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      The Traditional Chinese Medicine Compound, GRS, Alleviates Blood–Brain Barrier Dysfunction

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          Abstract

          Introduction

          Traditional Chinese medicine (TCM) provides unique advantages for treatment of ischemic stroke, an aging-related vascular disease. Shengmai powder (GRS) is composed of three active components, specifically, ginsenoside Rb1, ruscogenin and schisandrin A, at a ratio of 6:0.75:6. The main objective of this study was to evaluate the effects of GRS on blood–brain barrier (BBB) dysfunction under conditions of middle cerebral artery occlusion/reperfusion (MCAO/R).

          Methods

          C57BL/6J mice subjected to MCAO/R were used as a model to assess the protective effects of varying doses of GRS (6.4, 12.8, and 19.2 mg/kg) on BBB dysfunction.

          Results

          GRS reduced cerebral infarct volume and degree of brain tissue damage, improved behavioral scores, decreased water content and BBB permeability, and restored cerebral blood flow. Moreover, GRS promoted expression of zona occludens-1 (ZO-1) and claudin-5 while inhibiting matrix metalloproteinase 2/9 (MMP-2/9) expression and myosin light chain (MLC) phosphorylation. In vitro, GRS (1, 10, and 100 ng/mL) enhanced the viability of bEnd.3 cells subjected to oxygen glucose deprivation/reoxygenation (OGD/R) and decreased sodium fluorescein permeability.

          Conclusion

          Consistent with in vivo findings, ZO-1 and claudin-5 were significantly upregulated by GRS in bEnd.3 cells under OGD/R and MMP-2/9 levels and MLC phosphorylation reduced through the Rho-associated coil-forming protein kinase (ROCK)/cofilin signaling pathway. Based on the collective findings, we propose that the TCM compound, GRS, plays a protective role against I/R-induced BBB dysfunction.

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          Most cited references 37

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          Regulation of Myosin Phosphatase by Rho and Rho-Associated Kinase (Rho-Kinase)

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            Permeability studies on in vitro blood-brain barrier models: physiology, pathology, and pharmacology.

            (1) The specifically regulated restrictive permeability barrier to cells and molecules is the most important feature of the blood-brain barrier (BBB). The aim of this review was to summarize permeability data obtained on in vitro BBB models by measurement of transendothelial electrical resistance and by calculation of permeability coefficients for paracellular or transendothelial tracers. (2) Results from primary cultures of cerebral microvascular endothelial cells or immortalized cell lines from bovine, human, porcine, and rodent origin are presented. Effects of coculture with astroglia, neurons, mesenchymal cells, blood cells, and conditioned media, as well as physiological influence of serum components, hormones, growth factors, lipids, and lipoproteins on the barrier function are discussed. (3) BBB permeability results gained on in vitro models of pathological conditions including hypoxia and reoxygenation, neurodegenerative diseases, or bacterial and viral infections have been reviewed. Effects of cytokines, vasoactive mediators, and other pathogenic factors on barrier integrity are also detailed. (4) Pharmacological treatments modulating intracellular cyclic nucleotide or calcium levels, and activity of protein kinases, protein tyrosine phosphatases, phospholipases, cyclooxygenases, or lipoxygenases able to change BBB integrity are outlined. Barrier regulation by drugs involved in the metabolism of nitric oxide and reactive oxygen species, as well as influence of miscellaneous treatments are also listed and evaluated. (5) Though recent advances resulted in development of improved in vitro BBB model systems to investigate disease modeling, drug screening, and testing vectors targeting the brain, there is a need for checking validity of permeability models and cautious interpretation of data.
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              Architecture of tight junctions and principles of molecular composition.

              The tight junction creates an intercellular barrier limiting paracellular movement of solutes and material across epithelia. Currently many proteins have been identified as components of the tight junction and understanding their architectural organization and interactions is critical to understanding the biology of the barrier. In general the architecture can be conceptualized into compartments with the transmembrane barrier proteins (claudins, occludin, JAM-A, etc.), linked to peripheral scaffolding proteins (such as ZO-1, afadin, MAGI1, etc.) which are in turned linked to actin and microtubules through numerous linkers (cingulin, myosins, protein 4.1, etc.). Within this complex network are associated many signaling proteins that affect the barrier and broader cell functions. The PDZ domain is a commonly used motif to specifically link individual junction protein pairs. Here we review some of the key proteins defining the tight junction and general themes of their organization with the perspective that much will be learned about function by characterizing the detailed architecture and subcompartments within the junction. Published by Elsevier Ltd.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                28 February 2020
                2020
                : 14
                : 933-947
                Affiliations
                [1 ]Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University , Nanjing, People’s Republic of China
                Author notes
                Correspondence: Boyang Yu; Junping Kou Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University , Nanjing211198, People’s Republic of ChinaTel +86 25-86185157Fax +86 25-86185158 Email boyangyu59@163.com; junpingkou@cpu.edu.cn
                Article
                229302
                10.2147/DDDT.S229302
                7053822
                © 2020 Zhang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 7, References: 49, Pages: 15
                Categories
                Original Research

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