Soluble epoxide hydrolase inhibition decreases reperfusion injury after focal cerebral ischemia

Abstract Epoxyeicosatrienoic acids (EETs) are produced by cytochrome P450 epoxygenases from arachidonic acid, and their rapid metabolism is mainly through soluble epoxide hydrolase (sEH). EETs exert vasodilatory, anti-inflammatory, anti-apoptotic, and pro-angiogenic effects. Administration of sEH in...

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Autores principales:	Ranran Tu, Jillian Armstrong, Kin Sing Stephen Lee, Bruce D. Hammock, Adam Sapirstein, Raymond C. Koehler
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9d390b315d5e4a4193980594c7cc235f
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spelling	oai:doaj.org-article:9d390b315d5e4a4193980594c7cc235f2021-12-02T15:08:19ZSoluble epoxide hydrolase inhibition decreases reperfusion injury after focal cerebral ischemia10.1038/s41598-018-23504-12045-2322https://doaj.org/article/9d390b315d5e4a4193980594c7cc235f2018-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-23504-1https://doaj.org/toc/2045-2322Abstract Epoxyeicosatrienoic acids (EETs) are produced by cytochrome P450 epoxygenases from arachidonic acid, and their rapid metabolism is mainly through soluble epoxide hydrolase (sEH). EETs exert vasodilatory, anti-inflammatory, anti-apoptotic, and pro-angiogenic effects. Administration of sEH inhibitors before or at the onset of stroke is protective, but the effects of post-treatment at reperfusion, when inflammation is augmented, has not been as well studied. We tested the hypothesis that 1-Trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), a potent and highly selective sEH inhibitor, suppresses inflammation and protects the brain when administered at reperfusion. Vehicle or 1 mg/kg TPPU was administered at reperfusion after 90 minutes of focal ischemia and again 24 hours later. Protein expression and activity of sEH increased after reperfusion and activity was decreased by TPPU administration. TPPU decreased infarct volume by 50%, reduced neurologic deficits and improved performance on sensorimotor tasks. Furthermore, TPPU significantly lowered the mRNA expression of interleukin-1beta by 3.5-fold and tumor necrosis factor-alpha by 2.2-fold, increased transforming growth factor-beta mRNA by 1.8-fold, and augmented immunostaining of vascular endothelial growth factor in peri-infarct cortex. Thus, inhibition of sEH at reperfusion significantly reduces infarction and improves sensorimotor function, possibly by suppressing early proinflammatory cytokines and promoting reparative cytokines and growth factors.Ranran TuJillian ArmstrongKin Sing Stephen LeeBruce D. HammockAdam SapirsteinRaymond C. KoehlerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-11 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ranran Tu Jillian Armstrong Kin Sing Stephen Lee Bruce D. Hammock Adam Sapirstein Raymond C. Koehler Soluble epoxide hydrolase inhibition decreases reperfusion injury after focal cerebral ischemia
description	Abstract Epoxyeicosatrienoic acids (EETs) are produced by cytochrome P450 epoxygenases from arachidonic acid, and their rapid metabolism is mainly through soluble epoxide hydrolase (sEH). EETs exert vasodilatory, anti-inflammatory, anti-apoptotic, and pro-angiogenic effects. Administration of sEH inhibitors before or at the onset of stroke is protective, but the effects of post-treatment at reperfusion, when inflammation is augmented, has not been as well studied. We tested the hypothesis that 1-Trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), a potent and highly selective sEH inhibitor, suppresses inflammation and protects the brain when administered at reperfusion. Vehicle or 1 mg/kg TPPU was administered at reperfusion after 90 minutes of focal ischemia and again 24 hours later. Protein expression and activity of sEH increased after reperfusion and activity was decreased by TPPU administration. TPPU decreased infarct volume by 50%, reduced neurologic deficits and improved performance on sensorimotor tasks. Furthermore, TPPU significantly lowered the mRNA expression of interleukin-1beta by 3.5-fold and tumor necrosis factor-alpha by 2.2-fold, increased transforming growth factor-beta mRNA by 1.8-fold, and augmented immunostaining of vascular endothelial growth factor in peri-infarct cortex. Thus, inhibition of sEH at reperfusion significantly reduces infarction and improves sensorimotor function, possibly by suppressing early proinflammatory cytokines and promoting reparative cytokines and growth factors.
format	article
author	Ranran Tu Jillian Armstrong Kin Sing Stephen Lee Bruce D. Hammock Adam Sapirstein Raymond C. Koehler
author_facet	Ranran Tu Jillian Armstrong Kin Sing Stephen Lee Bruce D. Hammock Adam Sapirstein Raymond C. Koehler
author_sort	Ranran Tu
title	Soluble epoxide hydrolase inhibition decreases reperfusion injury after focal cerebral ischemia
title_short	Soluble epoxide hydrolase inhibition decreases reperfusion injury after focal cerebral ischemia
title_full	Soluble epoxide hydrolase inhibition decreases reperfusion injury after focal cerebral ischemia
title_fullStr	Soluble epoxide hydrolase inhibition decreases reperfusion injury after focal cerebral ischemia
title_full_unstemmed	Soluble epoxide hydrolase inhibition decreases reperfusion injury after focal cerebral ischemia
title_sort	soluble epoxide hydrolase inhibition decreases reperfusion injury after focal cerebral ischemia
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/9d390b315d5e4a4193980594c7cc235f
work_keys_str_mv	AT ranrantu solubleepoxidehydrolaseinhibitiondecreasesreperfusioninjuryafterfocalcerebralischemia AT jillianarmstrong solubleepoxidehydrolaseinhibitiondecreasesreperfusioninjuryafterfocalcerebralischemia AT kinsingstephenlee solubleepoxidehydrolaseinhibitiondecreasesreperfusioninjuryafterfocalcerebralischemia AT brucedhammock solubleepoxidehydrolaseinhibitiondecreasesreperfusioninjuryafterfocalcerebralischemia AT adamsapirstein solubleepoxidehydrolaseinhibitiondecreasesreperfusioninjuryafterfocalcerebralischemia AT raymondckoehler solubleepoxidehydrolaseinhibitiondecreasesreperfusioninjuryafterfocalcerebralischemia
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Soluble epoxide hydrolase inhibition decreases reperfusion injury after focal cerebral ischemia

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