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Selegiline Protects Against Lipopolysaccharide (LPS)–Induced Impairment of the Blood–Brain Barrier Through Regulating the NF-κB/MLCK/p-MLC Signaling Pathway

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Abstract

Disruption of the blood–brain barrier (BBB) is an important hallmark of sepsis-associated encephalopathy (SAE). Selegiline, a selective and irreversible inhibitor of monoamine oxidase type B, has been applied for the treatment of nervous disorders. In this study, we aimed to investigate whether selegiline has a protective capacity in the impairment of the BBB in both in vivo and in vitro experiments. In a sepsis mouse model, administration of selegiline ameliorated lipopolysaccharide (LPS)–induced impairment of BBB integrity. Additionally, treatment with selegiline increased the expression of the tight junction protein junctional adhesion molecule A (JAM-A) against LPS. Also, we found that selegiline inhibited the production of the proinflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-1β. In an in vitro experimental model, bEnd.3 brain endothelial cells were exposed to LPS. Results indicate that stimulation with LPS significantly increased the permeability of bEnd.3 cells and reduced the expression of JAM-A, both of which were rescued by treatment with selegiline. Additionally, selegiline prevented the activation of the NF-κB/MLCK/p-MLC signaling pathway in LPS-challenged bEnd.3 cells. These results indicate that selegiline exerted a protective effect on BBB dysfunction, which might be attributed to the inhibition of the NF-κB/MLCK/p-MLC signaling pathway. These findings provide a basis for further research into the neuroprotective mechanism of selegiline.

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Data Availability

The data and materials of this study are available upon reasonable request from the corresponding authors.

References

  • Abbott NJ, Patabendige AA, Dolman DE et al (2010) Structure and function of the blood-brain barrier. Neurobiol Dis 37:13–25

    Article  CAS  Google Scholar 

  • Afonina IS, Zhong Z, Karin M et al (2017) Limiting inflammation-the negative regulation of NF-kappaB and the NLRP3 inflammasome. Nat Immunol 18:861–869

    Article  CAS  Google Scholar 

  • Berndt P, Winkler L, Cording J et al (2019) Tight junction proteins at the blood-brain barrier: far more than claudin-5. Cell Mol Life Sci 76:1987–2002

    Article  CAS  Google Scholar 

  • Birks J, Flicker L (2000) Selegiline for Alzheimer’s disease. Cochrane Database Syst Rev 2000:CD000442

  • Cui Y, Liu KWK, Ip MSM et al (2020) Protective effect of selegiline on cigarette smoke-induced oxidative stress and inflammation in rat lungs in vivo. Ann Transl Med 8:1418

    Article  CAS  Google Scholar 

  • Cui Y, Liu KWK, Liang Y et al (2017) Inhibition of monoamine oxidase-B by selegiline reduces cigarette smoke-induced oxidative stress and inflammation in airway epithelial cells. Toxicol Lett 268:44–50

    Article  CAS  Google Scholar 

  • Fabbrini G, Abbruzzese G, Marconi S et al (2012) Selegiline: a reappraisal of its role in Parkinson disease. Clin Neuropharmaco 35:134–140

    Article  CAS  Google Scholar 

  • Greene C, Campbell M (2016) Tight junction modulation of the blood brain barrier: CNS delivery of small molecules. Tissue Barriers 4:e1138017

  • Gu M, Mei XL, Zhao YN (2021) Sepsis and cerebral dysfunction: BBB damage, neuroinflammation, oxidative stress, apoptosis and autophagy as key mediators and the potential therapeutic approaches. Neurotox Res 39:489–503

    Article  CAS  Google Scholar 

  • Gao Q, Hernandes MS (2021) Sepsis-associated encephalopathy and blood-brain barrier dysfunction. Inflammation. https://doi.org/10.1007/s10753-021-01501-3

    Article  PubMed  Google Scholar 

  • Gotts JE, Matthay MA (2016) Sepsis: pathophysiology and clinical management. BMJ 353:i1585

  • Guo S, Chen S, Ma J et al (2019) Escherichia coli Nissle 1917 protects intestinal barrier function by inhibiting NF-kappaB-mediated activation of the MLCK-P-MLC signaling pathway. Mediators Inflamm 2019:5796491

    PubMed  PubMed Central  Google Scholar 

  • Haseloff RF, Dithmer S, Winkler L et al (2015) Transmembrane proteins of the tight junctions at the blood-brain barrier: structural and functional aspects. Semin Cell Dev Biol 38:16–25

    Article  CAS  Google Scholar 

  • Huang M, Cai S, Su J (2019) The pathogenesis of sepsis and potential therapeutic targets. Int J Mol Sci 20:5376

    Article  CAS  Google Scholar 

  • Hu S, Wu Y, Zhao B et al (2018) Panax notoginseng saponins protect cerebral microvascular endothelial cells against oxygen-glucose deprivation/reperfusion-induced barrier dysfunction via activation of PI3K/Akt/Nrf2 antioxidant signaling pathway. Molecules 23:2781

    Article  Google Scholar 

  • Haarmann A, Deiss A, Prochaska J et al (2010) Evaluation of soluble junctional adhesion molecule-A as a biomarker of human brain endothelial barrier breakdown. PLoS One 5:e13568

  • Kaya M, Ahishali B (2011) Assessment of permeability in barrier type of endothelium in brain using tracers: Evans blue, sodium fluorescein, and horseradish peroxidase. Methods Mol Biol 763:369–382

    Article  CAS  Google Scholar 

  • Kim Y, Lee S, Zhang H et al (2020) CLEC14A deficiency exacerbates neuronal loss by increasing blood-brain barrier permeability and inflammation. J Neuroinflammation 17:48

    Article  CAS  Google Scholar 

  • Monteiro AC, Parkos CA (2012) Intracellular mediators of JAM-A-dependent epithelial barrier function. Ann N Y Acad Sci 1257:115–124

    Article  CAS  Google Scholar 

  • Nwafor DC, Brichacek AL, Mohammad AS et al (2019) Targeting the blood-brain barrier to prevent sepsis-associated cognitive impairment. J Cent Nerv Syst Dis 11:1179573519840652

    Article  Google Scholar 

  • Salomao R, Ferreira BL, Salomão MC et al (2019) Sepsis: evolving concepts and challenges. Braz J Med Biol Res 52:e8595

  • Saia RS, Ribeiro AB, Giusti H (2020) Cholecystokinin modulates the mucosal inflammatory response and prevents the lipopolysaccharide-induced intestinal epithelial barrier dysfunction. Shock 53:242–251

    Article  CAS  Google Scholar 

  • Shawki A, McCole DF (2017) Mechanisms of intestinal epithelial barrier dysfunction by adherent-invasive Escherichia coli. Cell Mol Gastroenterol Hepatol 3:41–50

    Article  Google Scholar 

  • Tabi T, Vécsei L, Youdim MB et al (2020) Selegiline: a molecule with innovative potential. J Neural Transm (vienna) 127:831–842

    Article  Google Scholar 

  • Tsao CM, Jhang JG, Chen SJ et al (2014) Adjuvant potential of selegiline in attenuating organ dysfunction in septic rats with peritonitis. PLoS One 9:e108455

  • Vetrano S, Ploplis VA, Sala E et al (2011) Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation. Proc Natl Acad Sci U S A 108:19830–19835

    Article  CAS  Google Scholar 

  • Xia W, Pan Z, Zhang H et al (2020) Inhibition of ERRalpha aggravates sepsis-induced acute lung injury in rats via provoking inflammation and oxidative stress. Oxid Med Cell Longev 2020:2048632

    PubMed  PubMed Central  Google Scholar 

  • Yang Q, Yu J, Qin H et al (2021) Irbesartan suppresses lipopolysaccharide (LPS)-induced blood-brain barrier (BBB) dysfunction by inhibiting the activation of MLCK/MLC. Int Immunopharmacol 98:107834

  • Ye X, Sun M (2017) AGR2 ameliorates tumor necrosis factor-alpha-induced epithelial barrier dysfunction via suppression of NF-kappaB p65-mediated MLCK/p-MLC pathway activation. Int J Mol Med 39:1206–1214

    Article  CAS  Google Scholar 

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Acknowledgements

The authors would like to express our appreciation to “Shanghai University of Traditional Chinese Medicine”.

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Authors and Affiliations

  1. Department of Emergency Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, No.110 Ganhe Road, Hongkou District, Shanghai, 200437, China

    Yuehong Pu, Fenghua Qian, Jian Guo, Yuanyuan Sha & Yiming Qian

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  1. Yuehong Pu
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  2. Fenghua Qian
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  3. Jian Guo
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  4. Yuanyuan Sha
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  5. Yiming Qian
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Contributions

Yuehong Pu and Yiming Qian guaranteed the integrity of the entire study; Yuehong Pu, Fenghua Qian, Jian Guo, and Yuanyuan Sha contributed to experimental investigation and data collection; Yuehong Pu went on literature research; Yiming Qian was responsible for manuscript preparation and review. All the authors have read and agreed with the submission of the manuscript.

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Correspondence to Yiming Qian.

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I confirm that all the research meets ethical guidelines and adheres to the legal requirements of the study country. Protocols of animal experiments were approved by the Ethical Committee of Shanghai University of Traditional Chinese Medicine.

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Pu, Y., Qian, F., Guo, J. et al. Selegiline Protects Against Lipopolysaccharide (LPS)–Induced Impairment of the Blood–Brain Barrier Through Regulating the NF-κB/MLCK/p-MLC Signaling Pathway. Neurotox Res 40, 267–275 (2022). https://doi.org/10.1007/s12640-021-00448-5

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  • DOI: https://doi.org/10.1007/s12640-021-00448-5

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