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GKT136901 protects primary human brain microvascular endothelial cells against methamphetamine-induced blood-brain barrier dysfunction

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Author(s)
하은영서지혜
Alternative Author(s)
Ha, Eun YoungSeo, Ji Hye
Issued Date
2020
Keyword
Blood-brain barrierGKT136901Human brain microvascular endothelial cellsMethamphetamineNOX1/4Reactive oxygen species (ROS)
Abstract
Aims:
Methamphetamine (METH) is an abused psychostimulant causing public health concern worldwide. While most studies have focused on the neurotoxic effects of METH, METH-induced cerebrovascular dysfunction has recently drawn attention as an important facet of METH-related pathophysiology. In this study, we investigated the protective role of GKT136901, a NOX1/4 inhibitor, against METH-induced blood-brain barrier (BBB) dysfunction.

Main methods:
Primary human brain microvascular endothelial cells (HBMECs) were used as an in vitro BBB model. HBMECs were treated with GKT136901, followed by METH exposure for 24 h. The generation of reactive oxidative species (ROS) was measured using 2',7'-dichlorofluorescin diacetate (DCF-DA) staining. To examine the BBB function, paracellular permeability of HBMEC monolayer was measured using FITC-labeled dextran. To evaluate structural properties of BBB in HBMECs, tight junction (TJ), adherent junction (AJ), and cytoskeletal proteins were stained and analyzed by confocal microscopy.

Key findings:
METH treatment rapidly increased ROS generation in HBMECs but GKT136901 treatment inhibited METH-induced ROS generation. Although METH increased the permeability of HBMEC monolayer, this effect was abolished upon GKT136901 treatment. Following METH exposure, the proteins Zonula occludens-1 (ZO-1) and vascular endothelial cadherin (VE-cadherin) were translocalized from the cell membrane to the cytoplasm, thereby destroying intercellular tight junction (TJ) and adherent junction (AJ) structures, which were ameliorated upon GKT136901 treatment. METH exposure altered the cellular morphology of HBMECs and induced stress fiber formation. However, GKT136901 prevented METH-induced morphological and cytoskeletal changes in HBMECs.

Significance:
These results suggest that GKT136901 prevents METH-induced BBB dysfunction in HBMECs through the inhibition of ROS generation.
Department
Dept. of Biochemistry (생화학)
Publisher
School of Medicine (의과대학)
Citation
Jong Su Hwang. (2020). GKT136901 protects primary human brain microvascular endothelial cells against methamphetamine-induced blood-brain barrier dysfunction. Life sciences, 256, 117917-. doi: 10.1016/j.lfs.2020.117917
Type
Article
ISSN
1879-0631
DOI
10.1016/j.lfs.2020.117917
URI
http://kumel.medlib.dsmc.or.kr/handle/2015.oak/43233
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Biochemistry (생화학)
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