Abstract
The specialized brain endothelial cells interconnected by unique junctions and adhesion molecules are distinctive features of the blood–brain barrier (BBB), maintaining the homeostasis of the cerebral microenvironment. This study was designed to investigate the protective effects of melatonin on methamphetamine (METH)-induced alterations of BBB integrity. Wistar rats were randomly distributed into groups and underwent melatonin pretreatment and escalating-high doses of METH treatment. Immunohistochemistry was performed to demonstrate the BBB leakage. Protein and RNA samples were isolated from hippocampal and prefrontal cortical tissues and measured expression levels of molecular markers associated with BBB structural components and inflammatory processes. METH provoked the loss of zonula occludens (ZO)-1, occludin, and claudin-5 tight junction proteins. Furthermore, METH caused an excessive increase in matrix metalloproteinase-9 (MMP-9) enzyme, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) and the increase in NAD(P)H oxidase 2 (NOX2). Melatonin exerted the protective effects by recovering tight junction loss; attenuating excessive MMP-9, NOX2, and cell adhesion molecule expression; and reducing serum albumin in the brain. Our results also showed the protective effects of melatonin against METH neurotoxic profiles, characterized by reactive gliosis: microglia (integrin-αM) and astrocyte (GFAP); an excessive upregulation of primary pro-inflammatory cytokines: interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α); activation of neuroinflammatory signaling: nuclear factor-kappa B (NF-κB); and suppression of anti-oxidative signaling: nuclear factor erythroid 2-related factor (Nrf2), that may exacerbate BBB structural impairment. Our results provide insights into the beneficial effects of melatonin against METH-induced BBB disruption and mechanisms that play detrimental roles in BBB impairment by in vivo design.
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The research study was supported by the Thailand Research Fund (DPG 5780001), Mahidol University, and Chulabhorn Graduate Institute to PG.
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All authors contributed toward the original idea. JN, KP, and CN performed experiments and data analyses. JN drafted the manuscript, and CN and PG revised the paper. The final draft of manuscript was read and approved by all authors.
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All procedures performed in this study involving animals were in accordance with Mahidol University guidelines for the care and use of laboratory animals. All the protocols were approved by the Institutional Animal Care and Use Committee of Mahidol University (MU-IACUC; COA. NO. IMB-ACUC 2017/009).
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Namyen, J., Permpoonputtana, K., Nopparat, C. et al. Protective Effects of Melatonin on Methamphetamine-Induced Blood–Brain Barrier Dysfunction in Rat Model. Neurotox Res 37, 640–660 (2020). https://doi.org/10.1007/s12640-019-00156-1
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DOI: https://doi.org/10.1007/s12640-019-00156-1