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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2018-03-01
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doaj-9d390b315d5e4a4193980594c7cc235f2020-12-08T06:24:28ZengNature Publishing GroupScientific Reports2045-23222018-03-018111110.1038/s41598-018-23504-1Soluble epoxide hydrolase inhibition decreases reperfusion injury after focal cerebral ischemiaRanran Tu0Jillian Armstrong1Kin Sing Stephen Lee2Bruce D. Hammock3Adam Sapirstein4Raymond C. Koehler5Department of Neurology, Second Xiangya Hospital, Central South UniversityDepartment of Anesthesiology and Critical Care Medicine, Johns Hopkins UniversityDepartment of Entomology and Nematology and UCD Comprehensive Cancer Center, University of CaliforniaDepartment of Entomology and Nematology and UCD Comprehensive Cancer Center, University of CaliforniaDepartment of Anesthesiology and Critical Care Medicine, Johns Hopkins UniversityDepartment of Anesthesiology and Critical Care Medicine, Johns Hopkins UniversityAbstract 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.https://doi.org/10.1038/s41598-018-23504-1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ranran Tu Jillian Armstrong Kin Sing Stephen Lee Bruce D. Hammock Adam Sapirstein Raymond C. Koehler |
spellingShingle |
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 Scientific Reports |
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 Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2018-03-01 |
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. |
url |
https://doi.org/10.1038/s41598-018-23504-1 |
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