title: Role of soluble epoxide hydrolase in exacerbation of stroke by streptozotocin-induced type 1 diabetes mellitus.
abstract: Hyperglycemia worsens stroke, yet rigorous glycemic control does not improve neurologic outcome. An alternative is to target downstream molecular mediator(s) triggered by hyperglycemia but independent of prevailing glycemia. Soluble epoxide hydrolase (sEH) is a potential mediator of injury via its metabolism of neuroprotective epoxyeicosatrienoic acids (EETs). We tested whether hyperglycemia exacerbates cerebral injury by upregulating sEH and decreasing brain EET levels. Type 1 diabetes mellitus was modeled by streptozotocin (STZ; 50 mg/kg per day intraperitoneally, 5 days) in male mice. At 4 weeks, STZ-treated and control mice underwent 45-minute middle cerebral artery occlusion (MCAO) with or without sEH blockade by trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB; 1 mg/kg intraperitoneally daily for 6 days before MCAO). The STZ-treated mice had increased sEH mRNA expression in cerebral vessels and decreased EET concentrations in brain. There was no difference in cortical perfusion between groups. The STZ-treated mice sustained larger brain infarct than controls. Pretreatment with t-AUCB eliminated the difference in infarct size and EETs concentration between STZ-treated mice and controls, without altering glycemia. We conclude that type 1 diabetes mellitus upregulates sEH mRNA and decreases concentrations of neuroprotective EETs within the brain, leading to worse stroke outcome. The data indicate that sEH antagonism may be beneficial in the setting of hyperglycemic stroke.
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: Sari A
authors.initials: SA
authors.lastname: Jouihan
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Zuloaga
authors.forename: Wenri
authors.initials: W
authors.lastname: Zhang
authors.forename: Robert E
authors.initials: RE
authors.lastname: Shangraw
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Krasnow
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Marks
authors.forename: Nabil J
authors.initials: NJ
authors.lastname: Alkayed
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001786:Blood Glucose / Q000032:analysis; D002533:Cerebral Angiography; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000201:enzymology*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000201:enzymology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D061848:Optical Imaging; D060888:Real-Time Polymerase Chain Reaction; D013311:Streptozocin / Q000494:pharmacology; D020521:Stroke / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control; D015854:Up-Regulation; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; D001565:Benzoates; D001786:Blood Glucose; D013311:Streptozocin; D014508:Urea; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse; D015126:8,11,14-Eicosatrienoic Acid
references.citation: J Cardiovasc Pharmacol. 2010 Jan;55(1):67-73
references.pmid: 19834332
references.citation: J Cereb Blood Flow Metab. 2007 Dec;27(12):1931-40
references.pmid: 17440491
references.citation: Am J Physiol Cell Physiol. 2007 Mar;292(3):C996-1012
references.pmid: 16987999
references.citation: J Clin Neurosci. 2002 Nov;9(6):618-26
references.pmid: 12604269
references.citation: J Neurosci. 2007 Apr 25;27(17):4642-9
references.pmid: 17460077
references.citation: Future Neurol. 2009 Mar 1;4(2):179-199
references.pmid: 19779591
references.citation: Br J Pharmacol. 2009 Jan;156(2):284-96
references.pmid: 19154430
references.citation: J Cereb Blood Flow Metab. 2009 Aug;29(8):1475-81
references.pmid: 19471280
references.citation: J Cereb Blood Flow Metab. 2011 Mar;31(3):807-18
references.pmid: 21157471
references.citation: Am J Physiol Heart Circ Physiol. 2010 Feb;298(2):H679-87
references.pmid: 20008276
references.citation: Stroke. 1991 Nov;22(11):1389-93
references.pmid: 1750047
references.citation: Am J Physiol Renal Physiol. 2009 Sep;297(3):F740-8
references.pmid: 19553349
references.citation: Stroke. 2008 Jul;39(7):2073-8
references.pmid: 18369166
references.citation: Biochem Pharmacol. 1989 Dec 1;38(23):4291-7
references.pmid: 2688656
references.citation: J Lipid Res. 1998 Aug;39(8):1713-21
references.pmid: 9717733
references.citation: Age Ageing. 2009 Sep;38(5):590-4
references.pmid: 19602513
references.citation: Mol Pharmacol. 2001 Aug;60(2):310-20
references.pmid: 11455018
references.citation: N Engl J Med. 2001 Nov 8;345(19):1359-67
references.pmid: 11794168
references.citation: Neurology. 1996 Dec;47(6):1420-8
references.pmid: 8960721
references.citation: Stroke. 2003 Sep;34(9):2208-14
references.pmid: 12893952
references.citation: Prostaglandins Other Lipid Mediat. 2010 Apr;91(3-4):68-84
references.pmid: 19545642
references.citation: Neurocrit Care. 2009;10(2):181-6
references.pmid: 18357419
references.citation: Drug Metab Pharmacokinet. 2009;24(5):438-45
references.pmid: 19881255
references.citation: J Histochem Cytochem. 2008 Jun;56(6):551-9
references.pmid: 18319271
references.citation: N Engl J Med. 2008 Jun 12;358(24):2545-59
references.pmid: 18539917
references.citation: Am J Pathol. 2009 Jun;174(6):2086-95
references.pmid: 19435785
references.citation: Am J Med. 1983 Apr;74(4):540-4
references.pmid: 6837584
references.citation: Front Biosci. 2008 Jan 01;13:2833-41
references.pmid: 17981757
references.citation: Am J Physiol Heart Circ Physiol. 2008 Nov;295(5):H2128-34
references.pmid: 18835921
references.citation: Hypertension. 2008 Feb;51(2):567-73
references.pmid: 18086949
references.citation: J Neurochem. 2010 Dec;115(6):1530-42
references.pmid: 20950340
references.citation: N Engl J Med. 2009 Mar 26;360(13):1283-97
references.pmid: 19318384
references.citation: J Pharmacol Exp Ther. 2010 Aug;334(2):430-8
references.pmid: 20439437
references.citation: Curr Treat Options Neurol. 2010 Nov;12(6):492-503
references.pmid: 20848328
references.citation: Neuroscience. 2009 Oct 6;163(2):646-61
references.pmid: 19540314
references.citation: Arch Neurol. 1990 Nov;47(11):1174-7
references.pmid: 2241612
references.citation: Stroke. 2010 Oct;41(10):2362-5
references.pmid: 20724713
references.citation: Lancet Neurol. 2007 May;6(5):397-406
references.pmid: 17434094
references.citation: Am J Physiol Renal Physiol. 2009 Mar;296(3):F556-63
references.pmid: 19129258
references.citation: Eur J Epidemiol. 2008;23(12):793-9
references.pmid: 19015938