Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
권호 표지
DOI QR코드

DOI QR Code

Ginsenoside Rh2 reduces depression in offspring of mice with maternal toxoplasma infection during pregnancy by inhibiting microglial activation via the HMGB1/TLR4/NF-κB signaling pathway

  • Xu, Xiang (Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University) ;
  • Lu, Yu-Nan (Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University) ;
  • Cheng, Jia-Hui (Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University) ;
  • Lan, Hui-Wen (Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University) ;
  • Lu, Jing-Mei (Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University) ;
  • Jin, Guang-Nan (Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University) ;
  • Xu, Guang-Hua (Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University) ;
  • Jin, Cheng-Hua (Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University) ;
  • Ma, Juan (Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University) ;
  • Piao, Hu-Nan (Department of Neurology, Affliated Hospital of Yanbian University) ;
  • Jin, Xuejun (Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University) ;
  • Piao, Lian-Xun (Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University)
  • Received : 2020.11.25
  • Accepted : 2021.04.09
  • Published : 2022.01.01
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Maternal Toxoplasma gondii (T. gondii) infection during pregnancy has been associated with various mental illnesses in the offspring. Ginsenoside Rh2 (GRh2) is a major bioactive compound obtained from ginseng that has an anti-T. gondii effect and attenuates microglial activation through toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway. GRh2 also alleviated tumor-associated or lipopolysaccharide-induced depression. However, the effects and potential mechanisms of GRh2 on depression-like behavior in mouse offspring caused by maternal T. gondii infection during pregnancy have not been investigated. Methods: We examined GRh2 effects on the depression-like behavior in mouse offspring, caused by maternal T. gondii infection during pregnancy, by measuring depression-like behaviors and assaying parameters at the neuronal and molecular level. Results: We showed that GRh2 significantly improved behavioral measures: sucrose consumption, forced swim time and tail suspended immobility time of their offspring. These corresponded with increased tissue concentrations of 5-hydroxytryptamine and dopamine, and attenuated indoleamine 2,3-dioxygenase or enhanced tyrosine hydroxylase expression in the prefrontal cortex. GRh2 ameliorated neuronal damage in the prefrontal cortex. Molecular docking results revealed that GRh2 binds strongly to both TLR4 and high mobility group box 1 (HMGB1). Conclusion: This study demonstrated that GRh2 ameliorated the depression-like behavior in mouse offspring of maternal T. gondii infection during pregnancy by attenuating the excessive activation of microglia and neuroinflammation through the HMGB1/TLR4/NF-κB signaling pathway. It suggests that GRh2 could be considered a potential therapy in preventing and treating psychiatric disorders in the offspring mice of mothers with prenatal exposure to T. gondii infection.

Keywords

Acknowledgement

This work was supported by the grants from the National Natural Science Foundation of China (81660344, 81960375 and 81260251), and partially supported by Jilin Province Science and Technology Development Plan item (20190201149JC). We thank Prof. Aosai Fumie at Shinshu University, Japan, for comments and suggestions of the manuscript.

References

  1. Kochanowsky JA, Koshy AA. Toxoplasma gondii. Curr Biol 2018;28:R770-1. https://doi.org/10.1016/j.cub.2018.05.035
  2. Brown AS, Schaefer CA, Quesenberry Jr CP, Liu L, Babulas VP, Susser ES. Maternal exposure to toxoplasmosis and risk of schizophrenia in adult offspring. Am J Psychiatry 2005;162:767-73. https://doi.org/10.1176/appi.ajp.162.4.767
  3. Mortensen PB, Norgaard-Pedersen B, Waltoft BL, Sorensen TL, Hougaard D, Torrey EF, Yolken RH. Toxoplasma gondii as a risk factor for early-onset schizophrenia: analysis of filter paper blood samples obtained at birth. Biol Psychiatry 2007;61:688-93. https://doi.org/10.1016/j.biopsych.2006.05.024
  4. Blomstrom A, Karlsson H, Wicks S, Yang S, Yolken RH, Dalman C. Maternal antibodies to infectious agents and risk for non-affective psychoses in the offspring a matched case-control study. Schizophr Res 2012;140:25-30. https://doi.org/10.1016/j.schres.2012.06.035
  5. Freedman D, Bao Y, Shen L, Schaefer CA, Brown AS, Maternal T. gondii, offspring bipolar disorder and neurocognition. Psychiatry Res 2016;243:3829.
  6. Blomstrom A, Gardner RM, Dalman C, Yolken RH, Karlsson H. In fluence of maternal infections on neonatal acute phase proteins and their interaction in the development of non-affective psychosis. Transl Psychiatry 2015;5:e502. https://doi.org/10.1038/tp.2014.142
  7. Grether JK, Croen LA, Anderson MC, Nelson KB, Yolken RH. Neonatally measured immunoglobulins and risk of autism. Autism Res 2010;3:323-32. https://doi.org/10.1002/aur.160
  8. Spann MN, Sourander A, Surcel HM, Hinkka-Yli-Salomaki S, Brown AS. Prenatal toxoplasmosis antibody and childhood autism. Autism Res 2017;10:769-77. https://doi.org/10.1002/aur.1722
  9. Al Malki JS, Hussien NA, Al Malki F. Maternal toxoplasmosis and the risk of childhood autism: serological and molecular small-scale studies. BMC Pediatr 2021;21:133. https://doi.org/10.1186/s12887-021-02604-4
  10. 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
  11. Lu Y, Xu X, Jiang T, Jin L, Zhao XD, Cheng JH, Jin XJ, Ma J, Piao HN, Piao LX. Sertraline ameliorates inflammation in CUMS mice and inhibits TNF-α-induced inflammation in microglia cells. Int Immunopharmacol 2019;67:119-28. https://doi.org/10.1016/j.intimp.2018.12.011
  12. Xu X, Jin L, Jiang T, Lu Y, Aosai F, Piao HN, Xu GH, Jin GH, Jin X, Ma J, et al. Ginsenoside Rh2 attenuates microglial activation against toxoplasmic encephalitis via TLR4/NF-κB signaling pathway. J Ginseng Res 2020;44:704-16. https://doi.org/10.1016/j.jgr.2019.06.002
  13. Cheng JH, Xu X, Li YB, Zhao XD, Aosai F, Shi SY, Jin CH, Piao JS, Ma J, Piao HN, et al. Arctigenin ameliorates depression-like behaviors in Toxoplasma gondii-infected intermediate hosts via the TLR4/NF-κB and TNFR1/NF-κB signaling pathways. Int Immunopharmacol 2020;82:106302. https://doi.org/10.1016/j.intimp.2020.106302
  14. Xu X, Zeng XY, Cui YX, Li YB, Cheng JH, Zhao XD, Xu GH, Ma J, Piao HN, Jin X, et al. Antidepressive effect of arctiin by attenuating neuroinflammation via HMGB1/TLR4- and TNF-α/TNFR1-mediated NF-κB activation. ACS Chem Neurosci 2020;11:2214-30. https://doi.org/10.1021/acschemneuro.0c00120
  15. Xu X, Piao HN, Aosai Fumie, Zeng XY, Cheng JH, Cui XY, Jing-Li, Ma J, Piao HR, Jin X, et al. Arctigenin protects against depression by inhibiting microglial activation and neuroinflammation via HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB pathways. Br J Pharmacol 2020;177:5224-45. https://doi.org/10.1111/bph.15261
  16. Huang Y, Yin H, Han J, Huang B, Xu J, Zheng F, Tan Z, Fang M, Rui L, Chen D, et al. Extracellular hmgb1 functions as an innate immune-mediator implicated in murine cardiac allograft acute rejection. Am J Transplant 2007;7:799-808. https://doi.org/10.1111/j.1600-6143.2007.01734.x
  17. Chen X, Wu S, Chen C, Xie B, Fang Z, Hu W, Chen J, Fu H, He H. Omega-3 polyunsaturated fatty acid supplementation attenuates microglial-induced inflammation by inhibiting the HMGB1/TLR4NF-κB pathway following experimental traumatic brain injury. J Neuroinflammation 2017;14:143. https://doi.org/10.1186/s12974-017-0917-3
  18. Lu YN, Zhao XD, Xu X, Piao J, Aosai F, Li YB, Shen LX, Shi SY, Xu GH, Ma J, et al. Arctigenin exhibits hepatoprotective activity in Toxoplasma gondii-infected host through HMGB1/TLR4/NF-κB pathway. Int Immunopharmacol 2020;84:106539. https://doi.org/10.1016/j.intimp.2020.106539
  19. Spini VBMG, Ferreira FR, Gomes AO, Duarte RMF, Oliveira VHS, Costa NB, Ferreira AFF, Dourado MPB, Ribeiro-Barbosa ER. Maternal immune activation with H1N1 or Toxoplasma gondii antigens induces behavioral impairments associated with mood disorders in rodents. Neuropsychobiology 2020;16:1-8. https://doi.org/10.1159/000118289
  20. Khan K, Khan W. Congenital toxoplasmosis: an overview of the neurological and ocular manifestations. Parasitol Int 2018;67:715-21. https://doi.org/10.1016/j.parint.2018.07.004
  21. Julliac B, Theophile H, Begorre M, Richez B, Haramburu F. Side effects of spi-ramycin masquerading as local anesthetic toxicity during labor epidural analgesia. Int J Obstet Anesth 2010;19:331-2. https://doi.org/10.1016/j.ijoa.2010.03.002
  22. Slatore CG, Tilles SA. Sulfonamide hypersensitivity. Immunol Allergy Clin North Am 2004;24:477-90. https://doi.org/10.1016/j.iac.2004.03.011
  23. 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
  24. 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
  25. Chen LX, Qi Z, Shao ZJ, Li SS, Qi YL, Gao K, Liu SX, Li Z, Sun YS, Li PY. Study on antidepressant activity of pseudo-ginsenoside HQ on depression-like behavior in mice. Molecules 2019;24:870. https://doi.org/10.3390/molecules24050870
  26. Wang J, Chen Y, Dai C, Shang Y, Xie J. Ginsenoside Rh2 alleviates tumor-associated depression in a mouse model of colorectal carcinoma. Am J Transl Res 2016;8:2189-95.
  27. Gao M, Hu P, Cai Z, Wu Y, Wang D, Hu W, Xu X, Zhang Y, Lu X, Chen D, et al. Identification of a microglial activation-dependent antidepressant effect of amphotericin B liposome. Neuropharmacology 2019;151:33-44. https://doi.org/10.1016/j.neuropharm.2019.04.005
  28. Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010;31:455-61. https://doi.org/10.1002/jcc.21334
  29. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 2009;30:2785-91. https://doi.org/10.1002/jcc.21256
  30. Sanner MF. Python: a programming language for software integration and development. J Mol Graph Model 1999;17:57-61.
  31. Dotters-Katz S, Kuller J, Heine RP. Parasitic infections in pregnancy. Obstet Gynecol Surv 2011;66:515-25. https://doi.org/10.1097/OGX.0b013e3182385fde
  32. Fallahi S, Rostami A, Nourollahpour Shiadeh M, Behniafar H, Paktinat S. An updated literature review on maternal-fetal and reproductive disorders of Toxoplasma gondii infection. J Gynecol Obstet Hum Reprod 2018;47:133-40. https://doi.org/10.1016/j.jogoh.2017.12.003
  33. Wang T, Tang ZH, Li JF, Li XN, Wang X, Zhao ZJ. A potential association between Toxoplasma gondii infection and schizophrenia in mouse models. Exp Parasitol 2013;135:497-502. https://doi.org/10.1016/j.exppara.2013.08.012
  34. Shiono Y, Mun HS, He N, Nakazaki Y, Fang H, Furuya M, Aosai F, Yano A. Maternal-fetal transmission of Toxoplasma gondii in interferon-gamma deficient pregnant mice. Parasitol Int 2007;56:141-8. https://doi.org/10.1016/j.parint.2007.01.008
  35. Simanek AM, Meier HC. Association between prenatal exposure to maternal infection and offspring mood disorders: a review of the literature. Curr Probl Pediatr Adolesc Health Care 2015;45(11):325-64. https://doi.org/10.1016/j.cppeds.2015.06.008
  36. Mahmoud ME, Fereig R, Nishikawa Y. Involvement of Host Defense mechanisms against Toxoplasma gondii infection in anhedonic and despair-like behaviors in mice. Infect Immun 2017;85:e00007-17.
  37. Wang T, Sun X, Qin W, Zhang X, Wu L, Li Y, Zhou C, Zhou H, He S, Cong H. From inflammatory reactions to neurotransmitter changes: implications for understanding the neurobehavioral changes in mice chronically infected with Toxoplasma gondii. Behav Brain Res 2019;359:737-48. https://doi.org/10.1016/j.bbr.2018.09.011
  38. Felger JC. The role of dopamine in inflammation-associated depression: mechanisms and therapeutic implications. Curr Top Behav Neurosci 2017;31:199-219. https://doi.org/10.1007/7854_2016_13
  39. Barbosa JL, Bela SR, Ricci MF, Noviello MLM, Cartelle CT, Pinheiro BV, Vitor RWA, Arantes RME, Spontaneous T. Gondii neuronal encystment induces structural neuritic network impairment associated with changes of tyrosine hydroxilase expression. Neurosci Lett 2020;718:134721. https://doi.org/10.1016/j.neulet.2019.134721
  40. Field T. Maternal depression effects on infants and early interventions. Prev Med 1998;27:200-3. https://doi.org/10.1006/pmed.1998.0293
  41. Lundy Brenda L, , Nancy Aaron Jones, Field Tiffany, Nearing Graciela, Davalos Marisabel, Pietro Paul A, Schanberg Saul, Kuhn Cynthia. Prenatal depression effects on neonates. Infant Behavior and Development 1999;22:119-29. https://doi.org/10.1016/S0163-6383(99)80009-5
  42. Goodwin D, Hrubec TC, Klein BG, Strobl JS, Werre SR, Han Q, Zajac AM, Lindsay DS. Congenital infection of mice with Toxoplasma gondii induces minimal change in behavior and no change in neurotransmitter concentrations. J Parasitol 2012;98:706-12. https://doi.org/10.1645/GE-3068.1
  43. Skallova A, Kodym P, Frynta D, Flegr J. The role of dopamine in Toxoplasma-induced ral alterations in mice: an ethological and ethopharmacological study. Parasitology 2006;133:525-35. https://doi.org/10.1017/S0031182006000886
  44. Wang H, Lei T, Liu J, Li M, Nan H, Liu Q. A nuclear factor of high mobility group box protein in Toxoplasma gondii. PLoS One 2014;9:e111993. https://doi.org/10.1371/journal.pone.0111993
  45. Liu L, Dong Y, Shan X, Li L, Xia B, Wang H. Anti-depressive effectiveness of baicalin in vitro and in vivo. Molecules 2019;24:326. https://doi.org/10.3390/molecules24020326
  46. Zhou YH, Wang SS, Yang J, Tao JP, Xu YL, Huang YZ, Gao Q. [Expression of Toll-like receptor 4 in brain tissue of chronic Toxoplasma gondii infection rats and its effect on brain injury]. Chinese Journal of Schistosomiasis Control 2012;24:58-61. https://doi.org/10.3969/j.issn.1005-6661.2012.01.014
  47. Zhang ZH, Mi C, Wang KS, Wang Z, Li MY, Zuo HX, Xu GH, Li X, Piao LX, Ma J, et al. Chelidonine inhibits TNF-α-induced inflammation by suppressing the NF-κB pathways in HCT116 cells. Phytother Res 2018;32:65-75. https://doi.org/10.1002/ptr.5948