PBN inhibits a detrimental effect of methamphetamine on brain endothelial cells by alleviating the generation of reactiv
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Online ISSN 1976-3786 Print ISSN 0253-6269
RESEARCH ARTICLE
PBN inhibits a detrimental effect of methamphetamine on brain endothelial cells by alleviating the generation of reactive oxygen species Jong Su Hwang1 · Eun Hye Cha1 · Byoungduck Park2 · Eunyoung Ha1 · Ji Hae Seo1
Received: 31 August 2020 / Accepted: 4 November 2020 / Published online: 16 November 2020 © The Pharmaceutical Society of Korea 2020
Abstract Methamphetamine (METH) is a powerful psychostimulant that is causing serious health problems worldwide owing to imprudent abuses. Recent studies have suggested that METH has deleterious effects on the blood–brain barrier (BBB). A few studies have also been conducted on the mechanisms whereby METH-induced oxidative stress causes BBB dysfunction. We investigated whether N-tertbutyl-α-phenylnitrone (PBN) has protective effects on BBB function against METH exposure in primary human brain microvascular endothelial cells (HBMECs). We found that METH significantly increased reactive oxygen species (ROS) generation in HBMECs. Pretreatment with PBN decreased METH-induced ROS production. With regard to BBB functional integrity, METH exposure elevated the paracellular permeability and reduced the monolayer integrity; PBN treatment reversed these effects. An analysis of the BBB structural properties, by immunostaining junction proteins and cytoskeleton in HBMECs, indicated that METH treatment changed the cellular localization of the tight (ZO-1) and adherens junctions (VE-cadherin) from the membrane to cytoplasm. Furthermore, METH induced cytoskeletal reorganization via the formation of robust stress fibers. METH-induced junctional protein redistribution and cytoskeletal reorganization were attenuated by PBN treatment. Our results suggest that PBN can act as a therapeutic
* Eunyoung Ha [email protected] * Ji Hae Seo [email protected] 1
Department of Biochemistry, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea
2
College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea
reagent for METH-induced BBB dysfunction by inhibiting excess ROS generation. Keywords Blood–brain barrier · Methamphetamine · N-tert-butyl-α-phenylnitrone · Reactive oxygen species
Introduction Methamphetamine (METH) is one of the most addictive psychostimulants that is abused worldwide for its euphoric effects (Seo et al. 2020). The acute and chronic use of METH is associated with neuropsychiatric disorders as a consequence of neurotoxicity in the dopaminergic and serotonergic neurons in the striatum, hippocampus, and prefrontal cortex (Gold et al. 2009; Yu et al. 2015). In addition, METH-mediated neurotoxicity causes neuro-inflammation via the activation of microglia and astrocytes, leading to cerebrovascular dysfunction (Krasnova and Cadet 2009; Sajja et al. 2016). Several reports state that METH exposure contributes to vascular dysfunction in cardio- and cerebrovessels (Natarajan et al. 2018; Kevil et al. 2019). The blood–brain barrier (BBB) is a critical border that maintains the homeostasis
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