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-ylureido)-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.

The Pharmacology of the Cytochrome P450 Epoxygenase/Soluble Epoxide Hydrolase Axis in the Vasculature and Cardiovascular Disease

“…In humans, the Arg287Gln polymorphism of the Ephx2 gene that results in increased plasma cholesterol levels (Sato et al, 2004) has also been linked with the incidence of Vascular P450/sEH Axis type 2 diabetes (Ohtoshi et al, 2005). However, the sEH has also been linked with type 2 diabetes because sEH expression is reportedly elevated in the hearts from Akita type 1 diabetic mice (Dewey et al, 2013), in macrophages from nonobese diabetic mice (Rodriguez and Clare-Salzler, 2006), as well as in livers (Thomas et al, 1989) and cerebral vessels (Jouihan et al, 2013) from animals made diabetic with STZ. sEH inhibition may therefore be an attractive strategy to address some of the complications of the metabolic syndrome.…”

Cytochrome P450 eicosanoids in cerebrovascular function and disease

“…Mice treated with streptozotocin (STZ) to induce hyperglycemia, a model of type 1 diabetes, have increased EPHX2 levels specifically in the cerebral vessels, though not in the brain as a whole (Jouihan et al, 2013). These mice have decreased EETs levels in the brain, which are restored by pharmacological sEH inhibition.…”

Cyclooxygenase- and cytochrome P450-derived eicosanoids in stroke

“…These findings support the notion that sEH blockade against cerebral ischemia via vascular and neural protection in SHRSP rats. Notably, several other interesting studies have demonstrated that sEH blockade is cerebroprotective in mouse model of ischemic stroke [106], rat model of ischemic stroke [107], type-1 diabetic stroke model [108], and type-2 diabetic stroke model [109]. …”