Generic placeholder image

Current Neurovascular Research


ISSN (Print): 1567-2026
ISSN (Online): 1875-5739

Research Article

The Effect of Dexamethasone on Lipopolysaccharide-induced Inflammation of Endothelial Cells of the Blood-brain Barrier/Brain Capillaries

Author(s): Tershlin Jeftha, Khayelihle Brian Makhathini and David Fisher*

Volume 20, Issue 3, 2023

Published on: 18 August, 2023

Page: [334 - 345] Pages: 12

DOI: 10.2174/1567202620666230703145707

Price: $65


Background: A protective and regulatory barrier between the blood and the brain is constituted by the blood-brain barrier (BBB), which comprises microvascular endothelial cells providing homeostatic regulation of the central nervous system (CNS). Inflammation compromises the BBB and contributes to many CNS disorders. Anti-inflammatory effects are exerted by glucocorticoids (GCs) on a variety of cells. These GCs include dexamethasone (Dex), which is used for the treatment of inflammatory diseases and recently for the treatment of COVID-19.

Aim: The purpose of this study was to determine whether low or high concentrations of Dex can attenuate the inflammatory response induced by lipopolysaccharide (LPS) in the in vitro BBB model.

Methods: Brain endothelial cells (bEnd.5) were cultured and exposed to LPS (100ng/ml) and subsequently co-treated with Dex to investigate whether selected concentrations of Dex (0.1, 5, 10, 20μM) can modulate the inflammatory effects of LPS on bEnd.5 cells. Cell viability, cell toxicity, and cell proliferation were investigated, as well as the monitoring of membrane permeability (Trans Endothelial Electrical Resistance-TEER), and Enzyme-Linked Immune Assay (ELISA) kits were used to identify and quantify the presence of inflammatory cytokines (TNF-α and IL-1β).

Results: Dex, at a lower dosage (0.1μM, but not higher doses), was able to attenuate the inflammatory effects of LPS on bEnd.5 cells. Lower doses of Dex (0.1μM) had no detrimental effects on bEnd.5 cells, while higher Dex doses (5-20μM) decreased bEnd.5 viability, increased bEnd.5 cell toxicity, increased bEnd.5 cell monolayer permeability, and increased proinflammatory cytokine secretion.

Conclusion: These results indicate that treatment of brain vascular inflammation with low doses of Dex should be advocated, while higher doses promote vascular inflammation.

Keywords: Blood-brain barrier, inflammation, tight junctions, permeability, integrity, central nervous system.

Abbott NJ, Rönnbäck L, Hansson E. Astrocyte–endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 2006; 7(1): 41-53.
[] [PMID: 16371949]
Markowicz-Piasecka M, Markiewicz A. Darłak P, et al. Current chemical, biological, and physiological views in the development of successful brain-targeted pharmaceutics. Neurotherapeutics 2022; 19(3): 942-76.
[] [PMID: 35391662]
Kelleher RJ, Soiza RL. Evidence of endothelial dysfunction in the development of Alzheimer’s disease: Is Alzheimer’s a vascular disorder? Am J Cardiovasc Dis 2013; 3(4): 197-226.
[PMID: 24224133]
Pohl D, Benseler S. Systemic inflammatory and autoimmune disorders. Handb Clin Neurol 2013; 112: 1243-52.
[] [PMID: 23622335]
Thomas J, Thomas CJ, Radcliffe J, Itsiopoulos C. Omega-3 fatty acids in early prevention of inflammatory neurodegenerative disease: a focus on alzheimer’s disease. BioMed Res Int 2015; 2015: 172801.
Baeten KM, Akassoglou K. Extracellular matrix and matrix receptors in blood-brain barrier formation and stroke. Dev Neurobiol 2011; 71(11): 1018-39.
[] [PMID: 21780303]
Straub RH. The brain and immune system prompt energy shortage in chronic inflammation and ageing. Nat Rev Rheumatol 2017; 13(12): 743-51.
[] [PMID: 29021568]
Lukiw WJ, Pogue A, Hill JM. SARS-CoV-2 infectivity and neurological targets in the brain. Cell Mol Neurobiol 2022; 42(1): 217-24.
[] [PMID: 32840758]
Giles AJ, Hutchinson MKND, Sonnemann HM, et al. Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy. J Immunother Cancer 2018; 6(1): 51.
[] [PMID: 29891009]
Theoharides TC, Conti P. Dexamethasone for COVID-19? Not so fast. J Biol Regul Homeost Agents 2020; 34(3): 1241-3.
[PMID: 32551464]
Lammers T, Sofias AM, van der Meel R, et al. Dexamethasone nanomedicines for COVID-19. Nat Nanotechnol 2020; 15(8): 622-4.
[] [PMID: 32747742]
McMahon D, Oakden W, Hynynen K. Investigating the effects of dexamethasone on blood-brain barrier permeability and inflammatory response following focused ultrasound and microbubble exposure. Theranostics 2020; 10(4): 1604-18.
[] [PMID: 32042325]
Zhou HQ, Zhang M, Li X, Huang Z. Crosstalk between autophagy and inflammation in chronic cerebral ischaemia. Cell Mol Neurobiol 2023; 2023: 1-10.
Badshah H, Ali T, Rehman S, et al. Protective effect of lupeol against lipopolysaccharide-induced neuroinflammation via the p38/c-jun n-terminal kinase pathway in the adult mouse brain. J Neuroimmune Pharmacol 2016; 11(1): 48-60.
[] [PMID: 26139594]
Okun E, Griffioen KJ, Mattson MP. Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci 2011; 34(5): 269-81.
[] [PMID: 21419501]
Gárate I, García-Bueno B, Madrigal JLM, et al. Toll-like 4 receptor inhibitor TAK-242 decreases neuroinflammation in rat brain frontal cortex after stress. J Neuroinflammation 2014; 11(1): 8.
[] [PMID: 24410883]
Sambamurti K, Kinsey R, Maloney B, Ge YW, Lahiri DK. Gene structure and organization of the human β‐secretase (BACE) promoter. FASEB J 2004; 18(9): 1034-6.
[] [PMID: 15059975]
van den Boogaard M, Ramakers BP, van Alfen N, et al. Endotoxemia-induced inflammation and the effect on the human brain. Crit Care 2010; 14(3): R81.
[] [PMID: 20444270]
Brandenburg LO, Kipp M, Lucius R, Pufe T, Wruck CJ. Sulforaphane suppresses LPS-induced inflammation in primary rat microglia. Inflamm Res 2010; 59(6): 443-50.
[] [PMID: 19924513]
Li T, Zheng LN, Han XH. Fenretinide attenuates lipopolysaccharide (LPS)-induced blood-brain barrier (BBB) and depressive-like behavior in mice by targeting Nrf-2 signaling. Biomed Pharmacother 2020; 125: 109680.
[] [PMID: 32106372]
Seemann S, Zohles F, Lupp A. Comprehensive comparison of three different animal models for systemic inflammation. J Biomed Sci 2017; 24(1): 60.
[] [PMID: 28836970]
Young GB. Encephalopathy of infection and systemic inflammation. J Clin Neurophysiol 2013; 30(5): 454-61.
[] [PMID: 24084178]
Jaishankar M, Tseten T, Anbalagan N, Mathew BB, Beeregowda KN. Toxicity, mechanism and health effects of some heavy metals. Interdiscip Toxicol 2014; 7(2): 60-72.
[] [PMID: 26109881]
Wyss-Coray T. Ageing, neurodegeneration and brain rejuvenation. Nature 2016; 539(7628): 180-6.
[] [PMID: 27830812]
Chesnokova V, Pechnick RN, Wawrowsky K. Chronic peripheral inflammation, hippocampal neurogenesis, and behavior. Brain Behav Immun 2016; 58: 1-8.
[] [PMID: 26802985]
Tietz S, Engelhardt B. Brain barriers: Crosstalk between complex tight junctions and adherens junctions. J Cell Biol 2015; 209(4): 493-506.
[] [PMID: 26008742]
Rhea EM, Banks WA. Role of the blood-brain barrier in central nervous system insulin resistance. Front Neurosci 2019; 13(JUN): 521.
[] [PMID: 31213970]
Tucureanu MM, Rebleanu D, Constantinescu CA, et al. Lipopolysaccharide-induced inflammation in monocytes/macrophages is blocked by liposomal delivery of Gi-protein inhibitor. Int J Nanomedicine 2017; 13: 63-76.
[] [PMID: 29317816]
Li JC, Wang S, Wang HC, et al. Dexamethasone affects the chemotaxis and phagocytic activity of neutrophils for boar spermatozoa and the quality of liquid preserved boar semen in vitro. Theriogenology 2023; 195: 46-54.
[] [PMID: 36283226]
Huang Z, Kraus VB. Does lipopolysaccharide-mediated inflammation have a role in OA? Nat Rev Rheumatol 2016; 12(2): 123-9.
[] [PMID: 26656661]
Dauphinee SM, Karsan A. Lipopolysaccharide signaling in endothelial cells. Lab Invest 2006; 86(1): 9-22.
[] [PMID: 16357866]
Yasir M, Goyal A, Sonthalia S. Corticosteroid Adverse Effects. Treasure Island, FL. StatPearls Publishing 2022.
[PMID: 30285357]
Hübner M, Hochhaus G, Derendorf H. Comparative pharmacology, bioavailability, pharmacokinetics, and pharmacodynamics of inhaled glucocorticosteroids. Immunol Allergy Clin North Am 2005; 25(3): 469-88.
[] [PMID: 16054538]
Brandt M, Gerke V, Betz T. Human endothelial cells display a rapid tensional stress increase in response to tumor necrosis factor-α. PLoS One 2022; 17(6): e0270197.
[] [PMID: 35749538]
Suprewicz Ł, Fiedoruk K, Czarnowska A, et al. Blood-brain barrier function in response to SARS-CoV-2 and its spike protein. Neurol Neurochir Pol 2023; 57(1): 14-25.
[] [PMID: 36810757]
Kircheis R, Planz O. The role of toll-like receptors (TLRs) and their related signaling pathways in viral infection and inflammation. Int J Mol Sci 2023; 24(7): 6701.
[] [PMID: 37047674]
Asif S, Frithiof R, Larsson A, et al. Immuno-modulatory effects of dexamethasone in severe COVID-19-A swedish cohort study. Biomedicines 2023; 11(1): 164.
[] [PMID: 36672672]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy