1-Trifluoromethoxyphenyl-3-(1-Propionylpiperidin-4-yl) Urea Protects the Blood-Brain Barrier Against Ischemic Injury by Upregulating Tight Junction Protein Expression, Mitigating Apoptosis and Inflammation In Vivo and In Vitro Model

Xingyang Yi; Chongxi Xu; Pan Huang; Linlei Zhang; Ting Qing; Jie Li; Chun Wang; Tao Zeng; Jing Lu; Zhao Han

doi:10.3389/fphar.2020.01197

1-Trifluoromethoxyphenyl-3-(1-Propionylpiperidin-4-yl) Urea Protects the Blood-Brain Barrier Against Ischemic Injury by Upregulating Tight Junction Protein Expression, Mitigating Apoptosis and Inflammation In Vivo and In Vitro Model

Front Pharmacol. 2020 Aug 7:11:1197. doi: 10.3389/fphar.2020.01197. eCollection 2020.

Authors

Xingyang Yi^{1

2}, Chongxi Xu³, Pan Huang¹, Linlei Zhang⁴, Ting Qing^{1

2}, Jie Li¹, Chun Wang¹, Tao Zeng^{1

5}, Jing Lu^{2

6}, Zhao Han⁷

Affiliations

¹ Department of Neurology, People's Hospital of Deyang City, Deyang, China.
² Department of Neurology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
³ Department of Neurosurgery, West China Hospital of Sichuan University, Chendu, China.
⁴ Department of General Intensive Care Unit, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
⁵ Department of Neurology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.
⁶ Department of Neurology, Chengdu Fifth People's Hospital, Chengdu, China.
⁷ Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.

Abstract

We previously have revealed that 1-trifluoromethoxyphenyl-3-(1- propionylpiperidin-4-yl) urea (TPPU), as a soluble epoxide hydrolase (sEH) inhibitor can reduce infarct volume, protect blood-brain barrier (BBB) and brain against ischemic injury in rats. Here, we investigated the potential mechanisms of TPPU on BBB integrity in both in permanent middle cerebral artery occlusion (pMCAO) rat model and in oxygen-glucose deprivation/reperfusion (OGD/R)-induced human brain microvascular endothelial cells (HBMVECs) model. In pMCAO rat, TPPU administration decreased brain edema and Evans blue content, increased tight junction proteins (TJs) expression of claudin-5, occludin, and zonula occludens-1 (ZO-1). In OGD/R model, OGD/R significantly increased permeability and cell apoptosis, downregulated the expression of claudin-5, ZO-1, occludin, and lymphoma (Bcl)-2. Notably, TPPU pretreatment effectively protected the BBB integrity by reducing the permeability, promoting expression of claudin-5, ZO-1, occluding and Bcl-2, mitigating reactive oxygen species (ROS) injury and release of interleukin-1β (IL-1β), IL-6β, and tumor necrosis factor-α (TNF-α), downregulating expression of matrix metalloproteinase-9 (MMP-9), MMP-2, bcl-2-associated X protein (Bax), IL-1β, IL-6β, and TNF-α. Moreover, OGD/R induced the up-regulation of p-p65, p-IκB, and p-p38, which were effectively decreased after TPPU pretreatment in comparison with that of the OGD/R group. Furthermore, pyrrolidinedithiocarbamate (PDTC, a selective inhibitor of NF-κB p65) not only alleviated the OGD/R-induced HBMVECs injury and permeability, but also reduced the expression of TNF-α, IL-6, IL-1β, p-p65, and p-IκB, and the protective effect of PDTC was equivalent to that of TPPU. These results indicate that TPPU protects BBB integrity against ischemic injury by multiple protective mechanisms, at least in part, by reducing ROS, inflammation, apoptosis, and suppressing the nuclear factor-κB (NF-κB) and p38 signaling pathways.

Keywords: 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea; oxygen-glucose deprivation/reperfusion; NF-κB; apoptosis; blood-brain barrier; inflammation; ischemic stroke; tight junction proteins.