Protective Effects of the Soluble Epoxide Hydrolase Inhibitor 1-Trifluoromethoxyphenyl-3-(1-Propionylpiperidin-4-yl) Urea in a Rat Model of Permanent Middle Cerebral Artery Occlusion.

Linlei Zhang,Farah Mohamed Muse,Shasha Xu,Xiaoxiao Wu,Zhao Han,Yungang Cao,Jueyue Yan,Jiaou Chen,Zicheng Cheng,Xingyang Yi

doi:10.3389/fphar.2020.00182

Abstract

Acute ischemic stroke is a serious disease that endangers human health. In our efforts to develop an effective therapy, we previously showed that the potent, highly selective inhibitor of soluble epoxide hydrolase called 1-trifuoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) protects the brain against focal ischemia in rats. Here we explored the mechanism of TPPU action by assessing whether it could preserve blood-brain barrier integrity and reduce apoptosis in the brain during permanent middle cerebral artery occlusion in male Sprague-Dawley rats. TPPU administration at the onset of stroke and once daily thereafter led to smaller infarct volume and brain edema as well as milder neurological deficits. TPPU significantly inhibited the activity of soluble epoxide hydrolase and matrix metalloproteases 2 and 9, reducing 14,15-DHET levels, while increasing expression of tight junction proteins. TPPU decreased numbers of apoptotic cells by down-regulating the pro-apoptotic proteins BAX and Caspase-3, while up-regulating the anti-apoptotic protein BCL-2. Our results suggest that TPPU can protect the blood-brain barrier and reduce the apoptosis of brain tissue caused by ischemia.

Highlights

Ischemic stroke, caused by a cerebrovascular blockage, leads to death and long-term disability in many patients around the world (Moskowitz et al, 2010; Benjamin et al, 2018)
We focused on the potential effects of trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) on the expression of three tight junction proteins (ZO-1, occludin, claudin-5) whose downregulation in cerebral ischemia compromises the blood-brain barrier (BBB) (Fernandez-Lopez et al, 2012)
We examined the effects of TPPU on matrix metalloproteases (MMPs) 2 and 9, which are activated during cerebral ischemia and degrade the basal lamina of the BBB, further compromising its integrity (Chen et al, 2016)

Summary

Introduction

Ischemic stroke, caused by a cerebrovascular blockage, leads to death and long-term disability in many patients around the world (Moskowitz et al, 2010; Benjamin et al, 2018). While thrombolysis and thrombectomy can be effective treatments (Jauch et al, 2013), they can exacerbate the cerebral injury, compromise the blood-brain barrier (BBB) and extracellular matrix, Protective Effects of TPPU in pMCAO and increase the risk of intracerebral hemorrhage (Niego and Medcalf, 2014). Neuroprotectors to mitigate this injury have been reported in animal studies, but most have proven ineffective in clinical trials (O’Collins et al, 2006). EETs are rapidly catabolized by soluble epoxide hydrolase (sEH) into less bioactive products such as dihydroxyeicosatrienoic acids (DHETs) (Yu et al, 2000), and the extent of this degradation correlates with deterioration of neurological function, carotid artery stenosis, and plaque instability in patients with cerebral infarction (Yi et al, 2016; Yi et al, 2017)

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