Contribution of PGE2 EP1 receptor in hemin-induced neurotoxicity

Although hemin-mediated neurotoxicity has been linked to the production of free radicals and glutamate excitotoxicity, the role of the prostaglandin E2 (PGE2)-EP1 receptor remains unclear. Activation of the EP1 receptor in neurons results in increased intracellular calcium levels; therefore, we hypo...

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Main Authors:	Mohan, Shekher, Glushakov, Alexander V., deCurnou, Alexander, Narumiya, Shuh, Doré, Sylvain
Format:	Online
Language:	English
Published:	Frontiers Media S.A. 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791386/

id	pubmed-3791386
recordtype	oai_dc
spelling	pubmed-37913862013-10-09 Contribution of PGE2 EP1 receptor in hemin-induced neurotoxicity Mohan, Shekher Glushakov, Alexander V. deCurnou, Alexander Narumiya, Shuh Doré, Sylvain Neuroscience Although hemin-mediated neurotoxicity has been linked to the production of free radicals and glutamate excitotoxicity, the role of the prostaglandin E2 (PGE2)-EP1 receptor remains unclear. Activation of the EP1 receptor in neurons results in increased intracellular calcium levels; therefore, we hypothesize that the blockade of the EP1 receptor reduces hemin neurotoxicity. Using postnatal primary cortical neurons cultured from wild-type (WT) and EP1−/− mice, we investigated the EP1 receptor role in hemin neurotoxicity measured by lactate dehydrogenase (LDH) cell survival assay. Hemin (75 μM) induced greater release of LDH in WT (34.7 ± 4.5%) than in EP1−/− (27.6 ± 3.3%) neurons. In the presence of the EP1 receptor antagonist SC-51089, the hemin-induced release of LDH decreased. To further investigate potential mechanisms of action, we measured changes in the intracellular calcium level [Ca2+]i following treatment with 17-phenyl trinor PGE2 (17-pt-PGE2) a selective EP1 agonist. In the WT neurons, 17-pt-PGE2 dose-dependently increased [Ca2+]i. However, in EP1−/− neurons, [Ca2+]i was significantly attenuated. We also revealed that hemin dose-dependently increased [Ca2+]i in WT neurons, with a significant decrease in EP1−/− neurons. Both 17-pt-PGE2 and hemin-induced [Ca2+]i were abolished by N-methyl-D-aspartic (NMDA) acid receptor and ryanodine receptor blockers. These results suggest that blockade of the EP1 receptor may be protective against hemin neurotoxicity in vitro. We speculate that the mechanism of hemin neuronal death involves [Ca2+]i mediated by NMDA acid receptor-mediated extracellular Ca2+ influx and EP1 receptor-mediated intracellular release from ryanodine receptor-operated Ca2+ stores. Therefore, blockade of the EP1 receptor could be used to minimize neuronal damage following exposure to supraphysiological levels of hemin. Frontiers Media S.A. 2013-10-07 /pmc/articles/PMC3791386/ /pubmed/24109429 http://dx.doi.org/10.3389/fnmol.2013.00031 Text en Copyright © 2013 Mohan, Glushakov, deCurnou, Narumiya and Doré. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Mohan, Shekher Glushakov, Alexander V. deCurnou, Alexander Narumiya, Shuh Doré, Sylvain
spellingShingle	Mohan, Shekher Glushakov, Alexander V. deCurnou, Alexander Narumiya, Shuh Doré, Sylvain Contribution of PGE2 EP1 receptor in hemin-induced neurotoxicity
author_facet	Mohan, Shekher Glushakov, Alexander V. deCurnou, Alexander Narumiya, Shuh Doré, Sylvain
author_sort	Mohan, Shekher
title	Contribution of PGE2 EP1 receptor in hemin-induced neurotoxicity
title_short	Contribution of PGE2 EP1 receptor in hemin-induced neurotoxicity
title_full	Contribution of PGE2 EP1 receptor in hemin-induced neurotoxicity
title_fullStr	Contribution of PGE2 EP1 receptor in hemin-induced neurotoxicity
title_full_unstemmed	Contribution of PGE2 EP1 receptor in hemin-induced neurotoxicity
title_sort	contribution of pge2 ep1 receptor in hemin-induced neurotoxicity
description	Although hemin-mediated neurotoxicity has been linked to the production of free radicals and glutamate excitotoxicity, the role of the prostaglandin E2 (PGE2)-EP1 receptor remains unclear. Activation of the EP1 receptor in neurons results in increased intracellular calcium levels; therefore, we hypothesize that the blockade of the EP1 receptor reduces hemin neurotoxicity. Using postnatal primary cortical neurons cultured from wild-type (WT) and EP1−/− mice, we investigated the EP1 receptor role in hemin neurotoxicity measured by lactate dehydrogenase (LDH) cell survival assay. Hemin (75 μM) induced greater release of LDH in WT (34.7 ± 4.5%) than in EP1−/− (27.6 ± 3.3%) neurons. In the presence of the EP1 receptor antagonist SC-51089, the hemin-induced release of LDH decreased. To further investigate potential mechanisms of action, we measured changes in the intracellular calcium level [Ca2+]i following treatment with 17-phenyl trinor PGE2 (17-pt-PGE2) a selective EP1 agonist. In the WT neurons, 17-pt-PGE2 dose-dependently increased [Ca2+]i. However, in EP1−/− neurons, [Ca2+]i was significantly attenuated. We also revealed that hemin dose-dependently increased [Ca2+]i in WT neurons, with a significant decrease in EP1−/− neurons. Both 17-pt-PGE2 and hemin-induced [Ca2+]i were abolished by N-methyl-D-aspartic (NMDA) acid receptor and ryanodine receptor blockers. These results suggest that blockade of the EP1 receptor may be protective against hemin neurotoxicity in vitro. We speculate that the mechanism of hemin neuronal death involves [Ca2+]i mediated by NMDA acid receptor-mediated extracellular Ca2+ influx and EP1 receptor-mediated intracellular release from ryanodine receptor-operated Ca2+ stores. Therefore, blockade of the EP1 receptor could be used to minimize neuronal damage following exposure to supraphysiological levels of hemin.
publisher	Frontiers Media S.A.
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791386/
_version_	1612016595665682432

Contribution of PGE2 EP1 receptor in hemin-induced neurotoxicity

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