Panax notoginseng Saponins Protect Cerebral Microvascular Endothelial Cells against Oxygen-Glucose Deprivation/Reperfusion-Induced Barrier Dysfunction via Activation of PI3K/Akt/Nrf2 Antioxidant Signaling Pathway.

Shaonan Hu,Haiyan Hu,Bo Zhao,Shouying Du,Zongxi Sun,Yali Wu,Pengyue Li,Baochen Zhu

doi:10.3390/molecules23112781

Shaonan Hu, Haiyan Hu + Show 6 more

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https://doi.org/10.3390/molecules23112781

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Abstract

Oxidative stress plays a critical role in cerebral ischemia/reperfusion (I/R)-induced blood-brain barrier (BBB) disruption. Panax notoginseng saponins (PNS) possess efficient antioxidant activity and have been used in the treatment of cerebral ischemic stroke in China. In this study, we determined the protective effects of PNS on BBB integrity and investigated the underlying mechanism in cerebral microvascular endothelial cells (bEnd.3) exposed to oxygen-glucose deprivation/reperfusion (OGD/R). MTT and LDH release assays revealed that PNS mitigated the OGD/R-induced cell injury in a dose-dependent manner. TEER and paracellular permeability assays demonstrated that PNS alleviated the OGD/R-caused disruption of BBB integrity. Fluorescence probe DCFH-DA showed that PNS suppressed ROS generation in OGD/R-treated cells. Immunofluorescence and western blot analysis indicated that PNS inhibited the degradation of tight junction proteins triggered by OGD/R. Moreover, mechanism investigations suggested that PNS increased the phosphorylation of Akt, the activity of nuclear Nrf2, and the expression of downstream antioxidant enzyme HO-1. All the effects of PNS could be reversed by co-treatment with PI3K inhibitor LY294002. Taken together, these observations suggest that PNS may act as an extrinsic regulator that activates Nrf2 antioxidant signaling depending on PI3K/Akt pathway and protects against OGD/R-induced BBB disruption in vitro.

Highlights

IntroductionAcute ischemic stroke, resulting from arterial occlusion in the brain, makes up more than 80% of all the cases [1,2]
Stroke is one of the leading causes of adult death and long-term disability worldwide.Acute ischemic stroke, resulting from arterial occlusion in the brain, makes up more than 80% of all the cases [1,2]
These observations suggest that Panax notoginseng saponins (PNS) may act as an extrinsic regulator that activates Nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant signaling depending on PI3K/Akt pathway and protects against Oxygen-Glucose Deprivation/Reperfusion (OGD/R)-induced blood-brain barrier (BBB) disruption in vitro

Summary

Introduction

Acute ischemic stroke, resulting from arterial occlusion in the brain, makes up more than 80% of all the cases [1,2]. The cerebral ischemia and reperfusion with thrombolysis treatment may result in serious brain injury, such as intracerebral hemorrhagic transformation (HT), with complex pathological mechanisms, and partially due to the oxidative stress and disruption of the BBB [2,4]. BBB is mainly comprised of cerebral microvascular endothelial cells, pericytes, and astrocytic end-feet, together with the noncellular basement membranes (BMs) that surround and separate these cellular constituents from one another [6]. The core component of BBB, are connected by tight junction proteins (TJs), forming the integrated interface with high transendothelial electrical resistance (TEER)

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