Soluble Epoxide Hydrolase Blockade after Stroke Onset Protects Normal but Not Diabetic Mice

Area of Science:

• Neuroscience
• Pharmacology
• Endocrinology

Background:

• Soluble epoxide hydrolase (sEH) is upregulated in type 2 diabetes (DM2) and may mediate ischemic injury by degrading neuroprotective epoxyeicosatrienoic acids (EETs).
• Pre-ischemic blockade of sEH with tAUCB reduces stroke-induced infarcts, with greater neuroprotection observed in DM2 models.

Purpose of the Study:

• To investigate the efficacy of post-stroke administration of tAUCB in normal and DM2 mice.
• To determine if tAUCB-mediated neuroprotection is dependent on cerebral blood flow (CBF) and if it is affected by DM2-induced hyperglycemia.

Main Methods:

• Middle cerebral artery occlusion (MCAO) was performed in mice for 60 minutes.
• Mice were divided into normal or DM2 groups and received either tAUCB (2 mg/kg) or vehicle 30 minutes before reperfusion.
• Cerebral blood flow (CBF) was measured using laser Doppler, and brain infarct volume was assessed at 24 hours.

Main Results:

• In nondiabetic mice, tAUCB significantly reduced cortical infarct size by 30% and whole hemisphere infarct by 26% compared to vehicle.
• In DM2 mice, tAUCB failed to reduce either cortical or hemispheric infarct size.
• No significant differences in CBF were observed between treatment groups in either normal or DM2 mice.

Conclusions:

• Post-stroke administration of tAUCB provides neuroprotection in nondiabetic mice but not in DM2 mice.
• The observed neuroprotection is independent of changes in gross CBF.
• DM2-induced hyperglycemia abolishes the neuroprotective effects of tAUCB when administered after stroke onset.