Login Register Cart 0
Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Identifying the Anti-inflammatory Effects of Astragalus Polysaccharides in Anti-N-Methyl-D-Aspartate Receptor Encephalitis: Network Pharmacology and Experimental Validation

Author(s): Yuling Lu, Ying Wu, Lanfeng Sun, Shengyu Yang, Huimin Kuang, Rida Li, Youshi Meng and Yuan Wu*

Volume 27, Issue 7, 2024

Published on: 04 September, 2023

Page: [1022 - 1032] Pages: 11

DOI: 10.2174/1386207326666230816162113

Price: $65

Abstract

Background: Astragalus polysaccharides (APS), a group of bioactive compounds obtained from the natural source Astragalus membranaceus (AM), exhibits numerous pharmacological actions in the central nervous system, such as anti-inflammatory, antioxidant, and immunomodulatory properties. Despite the remarkable benefits, the effectiveness of APS in treating anti- N-methyl-D-aspartate receptor (NMDAR) encephalitis and the corresponding mechanism have yet to be fully understood. As such, this study aims to investigate the impact of APS on anti-NMDAR encephalitis and explore the potential molecular network mechanism.

Methods: The impact of APS intervention on mice with anti-NMDAR encephalitis was assessed, and the possible molecular network mechanism was investigated utilizing network pharmacology and bioinformatics techniques such as Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG),protein–protein interaction (PPI) network, and molecular docking. Enzymelinked immunosorbent assay (ELISA) was applied to detect the expression of core target proteins.

Results: APS significantly ameliorated cognitive impairment and reduced susceptibility to PTZinduced seizures in mice with anti-NMDAR encephalitis, confirming the beneficial effect of APS on anti-NMDAR encephalitis. Seventeen intersecting genes were identified between APS and anti- NMDAR encephalitis. GO and KEGG analyses revealed the characteristics of the intersecting gene networks. STRING interaction in the PPI network was applied to find crucial molecules. The results of molecular docking suggested that APS may regulate interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) as potential targets in anti-NMDAR encephalitis. Furthermore, the levels of IL-1β, IL-6, and TNF-α detected by ELISA in anti-NMDAR encephalitis mice were significantly downregulated in response to the administration of APS.

Conclusion: The findings of this study demonstrate the significant role of APS in the treatment of anti-NMDAR encephalitis, as it effectively suppresses inflammatory cytokines. These results suggest that APS has the potential to be considered as a viable herbal medication for the treatment of anti-NMDAR encephalitis.

Keywords: Astragalus polysaccharides, anti-N-methyl-D-aspartate receptor encephalitis, anti-inflammatory effects, experimental validation, network pharmacology, Astragalus membranaceus (AM).

« Previous Next »
Graphical Abstract

[1]
Dalmau, J.; Lancaster, E.; Martinez-Hernandez, E.; Rosenfeld, M.R.; Balice-Gordon, R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol., 2011, 10(1), 63-74.
[http://dx.doi.org/10.1016/S1474-4422(10)70253-2] [PMID: 21163445]
[2]
Dalmau, J.; Graus, F. Antibody-mediated encephalitis. N. Engl. J. Med., 2018, 378(9), 840-851.
[http://dx.doi.org/10.1056/NEJMra1708712] [PMID: 29490181]
[3]
Camdessanché, J.P.; Streichenberger, N.; Cavillon, G.; Rogemond, V.; Jousserand, G.; Honnorat, J.; Convers, P.; Antoine, J.C. Brain immunohistopathological study in a patient with anti-NMDAR encephalitis. Eur. J. Neurol., 2011, 18(6), 929-931.
[http://dx.doi.org/10.1111/j.1468-1331.2010.03180.x] [PMID: 20722705]
[4]
Taraschenko, O.; Fox, H.S.; Zekeridou, A.; Pittock, S.J.; Eldridge, E.; Farukhuddin, F.; Al-Saleem, F.; Devi Kattala, C.; Dessain, S.K.; Casale, G.; Willcockson, G.; Dingledine, R. Seizures and memory impairment induced by patient‐derived anti‐N‐methyl‐D‐aspartate receptor antibodies in mice are attenuated by anakinra, an interleukin‐1 receptor antagonist. Epilepsia, 2021, 62(3), 671-682.
[http://dx.doi.org/10.1111/epi.16838] [PMID: 33596332]
[5]
Abboud, H.; Probasco, J.C.; Irani, S.; Ances, B.; Benavides, D.R.; Bradshaw, M.; Christo, P.P.; Dale, R.C.; Fernandez-Fournier, M.; Flanagan, E.P.; Gadoth, A.; George, P.; Grebenciucova, E.; Jammoul, A.; Lee, S.T.; Li, Y.; Matiello, M.; Morse, A.M.; Rae-Grant, A.; Rojas, G.; Rossman, I.; Schmitt, S.; Venkatesan, A.; Vernino, S.; Pittock, S.J.; Titulaer, M.J. Autoimmune encephalitis: Proposed best practice recommendations for diagnosis and acute management. J. Neurol. Neurosurg. Psychiatry, 2021, 92(7), 757-768.
[http://dx.doi.org/10.1136/jnnp-2020-325300] [PMID: 33649022]
[6]
Graus, F.; Titulaer, M.J.; Balu, R.; Benseler, S.; Bien, C.G.; Cellucci, T.; Cortese, I.; Dale, R.C.; Gelfand, J.M.; Geschwind, M.; Glaser, C.A.; Honnorat, J.; Höftberger, R.; Iizuka, T.; Irani, S.R.; Lancaster, E.; Leypoldt, F.; Prüss, H.; Rae-Grant, A.; Reindl, M.; Rosenfeld, M.R.; Rostásy, K.; Saiz, A.; Venkatesan, A.; Vincent, A.; Wandinger, K.P.; Waters, P.; Dalmau, J. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol., 2016, 15(4), 391-404.
[http://dx.doi.org/10.1016/S1474-4422(15)00401-9] [PMID: 26906964]
[7]
Hacohen, Y.; Wright, S.; Waters, P.; Agrawal, S.; Carr, L.; Cross, H.; De Sousa, C.; DeVile, C.; Fallon, P.; Gupta, R.; Hedderly, T.; Hughes, E.; Kerr, T.; Lascelles, K.; Lin, J.P.; Philip, S.; Pohl, K.; Prabahkar, P.; Smith, M.; Williams, R.; Clarke, A.; Hemingway, C.; Wassmer, E.; Vincent, A.; Lim, M.J. Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens. J. Neurol. Neurosurg. Psychiatry, 2013, 84(7), 748-755.
[http://dx.doi.org/10.1136/jnnp-2012-303807] [PMID: 23175854]
[8]
Huang, Q.; Xie, Y.; Hu, Z.; Tang, X. Anti-N-methyl-D-aspartate receptor encephalitis: A review of pathogenic mechanisms, treatment, prognosis. Brain Res., 2020, 1727, 146549.
[http://dx.doi.org/10.1016/j.brainres.2019.146549] [PMID: 31726044]
[9]
Wang, D.Y.; Salem, J.E.; Cohen, J.V.; Chandra, S.; Menzer, C.; Ye, F.; Zhao, S.; Das, S.; Beckermann, K.E.; Ha, L.; Rathmell, W.K.; Ancell, K.K.; Balko, J.M.; Bowman, C.; Davis, E.J.; Chism, D.D.; Horn, L.; Long, G.V.; Carlino, M.S.; Lebrun-Vignes, B.; Eroglu, Z.; Hassel, J.C.; Menzies, A.M.; Sosman, J.A.; Sullivan, R.J.; Moslehi, J.J.; Johnson, D.B. Fatal toxic effects associated with immune checkpoint inhibitors. JAMA Oncol., 2018, 4(12), 1721-1728.
[http://dx.doi.org/10.1001/jamaoncol.2018.3923] [PMID: 30242316]
[10]
Morris, E.C.; Neelapu, S.S.; Giavridis, T.; Sadelain, M. Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nat. Rev. Immunol., 2022, 22(2), 85-96.
[http://dx.doi.org/10.1038/s41577-021-00547-6] [PMID: 34002066]
[11]
Zheng, Y.; Ren, W.; Zhang, L.; Zhang, Y.; Liu, D.; Liu, Y. A review of the pharmacological action of astragalus polysaccharide. Front. Pharmacol., 2020, 11, 349.
[http://dx.doi.org/10.3389/fphar.2020.00349] [PMID: 32265719]
[12]
Jia, X.; Xie, L.; Liu, Y.; Liu, T.; Yang, P.; Hu, J.; Peng, Z.; Luo, K.; Du, M.; Chen, C. Astragalus polysaccharide (APS) exerts protective effect against acute ischemic stroke (AIS) through enhancing M2 micoglia polarization by regulating adenosine triphosphate (ATP)/purinergic receptor (P2X7R) axis. Bioengineered, 2022, 13(2), 4468-4480.
[http://dx.doi.org/10.1080/21655979.2021.1980176] [PMID: 35166175]
[13]
Liu, X.; Ma, J.; Ding, G.; Gong, Q.; Wang, Y.; Yu, H.; Cheng, X. Microglia polarization from m1 toward m2 phenotype is promoted by Astragalus Polysaccharides mediated through inhibition of mir-155 in experimental autoimmune encephalomyelitis. Oxid. Med. Cell. Longev., 2021, 2021, 1-15.
[http://dx.doi.org/10.1155/2021/5753452] [PMID: 34976303]
[14]
Byun, J.I.; Lee, S.T.; Moon, J.; Jung, K.H.; Sunwoo, J.S.; Lim, J.A.; Kim, T.J.; Shin, Y.W.; Lee, K.J.; Jun, J.S.; Lee, H.S.; Lee, W.J.; Kim, Y.S.; Kim, S.; Jeon, D.; Park, K.I.; Jung, K.Y.; Kim, M.; Chu, K.; Lee, S.K. Distinct intrathecal interleukin-17/interleukin-6 activation in anti-N-methyl-d-aspartate receptor encephalitis. J. Neuroimmunol., 2016, 297, 141-147.
[http://dx.doi.org/10.1016/j.jneuroim.2016.05.023] [PMID: 27397087]
[15]
Nogales, C.; Mamdouh, Z.M.; List, M.; Kiel, C.; Casas, A.I.; Schmidt, H.H.H.W. Network pharmacology: Curing causal mechanisms instead of treating symptoms. Trends Pharmacol. Sci., 2022, 43(2), 136-150.
[http://dx.doi.org/10.1016/j.tips.2021.11.004] [PMID: 34895945]
[16]
Liu, M.; Li, Z.; Ouyang, Y.; Chen, M.; Guo, X.; Mazhar, M.; Kang, J.; Zhou, H.; Wu, Q.; Yang, S. Material basis and integrative pharmacology of danshen decoction in the treatment of cardiovascular diseases. Phytomedicine, 2023, 108, 154503.
[http://dx.doi.org/10.1016/j.phymed.2022.154503] [PMID: 36332387]
[17]
Liu, C.; Li, H.; Wang, K.; Zhuang, J.; Chu, F.; Gao, C.; Liu, L.; Feng, F.; Zhou, C.; Zhang, W.; Sun, C. Identifying the antiproliferative effect of Astragalus polysaccharides on breast cancer: Coupling network pharmacology with targetable screening from the cancer genome atlas. Front. Oncol., 2019, 9, 368.
[http://dx.doi.org/10.3389/fonc.2019.00368] [PMID: 31157164]
[18]
Zhao, Z.H.; Xu, M.; Fu, C.; Huang, Y.; Wang, T.H.; Zuo, Z.F.; Liu, X.Z. A mechanistic exploratory study on the therapeutic efficacy of astragaloside iv against diabetic retinopathy revealed by network pharmacology. Front. Pharmacol., 2022, 13, 903485.
[http://dx.doi.org/10.3389/fphar.2022.903485] [PMID: 35814228]
[19]
Li, M.; Zheng, Y.; Deng, S.; Yu, T.; Ma, Y.; Ge, J.; Li, J.; Li, X.; Ma, L. Potential therapeutic effects and applications of Eucommiae Folium in secondary hypertension. J. Pharm. Anal., 2022, 12(5), 711-718.
[http://dx.doi.org/10.1016/j.jpha.2021.10.004] [PMID: 36320603]
[20]
Jiao, W.; Mi, S.; Sang, Y.; Jin, Q.; Chitrakar, B.; Wang, X.; Wang, S. Integrated network pharmacology and cellular assay for the investigation of an anti-obesity effect of 6-shogaol. Food Chem., 2022, 374, 131755.
[http://dx.doi.org/10.1016/j.foodchem.2021.131755] [PMID: 34883426]
[21]
Xia, J.; Hu, J.N.; Wang, Z.; Cai, E.B.; Ren, S.; Wang, Y.P.; Lei, X.J.; Li, W. Based on network pharmacology and molecular docking to explore the protective effect of Epimedii Folium extract on cisplatin-induced intestinal injury in mice. Front. Pharmacol., 2022, 13, 1040504.
[http://dx.doi.org/10.3389/fphar.2022.1040504] [PMID: 36313368]
[22]
Wagnon, I.; Hélie, P.; Bardou, I.; Regnauld, C.; Lesec, L.; Leprince, J.; Naveau, M.; Delaunay, B.; Toutirais, O.; Lemauff, B.; Etard, O.; Vivien, D.; Agin, V.; Macrez, R.; Maubert, E.; Docagne, F. Autoimmune encephalitis mediated by B-cell response against N-methyl-d-aspartate receptor. Brain, 2020, 143(10), 2957-2972.
[http://dx.doi.org/10.1093/brain/awaa250] [PMID: 32893288]
[23]
Dang, R.; Wang, M.; Li, X.; Wang, H.; Liu, L.; Wu, Q.; Zhao, J.; Ji, P.; Zhong, L.; Licinio, J.; Xie, P. Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1/Nrf2/HO-1/Gpx4 pathway. J. Neuroinflammation, 2022, 19(1), 41.
[http://dx.doi.org/10.1186/s12974-022-02400-6] [PMID: 35130906]
[24]
Lüttjohann, A.; Fabene, P.F.; van Luijtelaar, G. A revised Racine’s scale for PTZ-induced seizures in rats. Physiol. Behav., 2009, 98(5), 579-586.
[http://dx.doi.org/10.1016/j.physbeh.2009.09.005] [PMID: 19772866]
[25]
Titulaer, M.J.; McCracken, L.; Gabilondo, I.; Armangué, T.; Glaser, C.; Iizuka, T.; Honig, L.S.; Benseler, S.M.; Kawachi, I.; Martinez-Hernandez, E.; Aguilar, E.; Gresa-Arribas, N.; Ryan-Florance, N.; Torrents, A.; Saiz, A.; Rosenfeld, M.R.; Balice-Gordon, R.; Graus, F.; Dalmau, J. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: An observational cohort study. Lancet Neurol., 2013, 12(2), 157-165.
[http://dx.doi.org/10.1016/S1474-4422(12)70310-1] [PMID: 23290630]
[26]
Dong, Q.; Li, Z.; Zhang, Q.; Hu, Y.; Liang, H.; Xiong, L. Astragalus mongholicus bunge (Fabaceae): Bioactive compounds and potential therapeutic mechanisms against alzheimer’s disease. Front. Pharmacol., 2022, 13, 924429.
[http://dx.doi.org/10.3389/fphar.2022.924429] [PMID: 35837291]
[27]
Huang, Y.C.; Tsay, H.J.; Lu, M.K.; Lin, C.H.; Yeh, C.W.; Liu, H.K.; Shiao, Y.J. Astragalus membranaceus-polysaccharides ameliorates obesity, hepatic steatosis, neuroinflammation and cognition impairment without affecting amyloid deposition in metabolically stressed APPswe/PS1dE9 mice. Int. J. Mol. Sci., 2017, 18(12), 2746.
[http://dx.doi.org/10.3390/ijms18122746] [PMID: 29258283]
[28]
Aldarmaa, J.; Liu, Z.; Long, J.; Mo, X.; Ma, J.; Liu, J. Anti-convulsant effect and mechanism of Astragalus mongholicus extract in vitro and in vivo: Protection against oxidative damage and mitochondrial dysfunction. Neurochem. Res., 2010, 35(1), 33-41.
[http://dx.doi.org/10.1007/s11064-009-0027-4] [PMID: 19578991]
[29]
Yang, J.; Jia, Z.; Xiao, Z.; Zhao, J.; Lu, Y.; Chu, L.; Shao, H.; Pei, L.; Zhang, S.; Chen, Y. Baicalin rescues cognitive dysfunction, mitigates neurodegeneration, and exerts anti-epileptic effects through activating TLR4/MYD88/Caspase-3 pathway in rats. Drug Des. Devel. Ther., 2021, 15, 3163-3180.
[http://dx.doi.org/10.2147/DDDT.S314076] [PMID: 34321866]
[30]
Jalsrai, A.; Grecksch, G.; Becker, A. Evaluation of the effects of astragalus mongholicus bunge saponin extract on central nervous system functions. J. Ethnopharmacol., 2010, 131(3), 544-549.
[http://dx.doi.org/10.1016/j.jep.2010.07.031] [PMID: 20655376]
[31]
Qin, X.; Hua, J.; Lin, S.; Zheng, H.; Wang, J.; Li, W.; Ke, J.; Cai, H. Astragalus polysaccharide alleviates cognitive impairment and β-amyloid accumulation in APP/PS1 mice via Nrf2 pathway. Biochem. Biophys. Res. Commun., 2020, 531(3), 431-437.
[http://dx.doi.org/10.1016/j.bbrc.2020.07.122] [PMID: 32800555]
[32]
Liu, Y.; Liu, W.; Li, J.; Tang, S.; Wang, M.; Huang, W.; Yao, W.; Gao, X. A polysaccharide extracted from astragalus membranaceus residue improves cognitive dysfunction by altering gut microbiota in diabetic mice. Carbohydr. Polym., 2019, 205, 500-512.
[http://dx.doi.org/10.1016/j.carbpol.2018.10.041] [PMID: 30446134]
[33]
Liu, J.; Liu, L.; Kang, W.; Peng, G.; Yu, D.; Ma, Q.; Li, Y.; Zhao, Y.; Li, L.; Dai, F.; Wang, J. Cytokines/Chemokines: Potential biomarkers for non-paraneoplastic anti-n-methyl-d-aspartate receptor encephalitis. Front. Neurol., 2020, 11, 582296.
[http://dx.doi.org/10.3389/fneur.2020.582296] [PMID: 33408682]
[34]
Peng, Y.; Liu, B.; Pei, S.; Zheng, D.; Wang, Z.; Ji, T.; Pan, S.; Shen, H.Y.; Wang, H. Higher CSF Levels of NLRP3 inflammasome is associated with poor prognosis of anti-n-methyl-d-aspartate receptor encephalitis. Front. Immunol., 2019, 10, 905.
[http://dx.doi.org/10.3389/fimmu.2019.00905] [PMID: 31214158]
[35]
Wang, D.; Wu, Y.; Pan, Y.; Wang, S.; Liu, G.; Gao, Y. Multi-proteomic analysis revealed distinct protein profiles in cerebrospinal fluid of patients between anti-nmdar encephalitis norse and cryptogenic norse. Mol. Neurobiol., 2022, 60(1), 98-115.
[PMID: 36224320]
[36]
Li, Q.; Chen, J.; Yin, M.; Zhao, J.; Lu, F.; Wang, Z.; Yu, X.; Wang, S.; Zheng, D.; Wang, H. High level of soluble cd146 in cerebrospinal fluid might be a biomarker of severity of anti-n-methyl-d-aspartate receptor encephalitis. Front. Immunol., 2021, 12, 680424.
[http://dx.doi.org/10.3389/fimmu.2021.680424] [PMID: 34220828]
[37]
Li, J.; Gu, Y.; An, H.; Zhou, Z.; Zheng, D.; Wang, Z.; Wen, Z.; Shen, H.Y.; Wang, Q.; Wang, H. Cerebrospinal fluid light and heavy neurofilament level increased in anti‐ N ‐methyl‐ D ‐aspartate receptor encephalitis. Brain Behav., 2019, 9(8), e01354.
[http://dx.doi.org/10.1002/brb3.1354] [PMID: 31313506]
[38]
Lee, W.J.; Lee, S.T.; Moon, J.; Sunwoo, J.S.; Byun, J.I.; Lim, J.A.; Kim, T.J.; Shin, Y.W.; Lee, K.J.; Jun, J.S.; Lee, H.S.; Kim, S.; Park, K.I.; Jung, K.H.; Jung, K.Y.; Kim, M.; Lee, S.K.; Chu, K. Tocilizumab in autoimmune encephalitis refractory to rituximab: An institutional cohort study. Neurotherapeutics, 2016, 13(4), 824-832.
[http://dx.doi.org/10.1007/s13311-016-0442-6] [PMID: 27215218]
[39]
Jiao, C.; Liang, H.; Liu, L.; Li, S.; Chen, J.; Xie, Y. Transcriptomic analysis of the anti-inflammatory effect of Cordyceps militaris extract on acute gouty arthritis. Front. Pharmacol., 2022, 13, 1035101.
[http://dx.doi.org/10.3389/fphar.2022.1035101] [PMID: 36313318]
[40]
Cao, Z.; Liu, Y.; Zhang, Z.; Yang, P.; Li, Z.; Song, M.; Qi, X.; Han, Z.; Pang, J.; Li, B.; Zhang, X.; Dai, H.; Wang, J.; Wang, C. Pirfenidone ameliorates silica-induced lung inflammation and fibrosis in mice by inhibiting the secretion of interleukin-17A. Acta Pharmacol. Sin., 2022, 43(4), 908-918.
[http://dx.doi.org/10.1038/s41401-021-00706-4] [PMID: 34316030]
[41]
Liu, N.; Liu, C.; Yang, Y.; Ma, G.; Wei, G.; Liu, S.; Kong, L.; Du, G. Xiao-Xu-Ming decoction prevented hemorrhagic transformation induced by acute hyperglycemia through inhibiting AGE-RAGE-mediated neuroinflammation. Pharmacol. Res., 2021, 169, 105650.
[http://dx.doi.org/10.1016/j.phrs.2021.105650] [PMID: 33964468]
[42]
Tong, M.; Kayani, T.; Jones, D.M.; Salmon, J.E.; Whirledge, S.; Chamley, L.W.; Abrahams, V.M. Antiphospholipid Antibodies Increase Endometrial Stromal Cell Decidualization, Senescence, and Inflammation via toll‐like receptor 4, reactive oxygen species, and p38 MAPK signaling. Arthritis Rheumatol., 2022, 74(6), 1001-1012.
[http://dx.doi.org/10.1002/art.42068] [PMID: 35044724]

Rights & Permissions Print Cite
Article Metrics
41
2
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy