Skip to main content
SpringerLink
Log in

The antidepressant effects of asperosaponin VI are mediated by the suppression of microglial activation and reduction of TLR4/NF-κB-induced IDO expression

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Aim

Indoleamine 2,3-dioxygenase 1 (IDO) is responsible for the progression of the kynurenine pathway, which has been implicated in the pathophysiology of inflammation-induced depression. It has been reported that asperosaponin VI (ASA VI) could play a neuroprotective role through anti-inflammatory and antioxidant. In this study, we examined the antidepressant effect of ASA VI in lipopolysaccharide (LPS)-treated mice and further explored its molecular mechanism by looking into the microglial kynurenine pathway.

Methods

To generate the model, LPS (0.83 mg/kg) was administered intraperitoneally to mice. The mice received ASA VI (10 mg/kg, 20 mg/kg, 40 mg/kg, and 80 mg/kg, i.p.) 30 min before LPS injection. Depressive-like behaviors were evaluated based on the duration of immobility in the forced swim test. Microglial activation and inflammatory cytokines were detected by immunohistochemistry, real-time PCR, and ELISA. The TLR4/NF-κB signaling pathway and the expression of IDO, GluA2, and CamKIIβ were also measured by western blotting.

Results

ASA VI exhibited significant antidepressant activity in the presence of LPS on immobility and latency times in the forced swim test. The LPS-induced activation of microglia and inflammatory response were inhibited by ASA VI, which showed a dose-dependent pattern. TLR4/NF-κB signaling pathway also was suppressed by ASA VI in the hippocampus and prefrontal cortex of LPS-treated mice. Furthermore, ASA VI inhibited the increase in IDO protein expression and normalized the aberrant glutamate transmission in the hippocampus and prefrontal cortex caused by LPS administration.

Conclusion

Our results propose a promising antidepressant effect for ASA VI possibly through the downregulation of IDO expression and normalization of the aberrant glutamate transmission. This remedying effect of ASA VI could be attributed to suppress microglia-mediated neuroinflammatory response via inhibiting the TLR4/NF-κB signaling pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Agudelo LZ, Femenia T, Orhan F, Porsmyr-Palmertz M, Goiny M, Martinez-Redondo V, Correia JC, Izadi M, Bhat M, Schuppe-Koistinen I, Pettersson AT, Ferreira DMS, Krook A, Barres R, Zierath JR, Erhardt S, Lindskog M, Ruas JL (2014) Skeletal muscle PGC-1alpha1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell 159:33–45

    CAS  PubMed  Google Scholar 

  • Al-Harbi KS (2012) Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence 6:369–388

    PubMed  PubMed Central  Google Scholar 

  • Brites D, Fernandes A (2015) Neuroinflammation and depression: microglia activation, extracellular microvesicles and microRNA dysregulation. Front Cell Neurosci 9:476

    PubMed  PubMed Central  Google Scholar 

  • Corona AW, Norden DM, Skendelas JP, Huang Y, O’Connor JC, Lawson M, Dantzer R, Kelley KW, Godbout JP (2013) Indoleamine 2,3-dioxygenase inhibition attenuates lipopolysaccharide induced persistent microglial activation and depressive-like complications in fractalkine receptor (CX(3)CR1)-deficient mice. Brain Behav Immun 31:134–142

    CAS  PubMed  Google Scholar 

  • Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9:46–56

    CAS  PubMed  PubMed Central  Google Scholar 

  • Du HX, Chen XG, Zhang L, Liu Y, Zhan CS, Chen J, Zhang Y, Yu ZQ, Zhang J, Yang HY, Zhong K, Liang CZ (2019) Microglial activation and neurobiological alterations in experimental autoimmune prostatitis-induced depressive-like behavior in mice. Neuropsychiatr Dis Treat 15:2231–2245

    CAS  PubMed  PubMed Central  Google Scholar 

  • Duman RS, Aghajanian GK (2012) Synaptic dysfunction in depression: potential therapeutic targets. Science 338:68–72

    CAS  PubMed  PubMed Central  Google Scholar 

  • Frick LR, Williams K, Pittenger C (2013) Microglial dysregulation in psychiatric disease. Clin Dev Immunol 2013:608654

    PubMed  PubMed Central  Google Scholar 

  • Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, Samokhvalov IM, Merad M (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845

    CAS  PubMed  PubMed Central  Google Scholar 

  • Guo DK, Zhu Y, Sun HY, Xu XY, Zhang S, Hao ZB, Wang GH, Mu CC, Ren HG (2019) Pharmacological activation of REV-ERBalpha represses LPS-induced microglial activation through the NF-kappaB pathway. Acta Pharmacol Sin 40:26–34

    CAS  PubMed  Google Scholar 

  • Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394

    CAS  PubMed  Google Scholar 

  • Hashmi AM, Butt Z, Umair M (2013) Is depression an inflammatory condition? A review of available evidence. J Pak Med Assoc 63:899–906

    PubMed  Google Scholar 

  • Hemmati S, Sadeghi MA, Mohammad Jafari R, Yousefi-Manesh H, Dehpour AR (2019) The antidepressant effects of GM-CSF are mediated by the reduction of TLR4/NF-kB-induced IDO expression. 16, 117

  • Jiang J, Jian Q, Jing M, Zhang Z, Zhang G, Shan L, Yu P, Wang Y, Xu L (2019) The novel N-methyl-d-aspartate receptor antagonist MN-08 ameliorates lipopolysaccharide-induced acute lung injury in mice. Int Immunopharmacol 66:109–118

    CAS  PubMed  Google Scholar 

  • Jung YS, Park JH, Kim H, Kim SY, Hwang JY, Hong KW, Bae SS, Choi BT, Lee SW, Shin HK (2016) Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice. Acta Pharmacol Sin 37:1031–1044

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ke K, Li Q, Yang X, Xie Z, Wang Y, Shi J, Chi L, Xu W, Hu L, Shi H (2016) Asperosaponin VI promotes bone marrow stromal cell osteogenic differentiation through the PI3K/AKT signaling pathway in an osteoporosis model. Sci Rep 6:35233

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kohler O, Krogh J, Mors O, Benros ME (2016) Inflammation in depression and the potential for anti-inflammatory treatment. Curr Neuropharmacol 14:732–742

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kubicova L, Hadacek F, Chobot V (2013) Quinolinic acid: neurotoxin or oxidative stress modulator? Int J Mol Sci 14:21328–21338

    CAS  PubMed  PubMed Central  Google Scholar 

  • Leal RB, Lopes MW (2018) Amygdala levels of the GluA1 subunit of glutamate receptors and its phosphorylation state at serine 845 in the anterior hippocampus are biomarkers of ictal fear but not anxiety

  • Lee JS, Song JH, Sohn NW, Shin JW (2013) Inhibitory effects of ginsenoside Rb1 on neuroinflammation following systemic lipopolysaccharide treatment in mice. Phytother Res 27:1270–1276

    CAS  PubMed  Google Scholar 

  • Martinez JA, Milagro FI, Claycombe KJ, Schalinske KL (2014) Epigenetics in adipose tissue, obesity, weight loss, and diabetes. Adv Nutr 5:71–81

    CAS  PubMed  PubMed Central  Google Scholar 

  • O’Connor JC, Andre C, Wang Y, Lawson MA, Szegedi SS, Lestage J, Castanon N, Kelley KW, Dantzer R (2009a) Interferon-gamma and tumor necrosis factor-alpha mediate the upregulation of indoleamine 2,3-dioxygenase and the induction of depressive-like behavior in mice in response to bacillus Calmette-Guerin. J Neurosci 29:4200–4209

    PubMed  PubMed Central  Google Scholar 

  • O’Connor JC, Lawson MA, Andre C, Moreau M, Lestage J, Castanon N, Kelley KW, Dantzer R (2009b) Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry 14:511–522

    PubMed  Google Scholar 

  • Ogyu K, Kubo K, Noda Y, Iwata Y, Tsugawa S, Omura Y, Wada M, Tarumi R, Plitman E, Moriguchi S, Miyazaki T, Uchida H, Graff-Guerrero A, Mimura M, Nakajima S (2018) Kynurenine pathway in depression: a systematic review and meta-analysis. Neurosci Biobehav Rev 90:16–25

    CAS  PubMed  Google Scholar 

  • Oxenkrug GF (2010) Tryptophan kynurenine metabolism as a common mediator of genetic and environmental impacts in major depressive disorder: the serotonin hypothesis revisited 40 years later. Isr J Psychiatry Relat Sci 47:56–63

    PubMed  PubMed Central  Google Scholar 

  • Pan N, Lu LY, Li M, Wang GH, Sun FY, Sun HS, Wen XJ, Cheng JD, Chen JW, Pang JY, Liu J, Guan YY, Zhao LY, Chen WL, Wang GL (2017) Xyloketal B alleviates cerebral infarction and neurologic deficits in a mouse stroke model by suppressing the ROS/TLR4/NF-kappaB inflammatory signaling pathway. Acta Pharmacol Sin 38:1236–1247

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rajabi M, Mohaddes G, Farajdokht F, Nayebi Rad S, Mesgari M, Babri S (2018) Impact of loganin on pro-inflammatory cytokines and depression- and anxiety-like behaviors in male diabetic rats. Physiol Int 105:199–209

    CAS  PubMed  Google Scholar 

  • Savitz J (2017) Role of kynurenine metabolism pathway activation in major depressive disorders. Curr Top Behav Neurosci 31:249–267

    CAS  PubMed  Google Scholar 

  • Schwarcz R, Stone TW (2017) The kynurenine pathway and the brain: challenges, controversies and promises. Neuropharmacology 112:237–247

    CAS  PubMed  Google Scholar 

  • Schwarcz R, Bruno JP, Muchowski PJ, Wu HQ (2012) Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci 13:465–477

    CAS  PubMed  PubMed Central  Google Scholar 

  • Song L, Wang S, Duan X, Liu X, Li Z, Nie L, Chu G (2014) Chromatographic fingerprint combined with content of asperosaponin VI and antioxidant activity for quality evaluation of wine-fried Dipsaci Radix. Nat Prod Commun 9:773–778

    CAS  PubMed  Google Scholar 

  • Subramaniapillai M, McIntyre RS (2017) A review of the neurobiology of obesity and the available pharmacotherapies. CNS Spectr 22:29–38

    PubMed  Google Scholar 

  • Walker AK, Budac DP, Bisulco S, Lee AW, Smith RA, Beenders B, Kelley KW, Dantzer R (2013) NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice. Neuropsychopharmacology 38:1609–1616

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Lawson MA, Dantzer R, Kelley KW (2010a) LPS-induced indoleamine 2,3-dioxygenase is regulated in an interferon-gamma-independent manner by a JNK signaling pathway in primary murine microglia. Brain Behav Immun 24:201–209

    PubMed  Google Scholar 

  • Wang Y, Lawson MA, Kelley KW, Dantzer R (2010b) Primary murine microglia are resistant to nitric oxide inhibition of indoleamine 2,3-dioxygenase. Brain Behav Immun 24:1249–1253

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Shen J, Yang X, Jin Y, Yang Z, Wang R, Zhang F, Linhardt RJ (2018) Akebia saponin D reverses corticosterone hypersecretion in an Alzheimer’s disease rat model. Biomed Pharmacother 107:219–225

    CAS  PubMed  Google Scholar 

  • Yan Y, Wang YL, Su Z, Zhang Y, Guo SX, Liu AJ, Wang CH, Sun FJ, Yang J (2014) Effect of oxytocin on the behavioral activity in the behavioral despair depression rat model. Neuropeptides 48:83–89

    CAS  PubMed  Google Scholar 

  • Yang S, Zhang W, Xuan LL, Han FF, Lv YL, Wan ZR, Liu H, Ren LL, Gong LL, Liu LH (2019) Akebia Saponin D inhibits the formation of atherosclerosis in ApoE(-/-) mice by attenuating oxidative stress-induced apoptosis in endothelial cells. Atherosclerosis 285:23–30

    CAS  PubMed  Google Scholar 

  • Yirmiya R, Rimmerman N, Reshef R (2015) Depression as a microglial disease. Trends Neurosci 38:637–658

    CAS  PubMed  Google Scholar 

  • Yu X, Wang LN, Du QM, Ma L, Chen L, You R, Liu L, Ling JJ, Yang ZL, Ji H (2012) Akebia Saponin D attenuates amyloid beta-induced cognitive deficits and inflammatory response in rats: involvement of Akt/NF-kappaB pathway. Behav Brain Res 235:200–209

    CAS  PubMed  Google Scholar 

  • Zhang JQ, Wu XH, Feng Y, Xie XF, Fan YH, Yan S, Zhao QY, Peng C, You ZL (2016) Salvianolic acid B ameliorates depressive-like behaviors in chronic mild stress-treated mice: involvement of the neuroinflammatory pathway. Acta Pharmacol Sin 37:1141–1153

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Xie X, Tang M, Zhang J, Zhang B, Zhao Q, Han Y, Yan W, Peng C, You Z (2017) Salvianolic acid B promotes microglial M2-polarization and rescues neurogenesis in stress-exposed mice. Brain Behav Immun 66:111–124

    CAS  PubMed  Google Scholar 

  • Zhang L, Zhang J, You Z (2018) Switching of the microglial activation phenotype is a possible treatment for depression disorder. Front Cell Neurosci 12:306

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang W, Xue K, Gao Y, Huai Y, Wang W, Miao Z, Dang K, Jiang S, Qian A (2019) Systems pharmacology dissection of action mechanisms of Dipsaci Radix for osteoporosis. Life Sci 235:116820

    CAS  PubMed  Google Scholar 

  • Zhu M, Liu M, Guo QL, Zhu CQ, Guo JC (2018) Prolonged DADLE exposure epigenetically promotes Bcl-2 expression and elicits neuroprotection in primary rat cortical neurons via the PI3K/Akt/NF-kappaB pathway. Acta Pharmacol Sin 39:1582–1589

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank Professor Lanping Guo at the Resource Center of the Chinese Academy of Traditional Chinese Medicine for giving us guidance on the experiment and writing. We are grateful to Jun Yu for help in revising the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (81860675), Guizhou Science and Technology Plan Project ([2019]5611), and Department of Science and Technology of Guizhou High-level Innovative Talents ([2018]5638).

Author information

Authors and Affiliations

  1. Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, China

    Jinqiang Zhang, Saini Yi, Yahui Li, Chenghong Xiao, Chan Liu, Weike Jiang, Changgui Yang & Tao Zhou

Authors
  1. Jinqiang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Saini Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yahui Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chenghong Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Weike Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Changgui Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tao Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JQZ, SNY, and TZ designed the conceptual idea for this study and wrote the manuscript. SNY, YHL, CHX, and CL performed the experiments and analyzed these data. CGY and WKJ contributed new analytical tools and reagents. All the authors participated in the discussion and approved the manuscript as submitted.

Corresponding author

Correspondence to Tao Zhou.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Table S1

(DOCX 16 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, J., Yi, S., Li, Y. et al. The antidepressant effects of asperosaponin VI are mediated by the suppression of microglial activation and reduction of TLR4/NF-κB-induced IDO expression. Psychopharmacology 237, 2531–2545 (2020). https://doi.org/10.1007/s00213-020-05553-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-020-05553-5

Keywords

Search

Navigation