci. 1975 May;25(1):75-92
references: 1141958
references: J Cereb Blood Flow Metab. 1998 May;18(5):570-9
references: 9591849
references: J Cereb Blood Flow Metab. 2004 Jan;24(1):107-13
references: 14688622
references: J Biol Chem. 2004 May 21;279(21):22539-47
references: 15024023
references: Brain Res. 1998 Jan 12;780(2):304-10
references: 9507171
references: J Cereb Blood Flow Metab. 1999 Nov;19(11):1213-9
references: 10566967