Download PDF
CC BY-NC-ND 4.0 · Planta Med 2023; 89(03): 262-272
DOI: 10.1055/a-1902-4244
Biological and Pharmacological Activity
Original Papers

Icariin Improves Glucocorticoid Resistance in a Murine Model of Asthma with Depression Associated with Enhancement of GR Expression and Function

Hualiang Jin  ‡
Department of Respiratory Diseases, Affiliated Hangzhou First Peopleʼs Hospital, Zhejiang University School of Medicine, Hangzhou, China
,
Yan Zhou‡
Department of Respiratory Diseases, Affiliated Hangzhou First Peopleʼs Hospital, Zhejiang University School of Medicine, Hangzhou, China
,
Jian Ye
Department of Respiratory Diseases, Affiliated Hangzhou First Peopleʼs Hospital, Zhejiang University School of Medicine, Hangzhou, China
,
Chenhui Qiu
Department of Respiratory Diseases, Affiliated Hangzhou First Peopleʼs Hospital, Zhejiang University School of Medicine, Hangzhou, China
,
Weizhong Jin
Department of Respiratory Diseases, Affiliated Hangzhou First Peopleʼs Hospital, Zhejiang University School of Medicine, Hangzhou, China
,
Limin Wang
Department of Respiratory Diseases, Affiliated Hangzhou First Peopleʼs Hospital, Zhejiang University School of Medicine, Hangzhou, China
› Author AffiliationsSupported by: Zhejiang Provincial Natural Science Foundation of China LY19H290011
› Further Information
   Permissions and Reprints

Abstract

Icariin, a flavonoid glycoside isolated from Epimedium brevicornum, exerts a variety of biological activities. However, its effects on depression-induced glucocorticoid resistance in asthma and the underlying mechanisms have not been elucidated. In this study, a murine model of asthma with depression was established by exposure to ovalbumin combined with chronic unpredictable mild stress, and icariin was given orally during ovalbumin challenge and chronic unpredictable mild stress exposure. Depression-like behaviors were assessed by the open field test, forced swim test, and tail suspension test. The characteristic features of allergic asthma, including airway hyperreactivity, histopathology, inflammatory cytokine levels in bronchoalveolar lavage fluid, and immunoglobulin E and corticosterone levels in serum, were examined. Following splenocyte isolation in vitro, the inhibitory effects of corticosterone on the proliferation and cytokine secretion of splenocytes, glucocorticoid receptor DNA-binding activity, and expression of p-glucocorticoid receptor s226, glucocorticoid receptor α, and p-p38 mitogen-activated protein kinase in splenocytes were determined. We found that icariin had limited effects on depression-like behaviors, however, it markedly suppressed airway hyperresponsiveness, inflammatory infiltration in lung tissues, levels of interleukin-4, interleukin-5, and interleukin-6 in bronchoalveolar lavage fluid, and immunoglobulin E in serum. Furthermore, icariin improved the inhibitory effects of corticosterone on lipopolysaccharide-stimulated splenocytes, increased the glucocorticoid receptor expression and glucocorticoid receptor DNA-binding activity, and inhibited the phosphorylation of glucocorticoid receptors S226 and p38 mitogen-activated protein kinase. Taken together, icariin improved glucocorticoid resistance in a murine model of asthma with depression associated with enhancement of glucocorticoid receptor function and glucocorticoid receptor expression, and its effects on the glucocorticoid receptor function were related to decreased phosphorylation of glucocorticoid receptors S226 and p38 mitogen-activated protein kinase.

Key words

icariin - Epimedium brevicornum - Berberidaceae - asthma - depression - glucocorticoid resistance


Publication History

Received: 28 February 2022

Accepted after revision: 11 July 2022

Accepted Manuscript online:
18 July 2022

Article published online:
22 August 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Beasley R, Hancox RJ. Reducing the burden of asthma: Time to set research and clinical priorities. Lancet Respir Med 2020; 8: 943-944
    CrossrefPubMedGoogle Scholar
  • 2 Choi HG, Kim JH, Park JY, Hwang YI, Jang SH, Jung KS. Association between asthma and depression: A national cohort study. J Allergy Clin Immunol Pract 2019; 7: 1239-1245.e1
    Google Scholar
  • 3 Li Y, Jiang Q, Ji Y, Cao C. Anxiety and depression may associate with poorer control and quality of life in adults with asthma. Allergy 2020; 75: 1759-1762
    CrossrefPubMedGoogle Scholar
  • 4 Anastasia P, Eleni T, Eleftheria M, Xenia N, Eygenia P, Kyriakos S, Katerina D, Petros B, Stelios L, Georgios H. Depression levels influence the rate of asthma exacerbations in females. J Pers Med 2021; 11: 586
    CrossrefPubMedGoogle Scholar
  • 5 Brunner WM, Schreiner PJ, Sood A, Jacobs jr. DR. Depression and risk of incident asthma in adults. The CARDIA study. Am J Respir Crit Care Med 2014; 189: 1044-1051
    CrossrefPubMedGoogle Scholar
  • 6 Li B, Duan XH, Wu JF, Liu BJ, Luo QL, Jin HL, Du YJ, Zhang HY, Cao YX, Dong JC. Impact of psychosocial stress on airway inflammation and its mechanism in a murine model of allergic asthma. Chin Med J (Engl) 2013; 126: 325-334
    PubMedGoogle Scholar
  • 7 Nikkheslat N, McLaughlin AP, Hastings C, Zajkowska Z, Nettis MA, Mariani N, Enache D, Lombardo G, Pointon L, Cowen PJ, Cavanagh J, Harrison NA, Bullmore ET, Consortium N, Pariante CM, Mondelli V. Childhood trauma, HPA axis activity and antidepressant response in patients with depression. Brain Behav Immun 2020; 87: 229-237
    CrossrefPubMedGoogle Scholar
  • 8 Coulthard LR, White DE, Jones DL, McDermott MF, Burchill SA. p38 (MAPK): Stress responses from molecular mechanisms to therapeutics. Trends Mol Med 2009; 15: 369-379
    CrossrefPubMedGoogle Scholar
  • 9 Lea S, Li J, Plumb J, Gaffey K, Mason S, Gaskell R, Harbron C, Singh D. P38 MAPK and glucocorticoid receptor crosstalk in bronchial epithelial cells. J Mol Med (Berl) 2020; 98: 361-374
    CrossrefPubMedGoogle Scholar
  • 10 Felger JC, Alagbe O, Pace TW, Woolwine BJ, Hu F, Raison CL, Miller AH. Early activation of p 38 mitogen activated protein kinase is associated with interferon-alpha-induced depression and fatigue. Brain Behav Immun 2011; 25: 1094-1098
    CrossrefPubMedGoogle Scholar
  • 11 Mercado N, Hakim A, Kobayashi Y, Meah S, Usmani OS, Chung KF, Barnes PJ, Ito K. Restoration of corticosteroid sensitivity by p38 mitogen activated protein kinase inhibition in peripheral blood mononuclear cells from severe asthma. PLoS One 2012; 7: e41582
    CrossrefPubMedGoogle Scholar
  • 12 Li SZ. Ben Cao Gang Mu. 1st edition. Beijing: Hua Xia Publishing House; 2011: 524-525
    Google Scholar
  • 13 Schluesener JK, Schluesener H. Plant polyphenols in the treatment of age-associated diseases: Revealing the pleiotropic effects of icariin by network analysis. Mol Nutr Food Res 2014; 58: 49-60
    CrossrefPubMedGoogle Scholar
  • 14 Sun X, Cheng H, Liu B, Du Y, Dong J, Huang J. Icariin reduces LPS-induced acute lung injury in mice undergoing bilateral adrenalectomy by regulating GRalpha. Eur J Pharmacol 2020; 876: 173032
    CrossrefPubMedGoogle Scholar
  • 15 Shen R, Wang JH. The effect of icariin on immunity and its potential application. Am J Clin Exp Immunol 2018; 7: 50-56
    PubMedGoogle Scholar
  • 16 Xiong W, Huang J, Li X, Zhang Z, Jin M, Wang J, Xu Y, Wang Z. Icariin and its phosphorylated derivatives alleviate intestinal epithelial barrier disruption caused by enterotoxigenic Escherichia coli through modulate p38 MAPK in vivo and in vitro . FASEB J 2020; 34: 1783-1801
    CrossrefPubMedGoogle Scholar
  • 17 Tang Y, Jacobi A, Vater C, Zou L, Zou X, Stiehler M. Icariin promotes angiogenic differentiation and prevents oxidative stress-induced autophagy in endothelial progenitor cells. Stem Cells 2015; 33: 1863-1877
    CrossrefPubMedGoogle Scholar
  • 18 Lavoie KL, Bacon SL, Barone S, Cartier A, Ditto B, Labrecque M. What is worse for asthma control and quality of life: Depressive disorders, anxiety disorders, or both?. Chest 2006; 130: 1039-1047
    CrossrefPubMedGoogle Scholar
  • 19 Barnig C, Frossard N, Levy BD. Towards targeting resolution pathways of airway inflammation in asthma. Pharmacol Ther 2018; 186: 98-113
    CrossrefPubMedGoogle Scholar
  • 20 Barnes PJ. Pathophysiology of allergic inflammation. Immunol Rev 2011; 242: 31-50
    CrossrefPubMedGoogle Scholar
  • 21 Barnes PJ, Adcock IM. Glucocorticoid resistance in inflammatory diseases. Lancet 2009; 373: 1905-1917
    CrossrefPubMedGoogle Scholar
  • 22 Caramori G, Nucera F, Mumby S, Lo Bello F, Adcock IM. Corticosteroid resistance in asthma: Cellular and molecular mechanisms. Mol Aspects Med 2022; 85: 100969
    CrossrefPubMedGoogle Scholar
  • 23 Webster MJ, Knable MB, OʼGrady J, Orthmann J, Weickert CS. Regional specificity of brain glucocorticoid receptor mRNA alterations in subjects with schizophrenia and mood disorders. Mol Psychiatry 2002; 7: 985-994 924
    CrossrefPubMedGoogle Scholar
  • 24 Canovas B, Nebreda AR. Diversity and versatility of p38 kinase signalling in health and disease. Nat Rev Mol Cell Biol 2021; 22: 346-366
    CrossrefPubMedGoogle Scholar
  • 25 McMillan SJ, Xanthou G, Lloyd CM. Therapeutic administration of Budesonide ameliorates allergen-induced airway remodelling. Clin Exp Allergy 2005; 35: 388-396
    CrossrefPubMedGoogle Scholar
  • 26 Zhuang TT, Pan C, Chen JJ, Han F, Zhu XL, Xu H, Lu YP. Chronic asthma-induced behavioral and hippocampal neuronal morphological changes are concurrent with BDNF, cofilin1 and Cdc42/RhoA alterations in immature mice. Brain Res Bull 2018; 143: 194-206
    CrossrefPubMedGoogle Scholar
  • 27 Tomida S, Mamiya T, Sakamaki H, Miura M, Aosaki T, Masuda M, Niwa M, Kameyama T, Kobayashi J, Iwaki Y, Imai S, Ishikawa A, Abe K, Yoshimura T, Nabeshima T, Ebihara S. Usp46 is a quantitative trait gene regulating mouse immobile behavior in the tail suspension and forced swimming tests. Nat Genet 2009; 41: 688-695
    CrossrefPubMedGoogle Scholar
  • 28 Pichavant M, Goya S, Hamelmann E, Gelfand EW, Umetsu DT. Animal models of airway sensitization. Curr Protoc Immunol 2007; Chapter 15 Unit: 15-18
    PubMedGoogle Scholar
  • 29 Finotto S, De Sanctis GT, Lehr HA, Herz U, Buerke M, Schipp M, Bartsch B, Atreya R, Schmitt E, Galle PR, Renz H, Neurath MF. Treatment of allergic airway inflammation and hyperresponsiveness by antisense-induced local blockade of GATA-3 expression. J Exp Med 2001; 193: 1247-1260
    CrossrefPubMedGoogle Scholar
  • 30 Jin H, Luo Q, Zheng Y, Nurahmat M, Wu J, Li B, Lv Y, Wang G, Duan X, Dong J. CD4+CD25+Foxp3+ T cells contribute to the antiasthmatic effects of Astragalus membranaceus extract in a rat model of asthma. Int Immunopharmacol 2013; 15: 42-49
    CrossrefPubMedGoogle Scholar
  • 31 Bailey MT, Kierstein S, Sharma S, Spaits M, Kinsey SG, Tliba O, Amrani Y, Sheridan JF, Panettieri RA, Haczku A. Social stress enhances allergen-induced airway inflammation in mice and inhibits corticosteroid responsiveness of cytokine production. J Immunol 2009; 182: 7888-7896
    CrossrefPubMedGoogle Scholar
  • 32 Li J, Hlavka-Zhang J, Shrimp JH, Piper C, Dupere-Richer D, Roth JS, Jing D, Casellas Roman HL, Troche C, Swaroop A, Kulis M, Oyer JA, Will CM, Shen M, Riva A, Bennett RL, Ferrando AA, Hall MD, Lock RB, Licht JD. PRC2 inhibitors overcome glucocorticoid resistance driven by NSD2 mutation in pediatric acute lymphoblastic leukemia. Cancer Discov 2022; 12: 186-203
    CrossrefPubMedGoogle Scholar