Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Ginsenoside Rh2 attenuates microglial activation against toxoplasmic encephalitis via TLR4/NF-κB signaling pathway

  • Xu, Xiang (Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University) ;
  • Jin, Lan (Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University) ;
  • Jiang, Tong (Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University) ;
  • Lu, Ying (Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University) ;
  • Aosai, Fumie (Department of Infection and Host Defense, Graduate School of Medicine, Shinshu University) ;
  • Piao, Hu-Nan (Department of Neurology, Affliated Hospital of Yanbian University) ;
  • Xu, Guang-Hua (Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University) ;
  • Jin, Cheng-Hua (Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University) ;
  • Jin, Xue-Jun (Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University) ;
  • Ma, Juan (Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University) ;
  • Piao, Lian-Xun (Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University)
  • Received : 2019.02.27
  • Accepted : 2019.06.05
  • Published : 2020.09.15
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Abstract

Background: Ginsenoside Rh2 (GRh2) is a characterized component in red ginseng widely used in Korea and China. GRh2 exhibits a wide range of pharmacological activities, such as anti-inflammatory, antioxidant, and anticancer properties. However, its effects on Toxoplasma gondii (T. gondii) infection have not been clarified yet. Methods: The effect of GRh2 against T. gondii was assessed under in vitro and in vivo experiments. The BV2 cells were infected with tachyzoites of T. gondii RH strain, and the effects of GRh2 were evaluated by MTT assay, morphological observations, immunofluorescence staining, a trypan blue exclusion assay, reverse transcription PCR, and Western blot analyses. The in vivo experiment was conducted with BALB/c mice inoculated with lethal amounts of tachyzoites with or without GRh2 treatment. Results and conclusion: The GRh2 treatment significantly inhibited the proliferation of T. gondii under in vitro and in vivo studies. Furthermore, GRh2 blocked the activation of microglia and specifically decreased the release of inflammatory mediators in response to T. gondii infection through TLR4/NF-κB signaling pathway. In mice, GRh2 conferred modest protection from a lethal dose of T. gondii. After the treatment, the proliferation of tachyzoites in the peritoneal cavity of infected mice markedly decreased. Moreover, GRh2 also significantly decreased the T. gondii burden in mouse brain tissues. These findings indicate that GRh2 exhibits an antieT. gondii effect and inhibits the microglial activation through TLR4/NF-κB signaling pathway, providing the basic pharmacological basis for the development of new drugs to treat toxoplasmic encephalitis.

Keywords

References

  1. Dubey JP, Jones JL. Toxoplasma gondii infection in humans and animals in the United States. Int J Parasitol 2008;38:1257-78. https://doi.org/10.1016/j.ijpara.2008.03.007
  2. Zhang JL, Si HF, Shang XF, Zhang XK, Li B, Zhou XZ, Zhang JY. New life for an old drug: In vitro and in vivo effects of the anthelmintic drug niclosamide against Toxoplasma gondii RH strain. Int J Parasitol Drugs Drug Resist 2018;9:27-34.
  3. Zhang YH, Chen H, Chen Y, Wang L, Cai YH, Li M, Wen HQ, Du J, An R, Luo QL, et al. Activated microglia contribute to neuronal apoptosis in Toxoplasmic encephalitis. Parasit Vectors 2014;7:372. https://doi.org/10.1186/1756-3305-7-372
  4. Connolly MP, Goodwin E, Schey C, Zummo J. Toxoplasmic encephalitis relapse rates with pyrimethamine-based therapy: systematic review and meta-analysis. Pathog Glob Health 2017;111:31-44. https://doi.org/10.1080/20477724.2016.1273597
  5. Ben-Harari RR, Goodwin E, Casoy J. Adverse event profile of pyrimethaminebased therapy in toxoplasmosis: a systematic review. Drugs R D 2017;17:523-44. https://doi.org/10.1007/s40268-017-0206-8
  6. Kim YS, Woo JY, Han CK, Chang IM. Safety analysis of Panax ginseng in randomized clinical trials: a systematic review. Medicines 2015;2:106-26. https://doi.org/10.3390/medicines2020106
  7. Hu JN, Xu XY, Li W, Wang YM, Liu Y, Wang Z, Wang YP. Ginsenoside Rk1 ameliorates paracetamol-induced hepatotoxicity in mice through inhibition of inflammation, oxidative stress, nitrative stress and apoptosis. J Ginseng Res 2019;43:10-19. https://doi.org/10.1016/j.jgr.2017.07.003
  8. Vinoth Kumar R, Oh TW, Park YK. Anti-inflammatory effects of ginsenoside-Rh2 Inhibits LPS-induced activation of microglia and overproduction of inflammatory mediators via modulation of TGF-b1/Smad pathway. Neurochem Res 2016;41:951-7. https://doi.org/10.1007/s11064-015-1804-x
  9. Li LC, Piao HM, Zheng MY, Lin ZH, Choi YH, Yan GH. Ginsenoside Rh2 attenuates allergic airway inflammation by modulating nuclear factor-kB activation in a murine model of asthma. Mol Med Rep 2015;12:6946-54. https://doi.org/10.3892/mmr.2015.4272
  10. Park HM, Kim SJ, Mun AR, Go HK, Kim GB, Kim SZ, Jang SI, Lee SJ, Kim JS, Kang HS. Korean red ginseng and its primary ginsenosides inhibit ethanolinduced oxidative injury by suppression of the MAPK pathway in TIB-73 cells. J Ethnopharmacol 2012;141:1071-6. https://doi.org/10.1016/j.jep.2012.03.038
  11. Kim KH, Lee D, Lee HL, Kim CE, Jung K, Kang KS. Beneficial effects of Panax ginseng for the treatment and prevention of neurodegenerative diseases: past findings and future directions. J Ginseng Res 2018;42:239-47. https://doi.org/10.1016/j.jgr.2017.03.011
  12. Zhuo XH, Sun HC, Wang SH, Guo XL, Ding HJ, Yang Y, Shan Y, Du AF. Ginseng stem-and-leaf saponin (GSLS)-enhanced protective immune responses induced by Toxoplasma gondii heat shocked protein 70 (HSP70) against toxoplasmosis in mice. J Parasitol 2017;103:111-7. https://doi.org/10.1645/16-54
  13. Qu D, Han J, Du A. Enhancement of protective immune response to recombinant Toxoplasma gondii ROP18 antigen by ginsenoside Re. Exp Parasitol 2013;135:234-9. https://doi.org/10.1016/j.exppara.2013.07.013
  14. Luo W, Aosai F, Ueda M, Yamashita K, Shimizu K, Sekiya S, Yano A. Kinetics in parasite abundance in susceptible and resistant mice infected with an avirulent strain of Toxoplasma gondii by using quantitative competitive PCR. J Parasitol 1997;83:1070-4. https://doi.org/10.2307/3284364
  15. Sudan V, Tewari AK, Singh H, Singh R. Pathobiology of human RH strain induced experimental toxoplasmosis in murine model. J Parasit Dis 2016;40:840-4. https://doi.org/10.1007/s12639-014-0589-1
  16. Powell HC, Gibbs JrJr, Lorenzo AM, Lampert PW, Gajdusek DC. Toxoplasmosis of the central nervous system in the adult. Electron microscopic observations. Acta Neuropathol 1978;41:211-6. https://doi.org/10.1007/BF00690438
  17. Carruthers VB, Suzuki Y. Effects of Toxoplasma gondii infection on the brain. Schizophr Bull 2007;33:745-51. https://doi.org/10.1093/schbul/sbm008
  18. El Temsahy MM, El Kerdany ED, Eissa MM, Shalaby TI, Talaat IM, Mogahed NM. The effect of chitosan nanospheres on the immunogenicity of Toxoplasma lysate vaccine in mice. Parasit Dis 2016;40:611-26. https://doi.org/10.1007/s12639-014-0546-z
  19. Dubey JP. Toxoplasmosis of animals and humans. 2nd ed. Boca Raton: CRC Press; 2010.
  20. Yuan Y, Rangarajan P, Kan EM, Wu Y, Wu C, Ling EA. Scutellarin regulates the Notch pathway and affects the migration and morphological transformation of activated microglia in experimentally induced cerebral ischemia in rats and in activated BV-2 microglia. J Neuroinflammation 2015;12:11. https://doi.org/10.1186/s12974-014-0226-z
  21. Henn A, Lund S, Hedtjarn M, Schrattenholz A, Porzgen P, Leist M. The suitability of BV2 cells as alternative model system for primary microglia cultures or for animal experiments examining brain inflammation. ALTEX 2009;26:83-94.
  22. Mineo JR, Kasper LH. Attachment of Toxoplasma gondii to host cells involves major surface protein, SAG-1 (P30). Exp Parasitol 1994;79:11-20. https://doi.org/10.1006/expr.1994.1054
  23. Moroda M, Takamoto M, Iwakura Y, Nakayama J, Aosai F. Interleukin-17Adeficient mice are highly susceptible to Toxoplasma gondii infection due to excessively induced T. gondii HSP70 and interferon gamma production. Infect Immun 2017;85. e00399-17.
  24. Alomar ML, Rasse-Suriani FA, Ganuza A, Coceres VM, Cabrerizo FM, Angel SO. In vitro evaluation of ${\beta}$-carboline alkaloids as potential anti-Toxoplasma agents. BMC Res Notes 2013;6:193. https://doi.org/10.1186/1756-0500-6-193
  25. Harker KS, Ueno N, Lodoen MB. Toxoplasma gondii dissemination: a parasite's journey through the infected host. Parasite Immunol 2015;37:141-9. https://doi.org/10.1111/pim.12163
  26. Hwang YS, Shin JH, Yang JP, Jung BK, Lee SH, Shin EH. Characteristics of infection immunity regulated by Toxoplasma gondii to maintain chronic infection in the brain. Front Immunol 2018;9:158. https://doi.org/10.3389/fimmu.2018.00158
  27. Dellacasa-Lindberg I, Fuks JM, Arrighi RB, Lambert H, Wallin RP, Chambers B, Barragan A. Migratory activation of primary cortical microglia upon infection with Toxoplasma gondii. Infect Immun 2011;79:3046-52. https://doi.org/10.1128/IAI.01042-10
  28. Lian LH, Jin Q, Song SZ, Wu YL, Bai T, Jiang S, Li Q, Yang N, Nan JX. Ginsenoside Rh2 downregulates LPS-induced NF-${\kappa}B$ activation through inhibition of TAK1 phosphorylation in RAW 264.7 murine macrophage. Evid Based Complement Alternat Med 2013;2013:646728.
  29. Denkers EY. Toll-like receptor initiated host defense against Toxoplasma gondii. J Biomed Biotechnol 2010;2010:737125. https://doi.org/10.1155/2010/737125
  30. Zhou YH, Wang SS, Yang J, Tao JP, Xu YL, Huang YZ, Gao Q. Expression of Tolllike receptor 4 in brain tissue of chronic Toxoplasma gondii infection rats and its effect on brain injury. Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi 2012;24:58-61.
  31. Zare-Bidaki M, Hakimi H, Abdollahi SH, Zainodini N, Arababadi MK, Kennedy D. TLR4 in Toxoplasmosis; friends or foe? Microb Pathog 2014;69-70:28-32. https://doi.org/10.1016/j.micpath.2014.03.006
  32. Aosai F, Chen M, Kang HK, Mun HS, Norose K, Piao LX, Kobayashi M, Takeuchi O, Akira S, Yano A. Toxoplasma gondii-derived heat shock protein HSP70 functions as a B cell mitogen. Cell Stress Chaperones 2002;7:357-64. https://doi.org/10.1379/1466-1268(2002)007<0357:TGDHSP>2.0.CO;2
  33. Makino M, Uemura N, Moroda M, Kikumura A, Piao LX, Mohamed RM, Aosai F. Innate immunity in DNA vaccine with Toxoplasma gondii-heat shock protein 70 gene that induces DC activation and Th1 polarization. Vaccine 2011;29:1899-905. https://doi.org/10.1016/j.vaccine.2010.12.118
  34. Fang H, Aosai F, Mun HS, Norose K, Ahmed AK, Furuya M, Yano A. Anaphylactic reaction induced by Toxoplasma gondii-derived heat shock protein 70. Int Immunol 2006;18:1487-97. https://doi.org/10.1093/intimm/dxl081
  35. Fang H, Mun HS, Kikumura A, Sayama Y, Norose K, Yano A, Aosai F. Toxoplasma gondii-derived heat shock protein 70 induces lethal anaphylactic reaction through activation of cytosolic phospholipase A2 and platelet-activating factor via Toll-like receptor 4/myeloid differentiation factor 88. Microbiol Immunol 2008;52:366-74. https://doi.org/10.1111/j.1348-0421.2008.00047.x
  36. Molestina RE, Payne TM, Coppens I, Sinai AP. Activation of NF-kappaB by Toxoplasma gondii correlates with increased expression of antiapoptotic genes and localization of phosphorylated IkappaB to the parasitophorous vacuole membrane. J Cell Sci 2003;116:4359-71. https://doi.org/10.1242/jcs.00683
  37. Wang S, Zhang Z, Wang Y, Gadahi JA, Xie Q, Xu L, Yan R, Song X, Li X. Toxoplasma gondii excretory/secretory antigens (TgESAs) suppress inflammatory cytokine secretion by inhibiting TLR-induced NF-${\kappa}B$ activation in LPSstimulated murine macrophages. Oncotarget 2017;8:88351-9. https://doi.org/10.18632/oncotarget.19362
  38. Guiton PS, Sagawa JM, Fritz HM, Boothroyd JC. An in vitro model of intestinal infection reveals a developmentally regulated transcriptome of Toxoplasma sporozoites and a NF-${\kappa}B$-like signature in infected host cells. PLoS One 2017;12:e0173018. https://doi.org/10.1371/journal.pone.0173018
  39. Glaser KC, Hagos B, Molestina RE. Effects of Toxoplasma gondii genotype and absence of host MAL/Myd88 on the temporal regulation of gene expression in infected microglia. Exp Parasitol 2011;129:409-13. https://doi.org/10.1016/j.exppara.2011.08.016
  40. Kim L, Butcher BA, Lee CW, Uematsu S, Akira S, Denkers EY. Toxoplasma gondii genotype determines MyD88-dependent signaling in infected macrophages. J Immunol 2006;177:2584-91. https://doi.org/10.4049/jimmunol.177.4.2584
  41. Lee CW, Sukhumavasi W, Denkers EY. Phosphoinositide-3-kinase-dependent, MyD88-independent induction of CC-type chemokines characterizes the macrophage response to Toxoplasma gondii strains with high virulence. Infect Immun 2007;75:5788-97. https://doi.org/10.1128/IAI.00821-07
  42. Dobbin CA, Smith NC, Johnson AM. Heat shock protein 70 is a potential virulence factor in murine Toxoplasma infection via immunomodulation of host NF-${\kappa}B$ and nitric oxide. J Immunol 2002;169:958-65. https://doi.org/10.4049/jimmunol.169.2.958
  43. Mun HS, Aosai F, Norose K, Piao LX, Fang H, Akira S, Yano A. Toll-like receptor 4 mediates tolerance in macrophages stimulated with Toxoplasma gondiiderived heat shock protein 70. Infect Immun 2005;73:4634-42. https://doi.org/10.1128/IAI.73.8.4634-4642.2005

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