Skip to main content
SpringerLink
Log in

Inulae Flos has Anti-Depressive Effects by Suppressing Neuroinflammation and Recovering Dysfunction of HPA-axis

  • Research
  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Depression is a debilitating mood disorder that causes persistent feelings of sadness, emptiness, and a loss of joy. However, the clinical efficacy of representative drugs for depression, such as selective serotonin reuptake inhibitors, remains controversial. Therefore, there is an urgent need for more effective therapies to treat depression. Neuroinflammation and the hypothalamic-pituitary-adrenal (HPA) axis are pivotal factors in depression. Inulae Flos (IF), the flower of Inula japonica Thunb, is known for its antioxidant and anti-inflammatory effects. This study explored whether IF alleviates depression in both in vitro and in vivo models. For in vitro studies, we treated BV2 and PC12 cells damaged by lipopolysaccharides or corticosterone (CORT) with IF to investigate the mechanisms of depression. For in vivo studies, C57BL/6 mice were exposed to chronic restraint stress and were administered IF at doses of 0, 100, and 300 mg/kg for 2 weeks. IF inhibited pro-inflammatory mediators, such as nitric oxide, inducible nitric oxide synthase, and interleukins in BV2 cells. Moreover, IF increased the viability of CORT-damaged PC12 cells by modulating protein kinase B, a mammalian target of the rapamycin pathway. Behavioral assessments demonstrated that IF reduced depression-like behaviors in mice. We found that IF reduced the activation of microglia and astrocytes, and regulated synapse plasticity in the mice brains. Furthermore, IF lowered elevated CORT levels in the plasma and restored glucocorticoid receptor expression in the hypothalamus. Collectively, these findings suggest that IF can alleviate depression by mitigating neuroinflammation and recovering dysfunction of the HPA-axis.

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

Similar content being viewed by others

Data Availability

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

References

  1. Clack S, Ward T (2019) The classification and explanation of depression. Behav Change 36(1):41–55

    Article  Google Scholar 

  2. Organization WH (2008) The global burden of disease: 2004 update. World Health Organization

  3. Coppen A (1967) The biochemistry of affective disorders. Br J Psychiatry 113(504):1237–1264. https://doi.org/10.1192/bjp.113.504.1237

    Article  CAS  PubMed  Google Scholar 

  4. Harmer CJ, Duman RS, Cowen PJ (2017) How do antidepressants work? New perspectives for refining future treatment approaches. Lancet Psychiatry 4(5):409–418. https://doi.org/10.1016/S2215-0366(17)30015-9

    Article  PubMed  PubMed Central  Google Scholar 

  5. Jakobsen JC, Gluud C, Kirsch I (2020) Should antidepressants be used for major depressive disorder? BMJ Evidence-Based Med 25(4):130–130

    Article  Google Scholar 

  6. Moncrieff J, Cohen D (2006) Do antidepressants cure or create abnormal brain states? PLoS Med 3(7):e240. https://doi.org/10.1371/journal.pmed.0030240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Miller AH, Raison CL (2016) The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 16(1):22–34. https://doi.org/10.1038/nri.2015.5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hu P, Lu Y, Pan BX, Zhang WH (2022) New insights into the pivotal role of the Amygdala in inflammation-related depression and anxiety disorder. Int J Mol Sci 23(19). https://doi.org/10.3390/ijms231911076

  9. Haapakoski R, Mathieu J, Ebmeier KP, Alenius H, Kivimaki M (2015) Cumulative meta-analysis of interleukins 6 and 1beta, tumour necrosis factor alpha and C-reactive protein in patients with major depressive disorder. Brain Behav Immun 49:206–215. https://doi.org/10.1016/j.bbi.2015.06.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang H, He Y, Sun Z, Ren S, Liu M, Wang G, Yang J (2022) Microglia in depression: an overview of microglia in the pathogenesis and treatment of depression. J Neuroinflammation 19(1):132. https://doi.org/10.1186/s12974-022-02492-0

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ting EY, Yang AC, Tsai SJ (2020) Role of Interleukin-6 in depressive disorder. Int J Mol Sci 21(6). https://doi.org/10.3390/ijms21062194

  12. Varghese FP, Brown ES (2001) The hypothalamic-pituitary-adrenal Axis in Major Depressive disorder: a brief primer for Primary Care Physicians. Prim Care Companion J Clin Psychiatry 3(4):151–155. https://doi.org/10.4088/pcc.v03n0401

    Article  PubMed  PubMed Central  Google Scholar 

  13. Keller J, Gomez R, Williams G, Lembke A, Lazzeroni L, Murphy GM Jr., Schatzberg AF (2017) HPA axis in major depression: cortisol, clinical symptomatology and genetic variation predict cognition. Mol Psychiatry 22(4):527–536. https://doi.org/10.1038/mp.2016.120

    Article  CAS  PubMed  Google Scholar 

  14. Holsboer F (2000) The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23(5):477–501. https://doi.org/10.1016/S0893-133X(00)00159-7

    Article  CAS  PubMed  Google Scholar 

  15. De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M (1998) Brain corticosteroid receptor balance in health and disease. Endocr Rev 19(3):269–301. https://doi.org/10.1210/edrv.19.3.0331

    Article  PubMed  Google Scholar 

  16. Gong S, Miao YL, Jiao GZ, Sun MJ, Li H, Lin J, Luo MJ, Tan JH (2015) Dynamics and correlation of serum cortisol and corticosterone under different physiological or stressful conditions in mice. PLoS ONE 10(2):e0117503. https://doi.org/10.1371/journal.pone.0117503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Berger S, Gureczny S, Reisinger SN, Horvath O, Pollak DD (2019) Effect of Chronic Corticosterone Treatment on Depression-Like Behavior and Sociability in Female and Male C57BL/6 N Mice. Cells 8(9). https://doi.org/10.3390/cells8091018

  18. Anacker C, Zunszain PA, Carvalho LA, Pariante CM (2011) The glucocorticoid receptor: pivot of depression and of antidepressant treatment? Psychoneuroendocrinology 36(3):415–425. https://doi.org/10.1016/j.psyneuen.2010.03.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Settle EC Jr. (1998) Antidepressant drugs: disturbing and potentially dangerous adverse effects. J Clin Psychiatry 59 Suppl 16:25–30 discussion 40 – 22

    Google Scholar 

  20. Braund TA, Tillman G, Palmer DM, Gordon E, Rush AJ, Harris AWF (2021) Antidepressant side effects and their impact on treatment outcome in people with major depressive disorder: an iSPOT-D report. Transl Psychiatry 11(1):417. https://doi.org/10.1038/s41398-021-01533-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Noori T, Sureda A, Sobarzo-Sanchez E, Shirooie S (2022) The role of Natural products in treatment of depressive disorder. Curr Neuropharmacol 20(5):929–949. https://doi.org/10.2174/1570159X20666220103140834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yeung KS, Hernandez M, Mao JJ, Haviland I, Gubili J (2018) Herbal medicine for depression and anxiety: a systematic review with assessment of potential psycho-oncologic relevance. Phytother Res 32(5):865–891. https://doi.org/10.1002/ptr.6033

    Article  PubMed  PubMed Central  Google Scholar 

  23. Li J, Guo X, Luo Z, Wu D, Shi X, Xu L, Zhang Q, Xie C, Yang C (2024) Chemical constituents from the flowers of Inula Japonica and their anti-inflammatory activity. J Ethnopharmacol 318 (Pt B) 117052. https://doi.org/10.1016/j.jep.2023.117052

  24. Qin J-J, Jin H-Z, Zhu J-X, Fu J-J, Zeng Q, Cheng X-R, Zhu Y, Shan L, Zhang S-D, Pan Y-X (2010) New sesquiterpenes from Inula Japonica Thunb. With their inhibitory activities against LPS-induced NO production in RAW264. 7 macrophages. Tetrahedron 66(48):9379–9388

    Article  CAS  Google Scholar 

  25. Qin JJ, Jin HZ, Fu JJ, Hu XJ, Wang Y, Yan SK, Zhang WD (2009) Japonicones A-D, bioactive dimeric sesquiterpenes from Inula Japonica Thunb. Bioorg Med Chem Lett 19(3):710–713. https://doi.org/10.1016/j.bmcl.2008.12.043

    Article  CAS  PubMed  Google Scholar 

  26. Qin JJ, Wang LY, Zhu JX, Jin HZ, Fu JJ, Liu XF, Li HL, Zhang WD (2011) Neojaponicone A, a bioactive sesquiterpene lactone dimer with an unprecedented carbon skeleton from Inula Japonica. Chem Commun (Camb) 47(4):1222–1224. https://doi.org/10.1039/c0cc03572f

    Article  CAS  PubMed  Google Scholar 

  27. Wang X, Li Y, Liu W, Shen Y, Lin Z, Nakajima A, Xu J, Guo Y (2023) A polysaccharide from Inula Japonica showing in vivo antitumor activity by interacting with TLR-4, PD-1, and VEGF. Int J Biol Macromol 246:125555. https://doi.org/10.1016/j.ijbiomac.2023.125555

    Article  CAS  PubMed  Google Scholar 

  28. Lu Y, Li Y, Jin M, Yang JH, Li X, Chao GH, Park HH, Park YN, Son JK, Lee E, Chang HW (2012) Inula Japonica extract inhibits mast cell-mediated allergic reaction and mast cell activation. J Ethnopharmacol 143(1):151–157. https://doi.org/10.1016/j.jep.2012.06.015

    Article  CAS  PubMed  Google Scholar 

  29. Kim SH, Ju IG, Kim JH, Eo H, Son SR, Jang DS, Oh MS (2023) Linderae Radix ameliorates cognitive dysfunction by inhibiting neuroinflammation and synaptic damage in Alzheimer’s Disease models. Mol Neurobiol. https://doi.org/10.1007/s12035-023-03544-z

    Article  PubMed  PubMed Central  Google Scholar 

  30. Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8(1):57–69. https://doi.org/10.1038/nrn2038

    Article  CAS  PubMed  Google Scholar 

  31. Heras-Sandoval D, Perez-Rojas JM, Hernandez-Damian J, Pedraza-Chaverri J (2014) The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cell Signal 26(12):2694–2701. https://doi.org/10.1016/j.cellsig.2014.08.019

    Article  CAS  PubMed  Google Scholar 

  32. Duman RS, Aghajanian GK, Sanacora G, Krystal JH (2016) Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med 22(3):238–249. https://doi.org/10.1038/nm.4050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jha MK, Jeon S, Suk K (2012) Glia as a link between Neuroinflammation and Neuropathic Pain. Immune Netw 12(2):41–47. https://doi.org/10.4110/in.2012.12.2.41

    Article  PubMed  PubMed Central  Google Scholar 

  34. Guo J, Qiu T, Wang L, Shi L, Ai M, Xia Z, Peng Z, Zheng A, Li X, Kuang L (2022) Microglia loss and astrocyte activation cause dynamic changes in hippocampal [(18)F]DPA-714 uptake in mouse models of Depression. Front Cell Neurosci 16:802192. https://doi.org/10.3389/fncel.2022.802192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Troncoso-Escudero P, Parra A, Nassif M, Vidal RL (2018) Outside in: unraveling the role of Neuroinflammation in the progression of Parkinson’s Disease. Front Neurol 9:860. https://doi.org/10.3389/fneur.2018.00860

    Article  PubMed  PubMed Central  Google Scholar 

  36. Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT (2018) Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement (N Y) 4:575–590. https://doi.org/10.1016/j.trci.2018.06.014

    Article  PubMed  Google Scholar 

  37. Skrzypczak-Wiercioch A, Salat K (2022) Lipopolysaccharide-Induced Model of Neuroinflammation: mechanisms of Action, Research Application and future directions for its use. Molecules 27(17). https://doi.org/10.3390/molecules27175481

  38. O’Connor JC, Lawson MA, Andre 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. https://doi.org/10.1038/sj.mp.4002148

    Article  CAS  PubMed  Google Scholar 

  39. Batista CRA, Gomes GF, Candelario-Jalil E, Fiebich BL, de Oliveira ACP (2019) Lipopolysaccharide-Induced Neuroinflammation as a bridge to Understand Neurodegeneration. Int J Mol Sci 20(9). https://doi.org/10.3390/ijms20092293

  40. Juruena MF, Cleare AJ, Papadopoulos AS, Poon L, Lightman S, Pariante CM (2006) Different responses to dexamethasone and prednisolone in the same depressed patients. Psychopharmacology 189(2):225–235. https://doi.org/10.1007/s00213-006-0555-4

    Article  CAS  PubMed  Google Scholar 

  41. Barnes PJ (2017) Glucocorticosteroids. Handb Exp Pharmacol 237:93–115. https://doi.org/10.1007/164_2016_62

    Article  CAS  PubMed  Google Scholar 

  42. Chourpiliadis C, Aeddula NR (2023) Physiology, glucocorticoids. In: StatPearls. Treasure Island (FL)

  43. Sousa N, Cerqueira JJ, Almeida OF (2008) Corticosteroid receptors and neuroplasticity. Brain Res Rev 57(2):561–570. https://doi.org/10.1016/j.brainresrev.2007.06.007

    Article  CAS  PubMed  Google Scholar 

  44. Neigh GN, Nemeroff CB (2006) Reduced glucocorticoid receptors: consequence or cause of depression? Trends Endocrinol Metab 17(4):124–125. https://doi.org/10.1016/j.tem.2006.03.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bridges N, Slais K, Sykova E (2008) The effects of chronic corticosterone on hippocampal astrocyte numbers: a comparison of male and female Wistar rats. Acta Neurobiol Exp (Wars) 68(2):131–138. https://doi.org/10.55782/ane-2008-1682

    Article  PubMed  Google Scholar 

  46. Khantakova JN, Mutovina A, Ayriyants KA, Bondar NP (2023) Th17 cells, glucocorticoid resistance, and Depression. Cells 12(23). https://doi.org/10.3390/cells12232749

  47. Barnes PJ (2010) Mechanisms and resistance in glucocorticoid control of inflammation. J Steroid Biochem Mol Biol 120(2–3):76–85. https://doi.org/10.1016/j.jsbmb.2010.02.018

    Article  CAS  PubMed  Google Scholar 

  48. O’Callaghan JP, Brinton RE, McEwen BS (1989) Glucocorticoids regulate the concentration of glial fibrillary acidic protein throughout the brain. Brain Res 494(1):159–161. https://doi.org/10.1016/0006-8993(89)90156-x

    Article  PubMed  Google Scholar 

  49. Rozovsky I, Laping NJ, Krohn K, Teter B, O’Callaghan JP, Finch CE (1995) Transcriptional regulation of glial fibrillary acidic protein by corticosterone in rat astrocytes in vitro is influenced by the duration of time in culture and by astrocyte-neuron interactions. Endocrinology 136(5):2066–2073. https://doi.org/10.1210/endo.136.5.7720656

    Article  CAS  PubMed  Google Scholar 

  50. Uno H, Eisele S, Sakai A, Shelton S, Baker E, DeJesus O, Holden J (1994) Neurotoxicity of glucocorticoids in the primate brain. Horm Behav 28(4):336–348. https://doi.org/10.1006/hbeh.1994.1030

    Article  CAS  PubMed  Google Scholar 

  51. Polman JA, Hunter RG, Speksnijder N, van den Oever JM, Korobko OB, McEwen BS, de Kloet ER, Datson NA (2012) Glucocorticoids modulate the mTOR pathway in the hippocampus: differential effects depending on stress history. Endocrinology 153(9):4317–4327. https://doi.org/10.1210/en.2012-1255

    Article  CAS  PubMed  Google Scholar 

  52. Ignacio ZM, Reus GZ, Arent CO, Abelaira HM, Pitcher MR, Quevedo J (2016) New perspectives on the involvement of mTOR in depression as well as in the action of antidepressant drugs. Br J Clin Pharmacol 82(5):1280–1290. https://doi.org/10.1111/bcp.12845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chuang HW, Wei IH, Lin FY, Li CT, Chen KT, Tsai MH, Huang CC (2020) Roles of Akt and ERK in mTOR-Dependent Antidepressant effects of Vanillic Acid. ACS Omega 5(7):3709–3716. https://doi.org/10.1021/acsomega.9b04271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This research was supported by grants from the National Research Foundation of Korea, funded by the Korean government (2022M3A9B6017813).

Author information

Author notes

  1. Jin Se Kim and Jin Hee Kim contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, Republic of Korea

    Jin Se Kim, Jin Hee Kim, Hyeyoon Eo, So-ri Son, Dae Sik Jang & Myung Sook Oh

  2. Department of Oriental Pharmaceutical Science and Kyung Hee East-West Pharmaceutical Research Institute, College of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea

    In Gyoung Ju & Myung Sook Oh

  3. College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea

    Ji-Woon Kim

Authors
  1. Jin Se Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jin Hee Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hyeyoon Eo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. In Gyoung Ju
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. So-ri Son
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ji-Woon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dae Sik Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Myung Sook Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Jin Se Kim: Conceptualization, Investigation, Writing – Original Draft Preparation; Jin Hee Kim: Investigation, Writing – Original Draft Preparation; Hyeyoon Eo: Writing – Review & Editing; In Gyoung Ju: Writing – Review & Editing; So-Ri Son: Investigation; Ji-Woon Kim: Supervision; Dae Sik Jang: Supervision; Myung Sook Oh: Conceptualization, Supervision, Writing – Review & Editing.

Corresponding author

Correspondence to Myung Sook Oh.

Ethics declarations

Ethical Approval

All animal studies were performed in accordance with the Guide for the Care and Use of Laboratory Animals, 8th edition (National Institutes of Health, 2011), and approved by the Animal Care and Use Guidelines of Kyung Hee University, Seoul, Republic of Korea (approval number: KHSASP-23–451).

Conflicts of Interest

The authors declare that there are no conflicts 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

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, J.S., Kim, J.H., Eo, H. et al. Inulae Flos has Anti-Depressive Effects by Suppressing Neuroinflammation and Recovering Dysfunction of HPA-axis. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04094-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12035-024-04094-8

Keywords

Search

Navigation