Soluble epoxide hydrolase inhibition decreases reperfusion injury after focal cerebral ischemia

• Published in: Scientific reports 2018-03, Vol.8 (1), p.5279-11, Article 5279
• Main Authors: Tu, Ranran, Armstrong, Jillian, Lee, Kin Sing Stephen, Hammock, Bruce D., Sapirstein, Adam, Koehler, Raymond C.
• Format: Article
• Language: English
• Subjects: 14; 14/63; 631/378/1934; 631/378/2607; 64; 692/308/575; 692/617/375/534; 82; 82/51; Angiogenesis; Animals; Apoptosis; Arachidonic acid; Brain - drug effects; Brain - immunology; Brain - pathology; Brain Ischemia - complications; Brain Ischemia - drug therapy; Brain Ischemia - immunology; Brain Ischemia - pathology; Cerebral infarction; Cerebral Infarction - complications; Cerebral Infarction - drug therapy; Cerebral Infarction - immunology; Cerebral Infarction - pathology; Cytochrome P450; Cytokines; Enzyme Inhibitors - therapeutic use; Epoxide hydrolase; Epoxide Hydrolases - antagonists & inhibitors; Epoxide Hydrolases - immunology; Gene expression; Growth factors; Humanities and Social Sciences; IL-1β; Inflammation; Inflammation - complications; Inflammation - drug therapy; Inflammation - immunology; Inflammation - pathology; Ischemia; multidisciplinary; Phenylurea Compounds - therapeutic use; Piperidines - therapeutic use; Rats; Rats, Sprague-Dawley; Reperfusion; Reperfusion Injury - complications; Reperfusion Injury - drug therapy; Reperfusion Injury - immunology; Reperfusion Injury - pathology; Science; Sensorimotor system; Staphylococcal enterotoxin H; Tumor necrosis factor-α; Urea; Vascular endothelial growth factor
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-23504-1

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.