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Research Paper

Protecting effect of emodin in experimental autoimmune encephalomyelitis mice by inhibiting microglia activation and inflammation via Myd88/PI3K/Akt/NF-κB signalling pathway

, , , , , , , & ORCID Icon show all
Pages 9322-9344 | Received 14 Dec 2021, Accepted 09 Mar 2022, Published online: 07 Apr 2022

References

  • Magyari M, Sorensen PS. The changing course of multiple sclerosis: rising incidence, change in geographic distribution, disease course, and prognosis.Curr Opin Neurol. 2019;324:320–326.
  • Berglund R, Guerreiro-Cacais AO, Adzemovic MZ, et al. Microglial autophagy–associated phagocytosis is essential for recovery from neuroinflammation. Sci Immunol. 2020;5(52):eabb5077. Accessed 2020 Oct 16: Available from
  • Lassmann H, Bradl M. Multiple sclerosis: experimental models and reality. Acta Neuropathol. 2017;133:223–244.
  • Qiu X, Guo Q, Liu X, et al. Pien Tze Huang alleviates relapsing-remitting experimental autoimmune encephalomyelitis mice by regulating Th1 and Th17 cells. Front Pharmacol. 2018;9:1–10.
  • Nakazato Y, Fujita Y, Nakazato M, et al. Neurons promote encephalitogenic CD4+ lymphocyte infiltration in experimental autoimmune encephalomyelitis. Sci Rep [Internet]. 2020;10(1) :7354. Accessed: 30 Apr 2020.
  • Mandolesi G, de Vito F, Musella A, et al. MiR-142-3p is a key regulator of IL-1β-dependent synaptopathy in neuroinflammation. J Neurosci. 2017;37 (3) :546–561.
  • Liu B, Gu Y, Pei S, et al. Interleukin-1 receptor associated kinase (IRAK)-M -mediated type 2 microglia polarization ameliorates the severity of experimental autoimmune encephalomyelitis (EAE). J Autoimmunity. 2019;102:77–88.
  • Rahimifard M, Maqbool F, Moeini-Nodeh S, et al. Targeting the TLR4 signaling pathway by polyphenols: a novel therapeutic strategy for neuroinflammation. Ageing Res Rev. 2017;36:11–19.
  • Tarassishin L, Suh HS, Lee SC. Interferon regulatory factor 3 plays an anti-inflammatory role in microglia by activating the PI3K/Akt pathway.J Neuroinflammation. 2011;8:187.
  • Datler H, Vogel A, Kerndl M, et al. PI3K activity in dendritic cells exerts paradoxical effects during autoimmune inflammation. Mol Immunol. 2019;111:32–42.
  • Montalban X, Gold R, Thompson AJ, et al. ECTRIMS/EAECTRIMS / EAN guideline on the pharmacological treatment of people with multiple sclerosis. Eur J Neurol. 2018;25 (2) :215–237.
  • Mpmchgad R-G. Diagnosis and treatment of multiple sclerosis a review. JAMA. 2021;325 (8) :765–779.
  • Obradović MMS, Hamelin B, Manevski N, et al. Glucocorticoids promote breast cancer metastasis. Nature. 2019;567 (7749) :540–544.
  • Prete A, Bancos I. Glucocorticoid induced adrenal insufficiency. BMJ. 2021;374:1–20.
  • Y CUI, Chen LJ, Huang T, et al. The pharmacology, toxicology and therapeutic potential of anthraquinone derivative emodin. Chin J Nat Med. 2020;18 (6) :425–435. Available from.
  • Shrimali D, Shanmugam MK, Kumar AP, et al. Targeted abrogation of diverse signal transduction cascades by emodin for the treatment of inflammatory disorders and cancer. Cancer Lett. 2013;341 (2) :139–149. Available from.
  • Hopkins AL. Network pharmacology: the next paradigm in drug discovery.Nat Chem Biol. 2008;4 (11) :682–690.
  • Zhang R, Zhu X, Bai H, et al. Network PharmacologyDatabases for Traditional Chinese Medicine: Review and Assessment. Front Pharmacol 2019;10:123. Accessed 2019 Feb 21. Available from
  • Stromnes IM, Goverman JM. Active induction of experimental allergic encephalomyelitis. Nat Protoc. 2006;1 (4) :1810–1819.
  • Shaw PJ, Barr MJ, Lukens JR, et al. Signaling via the RIP2 adaptor protein in central nervous system-infiltrating dendritic cells promotes inflammation and autoimmunity. Immunity. 2011;34 (1) :75–84. Available from.
  • Glenn JD, Smith MD, Xue P, et al. CNS-targeted autoimmunity leads to increased influenza mortality in mice. J Exp Med. 2017;214 (2) :297–307.
  • Ji X, Liu H, An C, et al. You-Gui pills promote nerve regeneration by regulating netrin 1, DCC and Rho family GTPases RhoA, Racl, Cdc42 in C57BL/6 mice with experimental autoimmune encephalomyelitis. J Ethnopharmacol. 2016;187:123–133.
  • Xu HY, Zhang YQ, Liu ZM, et al. ETCM: an encyclopaedia of traditional Chinese medicine. Nucleic Acids Res. 2019;47(D1): D976–D982.
  • Daina A, Michielin O, Zoete V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules.Nucleic Acids Res. 2019;47 (W1): W357–W364. 2 Jul 2019.
  • Wang X, Shen Y, Wang S, et al. PharmMapper 2017 update: a web server for potential drug target identification with a comprehensive target pharmacophore database.Nucleic Acids Res [Internet]. 2017;45(W1): W356–W360.
  • Fang S, Dong L, Liu L, et al. HERB: a high-throughput experiment- and reference-guided database of traditional Chinese medicine. Nucleic Acids Res [Internet]. 2021;49: D119i7–D1206. Jan 8 2021. Available from
  • The UniProt Consortium. UniProt: the universal protein knowledgebase. Nucleic Acids Res. 2017;45:D158–169. 2017 Jan 4. Available from
  • Safran M, Dalah I, Alexander J, et al. GeneCards version 3: the human gene integrator. Database(Oxford). 2010;2010:baq020. 2010 Aug 5. Available from
  • Piñero J, Bravo Á, Queralt-Rosinach N, et al. DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Res. 2017;45(D1): D833–D839. 4 Jan 2017.
  • Amberger JS, Bocchini CA, Schiettecatte F, et al. OMIM.org: online Mendelian inheritance in man (OMIM®), an online catalog of human genes and genetic disorders.Nucleic Acids Res. 2015;43(Database issue): D789–798.
  • Szklarczyk D, Morris JH, Cook H, et al. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 2017;45: D362–368.
  • Wishart DS, Feunang YD, Guo AC, et al. DrugBank 5.0: a major update to the drugbank database for 2018. Nucleic Acids Res. 2018;46(D1): D1074–D1082. 2018 Jan 4. Available from
  • Bai LL, Chen H, Zhou P, et al. Identification of tumor necrosis factor-alpha (TNF-α) inhibitor in rheumatoid arthritis using network pharmacology and molecular docking. Front Pharmacol. 2021;12:690118.
  • Hui Z, Dong QQ, Shu HP, et al. Mechanistic insights into the renoprotective role of curcumin in cisplatin-induced acute kidney injury: network pharmacology analysis and experimental validation. Bioengineered. 2021;12(2):11041–11056.
  • Yang L, Hu Z, Zhu J, et al. Systematic elucidation of the mechanism of quercetin against gastric cancer via network pharmacology approach. Biomed Res Int. 2020;2020:3860213.
  • Liu CS, Xia T, Luo ZY, et al. Network pharmacology and pharmacokinetics integrated strategy to investigate the pharmacological mechanism of xianglian pill on ulcerative colitis. Phytomedicine. 2021;82:153458.
  • Shannon P, Markiel A, Ozier O, et al. Cytoscape: a software environment for integrated models.Genome Research. 2003;13(11): 2498–2504.
  • Zhou Y, Zhou B, Pache L, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10(1): 1523.
  • Berman HM, Westbrook J, Feng Z, et al. The protein data bank. Nucleic Acids Res. 2000;28(1): 235–242.
  • Zheng Q, Liu L, Liu H, et al. The Bu Shen Yi Sui formula promotes axonal regeneration via regulating the neurotrophic factor BDNF/TrkB and the downstream PI3K/Akt signaling pathway. Front Pharmacol. 2019;10:796.
  • Navarrete C, García-Martin A, Garrido-Rodríguez M, et al. Effects of EHP-101 on inflammation and remyelination in murine models of multiple sclerosis. Neurobiol Dis. 2020;143:104994.
  • Fletcher JL, Murray SS, Xiao J. Brain-derived neurotrophic factor in central nervous system myelination: a new mechanism to promote myelin plasticity and repair. Int J Mol Sci. 2018;19(12): 4131.
  • Hilliard A, Mendonca P, Soliman KFA. Involvement of NFƙB and MAPK signaling pathways in the preventive effects of ganoderma lucidum on the inflammation of BV-2 microglial cells induced by LPS. J Neuroimmunol. 2020;345:577269.
  • da Silveira Cruz-machado S, Carvalho-Sousa CE, Tamura EK, et al. TLR4 and CD14 receptors expressed in rat pineal gland trigger NFKB pathway. J Pineal Res.2010;49(2):183–192. 2010 Sep. Available from
  • da Silva LC, Lima de A IV, da Silva MCM, et al. A new lipophilic amino alcohol, chemically similar to compound FTY720, attenuates the pathogenesis of experimental autoimmune encephalomyelitis by PI3K/Akt pathway inhibition. Int Immunopharmacol. 2020;88:106919.
  • Cong H, Zhang M, Chang H, et al. Icariin ameliorates the progression of experimental autoimmune encephalomyelitis by down-regulating the major inflammatory signal pathways in a mouse relapse-remission model of multiple sclerosis. Eur J Pharmacol. 2020;885:173523. 2020 Oct 15. doi:10.1016/j.ejphar.2020.173523.
  • Yang L, Han X, Xing F, et al. Total flavonoids of astragalus attenuates experimental autoimmune encephalomyelitis by suppressing the activation and inflammatory responses of microglia via JNK/AKT/NFκB signaling pathway. Phytomedicine. 2021;80:153385. 2021 Jan. doi:10.1016/j.phymed.2020.153385.
  • Ouyang S, Zeng Q, Tang N, et al. Akt-1 and Akt-2 differentially regulate the development of experimental autoimmune encephalomyelitis by controlling proliferation of thymus-derived regulatory t cells. J Immunol. 2019;202(5):1441–1452.
  • Zenke K, Muroi M, Tanamoto KI. AKT1 distinctively suppresses MyD88-dependent and TRIF-dependent toll-like receptor signaling in a kinase activity-independent manner. Cell Signalling. 2018;43:32–39.
  • van Kaer L, Postoak JL, Wang C, et al. Innate, innate-like and adaptive lymphocytes in the pathogenesis of MS and EAE. Cell Mol Immunol. 2019;16(6): 531–539.
  • Chu F, Shi M, Zheng C, et al. The roles of macrophages and microglia in multiple sclerosis and experimental autoimmune encephalomyelitis. J Neuroimmunol. 2018;318:1–7.
  • Rostami A, Ciric B. Role of Th17 cells in the pathogenesis of CNS inflammatory demyelination.J Neurol Sci. 2013;333(1–2): 76–87.
  • Voet S, Prinz M, van Loo G. Microglia in central nervous system inflammation and multiple sclerosis pathology.Trends Mol Med. 2019;25(2): 112–123.
  • Gentile A, Musella A, Bullitta S, et al. Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis. J Neuroinflammation [Internet]. 2016;13:1–13.
  • Cherry JD, Olschowka JA, O’Banion MK. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation. 2014;11: 1–15.
  • Cao L, He C. Polarization of macrophages and microglia in inflammatory demyelination. Neurosci Bull. 2013;29: 189–198.
  • Li Z, Liu F, He X, et al. Exosomes derived from mesenchymal stem cells attenuate inflammation and demyelination of the central nervous system in EAE rats by regulating the polarization of microglia. Int Immunopharmacol [Internet]. 2019;67:268–280.
  • Schampel A, Volovitch O, Koeniger T, et al. Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis. Proc Natl Acad Sci. 2017;114(16):E3295–E3304. 2017 Apr 18. Available from
  • Colonna M, Butovsky O. Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol. 2017;35: 441–468.
  • Moser T, Akgün K, Proschmann U, et al. The role of TH17 cells in multiple sclerosis: therapeutic implications. Autoimmunity Rev [Internet]. 2020;19: 102647.
  • Liu C, Li Y, Yu J, et al. Targeting the shift from M1 to M2 macrophages in experimental autoimmune encephalomyelitis mice treated with fasudil. PLoS ONE. 2013;8(2):e54841.
  • Lassmann H. Multiple sclerosis pathology. Cold Spring Harb Perspect Med. 2018;8(3): a028936.
  • Chen J, Liu X, Zhong Y. Interleukin-17A: the key cytokine in neurodegenerative diseases. Front Aging Neurosci. 2020;12:566922.
  • Rodríguez-Gómez JA, Kavanagh E, Engskog-Vlachos P, et al. Microglia: agents of the CNS pro-inflammatory response.Cells. 2020;9(7): 1717.
  • Liu Y, Yin H, Zhao M, et al. TLR2 and TLR4 in autoimmune diseases: a comprehensive review.Clin Rev Allergy Immunol. 2014;47(2): 136–147.
  • Kuzmich N, Sivak K, Chubarev V, et al. TLR4 signaling pathway modulators as potential therapeutics in inflammation and sepsis. Vaccines. 2017;5(4): 34.
  • Wang H, Liu C, Han M, et al. TRAM1 promotes microglia M1 polarization.J Mol Neurosci. 2016;58(2): 287–296.
  • Taetzsch T, Levesque S, Mcgraw C, et al. Redox regulation of NF-κB p50 and M1 polarization in microglia. Glia. 2015;63(3): 423–440.
  • Miranda-Hernandez S, Gerlach N, Fletcher JM, et al. Role for MyD88, TLR2 and TLR9 but not TLR1, TLR4 or TLR6 in experimental autoimmune encephalomyelitis.J Immunol. 2011;187(2): 791–804.
  • Marta M, Andersson Å, Isaksson M, et al. Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis. Eur J Immunol. 2008;38(2):565–575.
  • Dishon S, Cohen SJ, Cohen IR, et al. Inhibition of myeloid differentiation factor 88 reduces human and mouse T-cell interleukin-17 and IFNγ Production and ameliorates experimental autoimmune encephalomyelitis induced in mice. Front Immunol. 2017;8:615. 2017 May 29. Available from :
  • Wang X, Zheng X, Ma C, et al. Role of TRIF Small interference RNA (siRNA) in Chronic Experimental Allergic Encephalomyelitis (EAE). Med Sci Monit. 21:2583–2587. 2015 Sep1. Available from 10.12659/MSM.894564.