Abstract
Epoxyeicosatrienoic acids (EETs) are produced by cytochrome P450 epoxygenases from arachidonic acid, and their rapid metabolism is mainly through soluble epoxide hydrolase (sEH). EETs exert vasodilatory, anti-inflammatory, anti-apoptotic, and pro-angiogenic effects. Administration of sEH inhibitors before or at the onset of stroke is protective, but the effects of post-treatment at reperfusion, when inflammation is augmented, has not been as well studied. We tested the hypothesis that 1-Trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), a potent and highly selective sEH inhibitor, suppresses inflammation and protects the brain when administered at reperfusion. Vehicle or 1 mg/kg TPPU was administered at reperfusion after 90 minutes of focal ischemia and again 24 hours later. Protein expression and activity of sEH increased after reperfusion and activity was decreased by TPPU administration. TPPU decreased infarct volume by 50%, reduced neurologic deficits and improved performance on sensorimotor tasks. Furthermore, TPPU significantly lowered the mRNA expression of interleukin-1beta by 3.5-fold and tumor necrosis factor-alpha by 2.2-fold, increased transforming growth factor-beta mRNA by 1.8-fold, and augmented immunostaining of vascular endothelial growth factor in peri-infarct cortex. Thus, inhibition of sEH at reperfusion significantly reduces infarction and improves sensorimotor function, possibly by suppressing early proinflammatory cytokines and promoting reparative cytokines and growth factors.
Highlights
Thrombolysis with tissue plasminogen activator and endovascular thrombectomy are currently the major treatments for patients with acute ischemic stroke
Double-labeling immunofluorescence indicated that soluble epoxide hydrolase (sEH) co-localized with both glial fibrillary acidic protein (GFAP)-positive astrocytes (Fig. 1A) and NeuN-positive neurons (Fig. 1B), but rarely with ionized calcium-binding adapter molecule 1 (Iba1)-positive microglia (Fig. 1C)
We investigated whether administration of the sEH inhibitor the sEH inhibitor 1-(1-propanoylpiperidin-4-yl)− 3-[4-(trifluoromethoxy)phenyl]urea (TPPU) at reperfusion after transient focal ischemia provides neuroprotective effects and explored possible mechanisms for this protection
Summary
Thrombolysis with tissue plasminogen activator and endovascular thrombectomy are currently the major treatments for patients with acute ischemic stroke. The main objectives of the present study were to better characterize the response to administration of an sEH inhibitor at the time of reperfusion by examining effects on tissue cytokine responses, microglia number, and neurobehavior, in addition to infarct volume. We used the sEH inhibitor 1-(1-propanoylpiperidin-4-yl)− 3-[4-(trifluoromethoxy)phenyl]urea (TPPU) This newer generation sEH inhibitor possesses higher potency and a longer circulatory half-life[31,32,33] than many of the inhibitors previously used in stroke models. We tested the hypothesis that systemic administration of TPPU starting at reperfusion after MCAO in male rats reduces infarct volume, improves sensorimotor functional outcome, suppresses expression of proinflammatory IL-1β and TNF-α, augments expression of anti-inflammatory IL-10 and transforming growth factor-β (TGF-β), and decreases the number of peri-infarct microglia
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
