Metabolic Brain Disease

, Volume 33, Issue 5, pp 1413–1420 | Cite as

Gentiopicroside abrogates lipopolysaccharide-induced depressive-like behavior in mice through tryptophan-degrading pathway

  • Ya-ting DengEmail author
  • Ming-gao ZhaoEmail author
  • Tian-jiao Xu
  • Jin-Hou
  • Xin-hua Li
Original Article


Targeting neuroinflammatory disturbances has been acknowledged as a potential strategy for treatment of depressive disorder in humans. Over-activation of tryptophan-degrading pathway by pro-inflammatory cytokines resulted in N-methyl-d-aspartate (NMDA)-mediated excitotoxicity, which is implicated in pathophysiology of depression. Gentiopicroside (Gent) has powerful anti-inflammatory property and exhibits promising antidepressant effect in an animal model of pain/depression dyad by down-regulating GluN2B-containing NMDA receptors. Therefore, the present study aimed to investigate the ability of Gent to abolish depressive-like behavior induced by lipopolysaccharide (LPS) in mice. Acute administration of LPS (0.5 mg/kg, i.p.) increased immobility time in both forced swimming test (FST) and tail suspension test (TST) without affecting spontaneous locomotor activity, indicative of depressive-like behavior. Gent (50 mg/kg, i.p.) administered once a day for three consecutive days prevented the development of depressive-like behavior induced by LPS. The antidepressant-like effect was paralleled with restoration of LPS-induced alterations in brain inflammatory mediators (i.e. IL-1β and TNF-α). In addition, Gent prevented over-activation of indoleamine 2,3-double oxygen enzyme (IDO) and recovered GluN2B subunit expression in the PFC challenged by LPS. In conclusion, our results suggested that Gent pretreatment provided protection against LPS-induced depressive-like behavior and the effect appeared to be demonstrated, at least partially, by blocking various steps of tryptophan-degrading pathway.


Gentiopicroside Depressive-like behavior LPS Tryptophan-degrading pathway 







Major depressive disorder


Indoleamine 2,3-double oxygen enzyme


Forced swimming test


Tail suspension test


Open field




Central nervous system


Basolateral amygdala


Prefrontal cortex



This research was supported by National Natural Science Foundation of China, No. 81403064; Doctoral research foundation of Xi’an Medical University, No. 2016DOC23 and Nature science research plan in shannxi province of China, No.2016JM8047.


  1. Bossù P, Cutuli D, Palladino I et al (2012) A single intraperitoneal injection of endotoxin in rats induces long-lasting modifications in behavior and brain protein levels of TNF-α and IL-18. J Neuroinflammation 9(101).
  2. Chen L, Liu JC, Zhang XN et al (2008) Down-regulation of NR2B receptors partially contributes to analgesic effects of Gentiopicroside in persistent inflammatory pain. Neuropharmacology 54:1175–1181. CrossRefPubMedGoogle Scholar
  3. Custodio CS, Mello BS, Cordeiro RC et al (2013) Time course of the effects of lipopolysaccharide on prepulse inhibition and brain nitrite content in mice. Eur J Pharmacol 713:31–38. CrossRefPubMedGoogle Scholar
  4. Dobos N, de Vries EF, Kema IP et al (2012) The role of indoleamine 2,3-dioxygenase in a mouse model of neuroinflammation-induced depression. J Alzheimers Dis 28(4):905–915. CrossRefPubMedGoogle Scholar
  5. Fu X, Zunich SM, O'Connor JC, Kavelaars A, Dantzer R, Kelley KW (2010) Central administration of lipopolysaccharide induces depressive-like behavior in vivo and activates brain indoleamine 2,3 dioxygenase in murine organotypic hippocampal slice cultures. J Neuroinflammation 7:43–54. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Glowinski J, Iversen LL (1966) Regional studies of catecholamines in the rat brain. I. The disposition of [3H]norepinephrine, [3H]dopamine and [3H]dopa in various regions of the brain. J Neurochem 13(8):655–669CrossRefPubMedGoogle Scholar
  7. Guo J, Lin P, Zhao X et al (2014) Etazolate abrogates the lipopolysaccharide (LPS)-induced downregulation of the cAMP/pCREB/BDNF signaling, neuroinflammatory response and depressive-likebehavior in mice. Neuroscience 263:1–14. CrossRefPubMedGoogle Scholar
  8. Guo Y, Cai H, Chen L et al (2016) Quantitative profiling of neurotransmitter abnormalities in the hippocampus of rats treated with lipopolysaccharide: focusing on kynurenine pathway and implications for depression. J Neuroimmunol 295–296:41–46. CrossRefPubMedGoogle Scholar
  9. Heydarpour P, Salehi-Sadaghiani M, Javadi-Paydar M, Rahimian R, Fakhfouri G, Khosravi M, Khoshkish S, Gharedaghi MH, Ghasemi M, Dehpour AR (2013) Estradiol reduces depressive-like behavior through inhibiting nitric oxide/cyclic GMP pathway in ovariectomized mice. Horm Behav 63(2):361–369. CrossRefPubMedGoogle Scholar
  10. Huang Y, Louie A, Yang Q, Massenkoff N, Xu C, Hunt PW, Gee W (2013) A simple LC-MS/MS method for determination of kynurenine and tryptophan concentrations in human plasma from HIV-infected patients. Bioanalysis 5(11):1397–1407. CrossRefPubMedGoogle Scholar
  11. Jia N, Chu W, Li Y, Ding L, Duan J, Cui J, Cao S, Zhao C, Wu Y, Wen A (2016) Iridoid glycosides from the flowers of Gentiana macrophylla pall. Ameliorate collagen-induced arthritis in rats. J Ethnopharmacol 189:1–9. CrossRefPubMedGoogle Scholar
  12. Krause DL, Riedel M, Müller N, Weidinger E, Schwarz MJ, Myint AM (2012) Effects of antidepressants and cyclooxygenase-2 inhibitor on cytokines and kynurenines in stimulated in vitro blood culture from depressed patients. Inflammopharmacology 20(3):169–176. CrossRefPubMedGoogle Scholar
  13. Lejuez CW, Hopko DR, Acierno R, Daughters SB, Pagoto SL (2011) Ten year revision of the brief behavioral activation treatment for depression: revised treatment manual. Behav Modif 35:111–161. CrossRefPubMedGoogle Scholar
  14. Liu SB, Zhao R, Li XS, Guo HJ, Tian Z, Zhang N, Gao GD, Zhao MG (2014) Attenuation of reserpine-induced pain/depression dyad by gentiopicroside through downregulation of GluN2B receptors in the amygdala of mice. NeuroMolecular Med 16(2):350–359. CrossRefPubMedGoogle Scholar
  15. Mello BS, Monte AS, McIntyre RS et al (2013) Effects of doxycycline on depressive-like behavior in mice after lipopolysaccharide (LPS) administration. J Psychiatr Res 47(10):1521–1529. CrossRefPubMedGoogle Scholar
  16. Mendlewicz J, Kriwin P, Oswald P, Souery D, Alboni S, Brunello N (2006) Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int Clin Psychopharmacol 21(4):227–231CrossRefPubMedGoogle Scholar
  17. Müller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Müller B, Spellmann I, Hetzel G, Maino K, Kleindienst N, Möller HJ, Arolt V, Riedel M (2006) The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry 11(7):680–684CrossRefPubMedGoogle Scholar
  18. Nguyen KT, Deak T, Owens SM et al (1998) Exposure to acute stress induces brain interleukin-1beta protein in the rat, J Neurosci. 18(6):2239–2246
  19. Niu YT, Zhao YP, Jiao YF, Zheng J, Yang WL, Zhou R, Niu Y, Sun T, Li YX, Yu JQ (2016) Protective effect of gentiopicroside against dextran sodium sulfate induced colitis in mice. Int Immunopharmacol 39:16–22. CrossRefPubMedGoogle Scholar
  20. O'Connor JC, Lawson MA, André C, Moreau M, Lestage J, Castanon N, Kelley KW, Dantzer R (2009) Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry 14(5):511–522. CrossRefPubMedGoogle Scholar
  21. Patel A (2013) Review: the role of inflammation in depression. Psychiatr Danub Suppl 2:S216–S223Google Scholar
  22. Rothwell NJ, Luheshi GN (2000) Interleukin 1 in the brain: biology, pathology and therapeutic target. Trends Neurosci 23(12):618–625CrossRefPubMedGoogle Scholar
  23. Saito K, Markey SP, Heyes MP (1992) Effects of immune activation on quinolinic acid and neuroactive kynurenines in the mouse. Neurosci 51:25–39CrossRefGoogle Scholar
  24. Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new methodfor screening antidepressants in mice. Psychopharmacology 85:367–370CrossRefPubMedGoogle Scholar
  25. Tomaz VS, Cordeiro RC, Costa AM (2014) Antidepressant-like effect of nitric oxide synthase inhibitors and sildenafil against lipopolysaccharide-induced depressive-like behavior in mice. Neurosci 268:236–246. CrossRefGoogle Scholar
  26. Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A, Lalla D, Woolley M, Jahreis A, Zitnik R, Cella D, Krishnan R (2006) Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet 367(9504):29–35CrossRefPubMedGoogle Scholar
  27. Walker AK, Budac DP, Bisulco S, Lee AW, Smith RA, Beenders B, Kelley KW, Dantzer R (2013) NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induceddepressive-like behavior in C57BL/6J mice. Neuropsychopharmacology 38:1609–1616. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Walker AK, Kavelaars A, Heijnen CJ, Dantzer R (2014) Neuroinflammation and comorbidity of pain and depression. Pharmacol Rev 66:80–101CrossRefPubMedPubMedCentralGoogle Scholar
  29. Wang Z, Zhang Q, Yuan L et al (2014) The effects of curcumin on depressive-like behavior in mice after lipopolysaccharide administration. Behav Brain Res 274:282–290. CrossRefPubMedGoogle Scholar
  30. Young JJ, Bruno D, Pomara N (2014) A review of the relationship between proinflammatory cytokines and major depressive disorder. J Affect Disord 169:15–20. CrossRefPubMedGoogle Scholar
  31. Zhao L, Ye J, Wu GT, Peng XJ, Xia PF, Ren Y (2015) Gentiopicroside prevents interleukin-1 beta induced inflammation response in rat articular chondrocyte. J Ethnopharmacol 172:100–107. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmacology, School of PharmacyXi’an Medical UniversityXi’anChina
  2. 2.Department of PharmacologyFourth Military Medical UniversityXi’anChina

Personalised recommendations