June 2011

Document Type


Degree Name



Dept. of Molecular and Medical Genetics


Oregon Health & Science University


Background: Every 40 seconds someone in the United States has a stroke, and every year approximately 795,000 people suffer from stroke. Stroke is the leading cause of disability and the third leading cause of deaths in the United States. Hyperglycemia (HG), the hallmark of diabetes mellitus (DM), has been identified as a risk factor for stroke. Furthermore, HG not only increases the risk of having stroke, but it also exacerbates ischemic brain damage after stroke. The mechanism of increased stroke-related brain damage is not fully understood. We tested the hypothesis that HG depletes cerebrovascular endothelium from protective eicosanoids by upregulating their metabolizing enzyme. Specifically, we tested the hypothesis that HG increases the expression in cerebrovascular endothelium of the gene coding for soluble epoxide hydrolase (sEH), EPHX2. sEH metabolizes and inactivates a group of vasoprotective eicosanoids called epoxyeicosatrienoic acids (EETs). Clinical trials have provided contradicting results as to whether strict control of glucose during stroke improves outcome. Identifying sEH as a downstream mechanism of increased injury by HG may, therefore, offer an alternative therapeutic strategy aimed at decreasing brain damage after stroke by inhibiting sEH. Methods: to induce hyperglycemia, we utilized two different established animal models where, in the first, mice were injected intraperitoneally with Streptozotocin (STZ) to mimic a Type-I diabetes model while in the second, mice were placed on high fat diet to induce a type-II diabetes model. Hyperglycemia was confirmed if non-fasting blood glucose levels were higher than 300mg/dl. Stroke was induced by intraluminal middle cerebral artery occlusion (MCAO) for 45 minutes, and infarct size measured at 24 hrs after MCAO using 2,3,5-triphenyltetrazolium chloride (TTC) staining. Dextran gradient centrifugation was used to isolate cerebral vessels, and quantitative real time PCR was then used to measure changes in EPHX2 expression in cerebral vessels from type I and in whole brain tissue of type II diabetic mice. Results: EPHX2 expression was upregulated in the cerebrovasculature of hyperglycemic type 1 diabetic mice compared to normoglycemic controls. This upregulation was also detected in whole brain tissue from type II diabetic mice compared to control mice raised on low fat (chow) diet. Infarct analysis showed an increase in infarct size in type I diabetic mice compared to normoglycemic controls. Treating mice with sEH inhibitor t-AUCB significantly reduced the infarct size in both hyperglycemic and normoglycemic mice compared to vehicle injected controls. Conclusion: data from this study offered an alternative therapeutic strategy aimed at decreasing brain damage after stroke in hyperglycemic patients by inhibiting sEH enzyme.




School of Medicine



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