Mechanism of protection by soluble epoxide hydrolase inhibition in type 2 diabetic stroke.
Inhibition of soluble epoxide hydrolase (sEH) is a potential target of therapy for ischemic injury. sEH metabolizes neuroprotective epoxyeicosatrienoic acids (EETs). We recently demonstrated that sEH inhibition reduces infarct size after middle cerebral artery occlusion (MCAO) in type 1 diabetic mice. We hypothesized that inhibition of sEH would protect against ischemic injury in type 2 diabetic mice. Type 2 diabetes was produced by combined high-fat diet, nicotinamide and streptozotocin in male mice. Diabetic and control mice were treated with vehicle or the sEH inhibitor t-AUCB then subjected to 60-min MCAO. Compared to chow-fed mice, high fat diet-fed mice exhibited an upregulation of sEH mRNA and protein in brain, but no differences in brain EETs levels were observed between groups. Type 2 diabetic mice had increased blood glucose levels at baseline and throughout ischemia, decreased laser-Doppler perfusion of the MCA territory after reperfusion, and sustained larger cortical infarcts compared to control mice. t-AUCB decreased fasting glucose levels at baseline and throughout ischemia, improved cortical perfusion after MCAO and significantly reduced infarct size in diabetic mice. We conclude that sEH inhibition, as a preventative treatment, improves glycemic status, post-ischemic reperfusion in the ischemic territory, and stroke outcome in type 2 diabetic mice.
The Knight Cardiovascular Institute, Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, Oregon, United States of America.
Kristen L
KL
Zuloaga
Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, Oregon, United States of America.
Stephanie M
SM
Krasnow
Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, Oregon, United States of America.
Xinxia
X
Zhu
The Knight Cardiovascular Institute, Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, Oregon, United States of America.
Wenri
W
Zhang
The Knight Cardiovascular Institute, Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, Oregon, United States of America.
Sari A
SA
Jouihan
The Knight Cardiovascular Institute, Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, Oregon, United States of America.
Robert E
RE
Shangraw
The Knight Cardiovascular Institute, Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, Oregon, United States of America.
Nabil J
NJ
Alkayed
Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, Oregon, United States of America.
Daniel L
DL
Marks
D000704:Analysis of Variance; D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D059305:Diet, High-Fat; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism; D008297:Male; D051379:Mice; D009536:Niacinamide; D060888:Real-Time Polymerase Chain Reaction; D020521:Stroke / Q000209:etiology* / Q000517:prevention & control*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; D001565:Benzoates; D001786:Blood Glucose; D009536:Niacinamide; D014508:Urea; D004851:Epoxide Hydrolases