Abstract
Soluble epoxide hydrolase (sEH) is abundant in the brain, is upregulated in type 2 diabetes mellitus (DM2), and is possible mediator of ischemic injury via the breakdown of neuroprotective epoxyeicosatrienoic acids (EETs). Prophylactic, pre-ischemic sEH blockade with 4-[[trans-4-[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]cyclohexyl]oxy]-benzoic acid (tAUCB) reduces stroke-induced infarct in normal and diabetic mice, with larger neuroprotection in DM2. The present study tested whether benefit occurs in normal and DM2 mice if tAUCB is administered after stroke onset. We performed 60 min middle cerebral artery occlusion in young adult male C57BL mice divided into four groups: normal or DM2, with t-AUCB 2 mg/kg or vehicle 30 min before reperfusion. Endpoints were (1) cerebral blood flow (CBF) by laser Doppler, and (2) brain infarct at 24 h. In nondiabetic mice, t-AUCB reduced infarct size by 30% compared to vehicle-treated mice in the cortex (31.4 ± 4 vs. 43.8 ± 3 (SEM)%, respectively) and 26% in the whole hemisphere (26.3 ± 3 vs. 35.2 ± 2%, both p < 0.05). In contrast, in DM2 mice, tAUCB failed to ameliorate either cortical or hemispheric injury. No differences were seen in CBF. We conclude that tAUCB administered after ischemic stroke onset exerts brain protection in nondiabetic but not DM2 mice, that the neuroprotection appears independent of changes in gross CBF, and that DM2-induced hyperglycemia abolishes t-AUCB-mediated neuroprotection after stroke onset.
Highlights
Rapid brain reperfusion, either by pharmacologic thrombolysis or mechanical thrombectomy, is the definitive treatment for acute ischemic stroke if not contraindicated
We have previously shown that both insulin-resistant prediabetes, which leads to diabetes mellitus type 2 (DM2), or the much less common insulinopenic diabetes mellitus type 1 (DM1) both upregulate EPHX2 and increase Soluble epoxide hydrolase (sEH) protein expression [23,24]
Prophylactic subchronic blockade of sEH with tAUCB, which acts to restore brain EET concentration and reduces brain infarct size after transient middle cerebral artery occlusion (MCAO) in mice, an effect elicited in normal mice but even more robust in the setting of DM2 or DM1, leading to the possibility that the “penalty of diabetes” in stroke could be ameliorated by effective sEH blockade [23,24]
Summary
Either by pharmacologic thrombolysis or mechanical thrombectomy, is the definitive treatment for acute ischemic stroke if not contraindicated. We have previously shown that tAUCB, when administered subchronically before MCAO ischemia to inhibit sEH as a preventative agent, provides protection against focal transient ischemic brain injury in mice with type 2 or much less common type 1 DM, an effect even larger than observed in normoglycemic mice [23,24]. We found that sEH blockade with tAUCB functionally administered at carotid reperfusion limits brain infarct size after MCAO in normal mice, but this postischemic neuroprotection is abolished by uncontrolled DM2 This appears to limit the potential utility of tAUCB in the treatment of acute ischemic stroke in the setting of DM2, it leaves unanswered the possible consequence of administering a higher dose of tAUCB or of directly administering EETs or an EETs analog at reperfusion. It remains to be tested whether tAUCB exerts neuroprotection in nondiabetic mice which exhibit “stress hyperglycemia” at the time of stroke onset or in setting of DM2 with better regulated glycemia
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