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PBN inhibits a detrimental effect of methamphetamine on brain endothelial cells by alleviating the generation of reactive oxygen species


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-tert-butyl-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 reagent for METH-induced BBB dysfunction by inhibiting excess ROS generation.

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This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2016R1A6A1A03011325) and the Korean Government (MSIT) (NRF-2019R1C1C1005855, NRF-2018R1A2B6006175).

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Correspondence to Eunyoung Ha or Ji Hae Seo.

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Hwang, J.S., Cha, E.H., Park, B. et al. PBN inhibits a detrimental effect of methamphetamine on brain endothelial cells by alleviating the generation of reactive oxygen species. Arch. Pharm. Res. 43, 1347–1355 (2020).

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