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The Antidepressant Effect of Magnolol on Depression-Like Behavior of CORT-Treated Mice

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Abstract

Although the antidepressant-like effect of magnolol has been revealed in previous reports, the mechanism remains unclear. In this study, the antidepressant-like effect of magnolol on corticosterone-induced (CORT-induced) mice was investigated in vivo. After 21 days of CORT induction, the mice showed marked depressive-like behaviors, with a decrease in sucrose preference score and an increase in immobility time in the tail suspension test (TST) and forced swimming test (FST). Pretreatment with either magnolol (50 mg/kg, i.p.) or the kappa opioid receptor (KOR) antagonist nor-BNI (10 mg/kg, i.p.) prevented CORT-induced depression-like behavior and reduced CORT-induced dynorphin (DYN A) elevation in the hippocampal ventral DG. However, no depression-like behavior was observed in mice with KOR downregulation in the ventral DG. We further found that upregulation of DYN A in the DG caused depression-like behavior, which was blocked by intraperitoneal injection of nor-BNI and modulated by magnolol. The present study demonstrated that magnolol could ameliorate CORT-induced depression-like behaviors, by modulating the DYN A/KOR system in the ventral DG of the hippocampus.

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Availability of Data and Materials

The datasets and materials used or analyzed during the current study are available from the corresponding author on reasonable request.

References

  • Amigo J, Garro-Martinez E, Vidal Casado R, Compan V, Pilar-Cuéllar F, Pazos A, Díaz A, Castro E (2021) 5-HT(4) receptors are not involved in the effects of fluoxetine in the corticosterone model of depression. ACS Chem Neurosci 12:2036–2044

    Article  CAS  PubMed  Google Scholar 

  • Avula SK, Khan A, Halim SA, Rehman NU, Karim N, Khan I, Csuk R, Das B, Al-Harrasi A (2022) Synthesis and antidepressant-like effects of new 5-epi-incensole and 5-epi- incensole acetate in chronic unpredictable mild stress model of depression; behavioural and biochemical correlates. Biomed Pharmacother 156:113960

  • Bai Y, Song L, Dai G, Xu M, Zhu L, Zhang W, Jing W, Ju W (2018) Antidepressant effects of magnolol in a mouse model of depression induced by chronic corticosterone injection. Steroids 135:73–78

    Article  CAS  PubMed  Google Scholar 

  • Baird MA, Hsu TY, Wang R, Juarez B, Zweifel LS (2021) κ opioid receptor-dynorphin signaling in the central amygdala regulates conditioned threat discrimination and anxiety. eNeuro 8

  • Bassett B, Subramaniyam S, Fan Y, Varney S, Pan H, Carneiro AMD, Chung CY (2021) Minocycline alleviates depression-like symptoms by rescuing decrease in neurogenesis in dorsal hippocampus via blocking microglia activation/phagocytosis. Brain Behav Immun 91:519–530

    Article  CAS  PubMed  Google Scholar 

  • Bian XL, Qin C, Cai CY, Zhou Y, Tao Y, Lin YH, Wu HY, Chang L, Luo CX, Zhu DY (2019) Anterior cingulate cortex to ventral hippocampus circuit mediates contextual fear generalization. J Neurosci 39:5728–5739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bruchas MR, Land BB, Chavkin C (2010) The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res 1314:44–55

    Article  CAS  PubMed  Google Scholar 

  • Carlezon WA Jr, Thome J, Olson VG, Lane-Ladd SB, Brodkin ES, Hiroi N, Duman RS, Neve RL, Nestler EJ (1998) Regulation of cocaine reward by CREB. Science (new York, NY) 282:2272–2275

    Article  CAS  Google Scholar 

  • Carr GV, Lucki I (2010) Comparison of the kappa-opioid receptor antagonist DIPPA in tests of anxiety-like behavior between Wistar Kyoto and Sprague Dawley rats. Psychopharmacology 210:295–302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng J, Dong S, Yi L, Geng D, Liu Q (2018) Magnolol abrogates chronic mild stress-induced depressive-like behaviors by inhibiting neuroinflammation and oxidative stress in the prefrontal cortex of mice. Int Immunopharmacol 59:61–67

    Article  CAS  PubMed  Google Scholar 

  • Dai W, Yang M, Xia P, Xiao C, Huang S, Zhang Z, Cheng X, Li W, Jin J, Zhang J, Wu B, Zhang Y, Wu PH, Lin Y, Wu W, Zhao H, Zhang Y, Lin WJ, Ye X (2022) A functional role of meningeal lymphatics in sex difference of stress susceptibility in mice. Nat Commun 13:4825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ding H, Cui XY, Cui SY, Ye H, Hu X, Zhao HL, Liu YT, Zhang YH (2018) Depression-like behaviors induced by chronic corticosterone exposure via drinking water: time-course analysis. Neurosci Lett 687:202–206

    Article  CAS  PubMed  Google Scholar 

  • Du Preez A, Onorato D, Eiben I, Musaelyan K, Egeland M, Zunszain PA, Fernandes C, Thuret S, Pariante CM (2021) Chronic stress followed by social isolation promotes depressive-like behaviour, alters microglial and astrocyte biology and reduces hippocampal neurogenesis in male mice. Brain Behav Immun 91:24–47

    Article  PubMed  Google Scholar 

  • Dubovsky SL, Ghosh BM, Serotte JC, Cranwell V (2021) Psychotic depression: diagnosis, differential diagnosis, and treatment. Psychother Psychosom 90:160–177

    Article  PubMed  Google Scholar 

  • Franceschelli A, Herchick S, Thelen C, Papadopoulou-Daifoti Z, Pitychoutis PM (2014) Sex differences in the chronic mild stress model of depression. Behav Pharmacol 25:372–383

    Article  CAS  PubMed  Google Scholar 

  • Gao C, Wu M, Du Q, Deng J, Shen J (2022) Naringin mediates adult hippocampal neurogenesis for antidepression via activating CREB signaling. Front Cell Dev Biol 10:731831

  • Hang A, Wang YJ, He L, Liu JG (2015) The role of the dynorphin/κ opioid receptor system in anxiety. Acta Pharmacol Sin 36:783–790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He G, Song Q, Wang J, Xu A, Peng K, Zhu Q, Xu Y (2020) Design, synthesis and biological evaluation of N-hydroxy-aminobenzyloxyarylamide analogues as novel selective κ opioid receptor antagonists. Bioorg Med Chem Lett 30:127236

    Article  CAS  PubMed  Google Scholar 

  • Hill AS, Sahay A, Hen R (2015) Increasing adult hippocampal neurogenesis is sufficient to reduce anxiety and depression-like behaviors. Neuropsychopharmacol 40:2368–2378

    Article  CAS  Google Scholar 

  • Huang HL, Lim SL, Lu KH, Sheen LY (2018) Antidepressant-like effects of Gan-Mai-Dazao-Tang via monoamine regulatory pathways on forced swimming test in rats. J Tradit Complement Med 8:53–59

    Article  PubMed  Google Scholar 

  • Ji MJ, Gao ZQ, Yang J, Cai JH, Li KX, Wang J, Zhang H, Zhou CH, Cao JL, Liu C (2022) Dynorphin promotes stress-induced depressive behaviors by inhibiting ventral pallidal neurons in rats. Acta Physiol (oxf) 236:e13882

    Article  CAS  PubMed  Google Scholar 

  • Jin ZL, Gao N, Zhang JR, Li XR, Chen HX, Xiong J, Li YF, Tang Y (2014) The discovery of Yuanzhi-1, a triterpenoid saponin derived from the traditional Chinese medicine, has antidepressant-like activity. Prog Neuropsychopharmacol Biol Psychiatry 53:9–14

    Article  CAS  PubMed  Google Scholar 

  • Kastenberger I, Lutsch C, Herzog H, Schwarzer C (2012) Influence of sex and genetic background on anxiety-related and stress-induced behaviour of prodynorphin-deficient mice. PLoS ONE 7:e34251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Keers R, Aitchison KJ (2010) Gender differences in antidepressant drug response. Int Rev Psychiatry (Abingdon, England) 22:485–500

    Article  Google Scholar 

  • Kong H, Zeng XN, Fan Y, Yuan ST, Ge S, Xie WP, Wang H, Hu G (2014) Aquaporin-4 knockout exacerbates corticosterone-induced depression by inhibiting astrocyte function and hippocampal neurogenesis. CNS Neurosci Ther 20:391–402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Levone BR, Cryan JF, O’Leary OF (2021) Specific sub-regions of the longitudinal axis of the hippocampus mediate behavioural responses to chronic psychosocial stress. Neuropharmacology 201:108843

    Article  CAS  PubMed  Google Scholar 

  • Li CH, Ku MC, Lee KC, Yueh PF, Hsu FT, Lin RF, Yang CC, Wang WC, Chen JH, Hsu LC, Lee YH (2022a) Magnolol suppresses ERK/NF-κB signaling and triggers apoptosis through extrinsic/intrinsic pathways in osteosarcoma. Anticancer Res 42:4403–4410

    Article  CAS  PubMed  Google Scholar 

  • Li H, Li J, Zhang T, Xie X, Gong J (2022b) Antidepressant effect of Jujuboside A on corticosterone-induced depression in mice. Biochem Biophys Res Commun 620:56–62

    Article  CAS  PubMed  Google Scholar 

  • Li LF, Lu J, Li XM, Xu CL, Deng JM, Qu R, Ma SP (2012) Antidepressant-like effect of magnolol on BDNF up-regulation and serotonergic system activity in unpredictable chronic mild stress treated rats. Phytother Res 26:1189–1194

    Article  CAS  PubMed  Google Scholar 

  • Matsui N, Akae H, Hirashima N, Kido Y, Tanabe S, Koseki M, Fukuyama Y, Akagi M (2016) Magnolol enhances hippocampal neurogenesis and exerts antidepressant-like effects in olfactory bulbectomized mice. Phytother Res 30:1856–1861

    Article  CAS  PubMed  Google Scholar 

  • Missig G, Fritsch EL, Mehta N, Damon ME, Jarrell EM, Bartlett AA, Carroll FI, Carlezon WA Jr (2022) Blockade of kappa-opioid receptors amplifies microglia-mediated inflammatory responses. Pharmacol Biochem Behav 212:173301

    Article  CAS  PubMed  Google Scholar 

  • Motaghi S, Moghaddam Dizaj Herik H, Sepehri G, Abbasnejad M, Esmaeli-Mahani S (2022) The anxiolytic effect of salicylic acid is mediated via the GABAergic system in the fear potentiated plus maze behavior in rats. Mol Biol Rep 49:1133–1139

    Article  CAS  PubMed  Google Scholar 

  • Nakazawa T, Yasuda T, Ohsawa K (2003) Metabolites of orally administered Magnolia officinalis extract in rats and man and its antidepressant-like effects in mice. J Pharm Pharmacol 55:1583–1591

    Article  CAS  PubMed  Google Scholar 

  • Page S, Mavrikaki MM, Lintz T, Puttick D, Roberts E, Rosen H, Carroll FI, Carlezon WA, Chartoff EH (2019) Behavioral pharmacology of novel kappa opioid receptor antagonists in rats. Int J Neuropsychopharmacol 22:735–745

    CAS  PubMed  PubMed Central  Google Scholar 

  • Peng CY, Yu CC, Huang CC, Liao YW, Hsieh PL, Chu PM, Yu CH, Lin SS (2022) Magnolol inhibits cancer stemness and IL-6/Stat3 signaling in oral carcinomas. J Formos Med Assoc = Taiwan yi zhi 121:51–57

  • Pirino BE, Spodnick MB, Gargiulo AT, Curtis GR, Barson JR, Karkhanis AN (2020) Kappa-opioid receptor-dependent changes in dopamine and anxiety-like or approach-avoidance behavior occur differentially across the nucleus accumbens shell rostro-caudal axis. Neuropharmacology 181:108341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pliakas AM, Carlson RR, Neve RL, Konradi C, Nestler EJ, Carlezon WA Jr (2001) Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element-binding protein expression in nucleus accumbens. J Neurosci 21:7397–7403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schwalsberger K, Reininghaus B, Reiter A, Dalkner N, Fleischmann E, Fellendorf F, Platzer M, Reininghaus EZ (2022) Sex-related differences in the pharmacological treatment of major depression - are women and men treated differently? Psychiatr Danub 34:219–228

    Article  CAS  PubMed  Google Scholar 

  • Shorey S, Ng ED, Wong CHJ (2022) Global prevalence of depression and elevated depressive symptoms among adolescents: a systematic review and meta-analysis. Br J Clin Psychol 61:287–305

    Article  PubMed  Google Scholar 

  • Sramek JJ, Murphy MF, Cutler NR (2016) Sex differences in the psychopharmacological treatment of depression. Dialogues Clin Neurosci 18:447–457

    Article  PubMed  PubMed Central  Google Scholar 

  • Stickel S, Wagels L, Wudarczyk O, Jaffee S, Habel U, Schneider F, Chechko N (2019) Neural correlates of depression in women across the reproductive lifespan - An fMRI review. J Affect Disord 246:556–570

    Article  PubMed  Google Scholar 

  • Tang Y, Wang L, Yi T, Xu J, Wang J, Qin JJ, Chen Q, Yip KM, Pan Y, Hong P, Lu Y, Shen HM, Chen HB (2021) Synergistic effects of autophagy/mitophagy inhibitors and magnolol promote apoptosis and antitumor efficacy. Acta Pharmaceutica Sinica B 11:3966–3982

    Article  PubMed  PubMed Central  Google Scholar 

  • Tao W, Hu Y, Chen Z, Dai Y, Hu Y, Qi M (2021) Magnolol attenuates depressive-like behaviors by polarizing microglia towards the M2 phenotype through the regulation of Nrf2/HO-1/NLRP3 signaling pathway. Phytomedicine 91:153692

  • Tartt AN, Mariani MB, Hen R, Mann JJ, Boldrini M (2022) Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications. Mol Psychiatry 27:2689–2699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tunc-Ozcan E, Peng CY, Zhu Y, Dunlop SR, Contractor A, Kessler JA (2019) Activating newborn neurons suppresses depression and anxiety-like behaviors. Nat Commun 10:3768

    Article  PubMed  PubMed Central  Google Scholar 

  • Van’t Veer A, Carlezon WA Jr (2013) Role of kappa-opioid receptors in stress and anxiety-related behavior. Psychopharmacology 229:435–452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vandeleur CL, Fassassi S, Castelao E, Glaus J, Strippoli MF, Lasserre AM, Rudaz D, Gebreab S, Pistis G, Aubry JM, Angst J, Preisig M (2017) Prevalence and correlates of DSM-5 major depressive and related disorders in the community. Psychiatry Res 250:50–58

    Article  PubMed  Google Scholar 

  • Vergara F, Sardi NF, Pescador AC, Guaita GO, Jark Stern CA, Chichorro JG, Fischer L (2020) Contribution of mesolimbic dopamine and kappa opioid systems to the transition from acute to chronic pain. Neuropharmacology 178:108226

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Song Q, Xu A, Bao Y, Xu Y, Zhu Q (2017) Design, synthesis and biological evaluation of aminobenzyloxyarylamide derivatives as selective κ opioid receptor antagonists. Eur J Med Chem 130:15–25

    Article  CAS  PubMed  Google Scholar 

  • Wang Q, Long Y, Hang A, Zan GY, Shu XH, Wang YJ, Liu JG (2016) The anxiolytic- and antidepressant-like effects of ATPM-ET, a novel κ agonist and μ partial agonist, in mice. Psychopharmacology 233:2411–2418

    Article  CAS  PubMed  Google Scholar 

  • Xia J, Wang H, Zhang C, Liu B, Li Y, Li K, Li P, Song C (2022) The comparison of sex differences in depression-like behaviors and neuroinflammatory changes in a rat model of depression induced by chronic stress. Front Behav Neurosci 16:1059594

    Article  CAS  PubMed  Google Scholar 

  • Xu Q, Yi LT, Pan Y, Wang X, Li YC, Li JM, Wang CP, Kong LD (2008) Antidepressant-like effects of the mixture of honokiol and magnolol from the barks of Magnolia officinalis in stressed rodents. Prog Neuropsychopharmacol Biol Psychiatry 32:715–725

    Article  CAS  PubMed  Google Scholar 

  • Xu C, Fan W, Zhang Y, Loh HH, Law PY (2021) Kappa opioid receptor controls neural stem cell differentiation via a miR-7a/Pax6 dependent pathway. Stem Cells 39:600–616

    Article  CAS  PubMed  Google Scholar 

  • Yang TH, Ma YB, Geng CA, Yan DX, Huang XY, Li TZ, Zhang XM, Chen JJ (2018) Synthesis and biological evaluation of magnolol derivatives as melatonergic receptor agonists with potential use in depression. Eur J Med Chem 156:381–393

    Article  CAS  PubMed  Google Scholar 

  • Yang J, Wei Y, Zhao T, Li X, Zhao X, Ouyang X, Zhou L, Zhan X, Qian M, Wang J, Shen X (2022) Magnolol effectively ameliorates diabetic peripheral neuropathy in mice. Phytomedicine: international journal of phytotherapy and phytopharmacology 107:154434

  • Zan GY, Sun X, Wang YJ, Liu R, Wang CY, Du WJ, Guo LB, Chai JR, Li QL, Liu ZQ, Liu JG (2022) Amygdala dynorphin/κ opioid receptor system modulates depressive-like behavior in mice following chronic social defeat stress. Acta Pharmacol Sin 43:577–587

    Article  CAS  PubMed  Google Scholar 

  • Zhang FH, Wang ZM, Liu YT, Huang JS, Liang S, Wu HH, Xu YT (2019) Bioactivities of serotonin transporter mediate antidepressant effects of Acorus tatarinowii Schott. J Ethnopharmacol 241:111967

    Article  PubMed  Google Scholar 

  • Zhang J, Rong P, Zhang L, He H, Zhou T, Fan Y, Mo L, Zhao Q, Han Y, Li S, Wang Y, Yan W, Chen H, You Z (2021) IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis. Sci Adv 7

  • Zhang K, Wang F, Zhai M, He M, Hu Y, Feng L, Li Y, Yang J, Wu C (2023) Hyperactive neuronal autophagy depletes BDNF and impairs adult hippocampal neurogenesis in a corticosterone-induced mouse model of depression. Theranostics 13:1059–1075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We appreciate the technical support from the Public Platform of Medical Research Center, Academy of Chinese Medical Science, Zhejiang Chinese Medical University.

Funding

This work was supported by the Zhejiang Provincial Natural Science Foundation of China under Grant No. LY22H270004, by the National Natural Science Foundation of China under Grant No. 82030112, and by Zhejiang Chinese Medical University under Grant No. 2022 FSYYZZ11.

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Author notes

  1. Chi Xu and Jiayu Ye contributed equally to this work.

Authors and Affiliations

  1. Department of Neurobiology and Acupuncture Research, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, The Third Affiliated Hospital of Zhejiang Chinese Medical University, No.548 Binwen Road Binjiang District, Hangzhou, 310053, Zhejiang, China

    Chi Xu & Jing-gen Liu

  2. Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, No.260 Baichuan Road, Fuyang District, Hangzhou, 311400, Zhejiang, China

    Chi Xu, Jiayu Ye, Yanting Sun, Xiujian Sun & Jing-gen Liu

  3. Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No.555 Zuchongzhi Road Pudong District, Shanghai, 200120, China

    Jing-gen Liu

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  1. Chi Xu
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  2. Jiayu Ye
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  3. Yanting Sun
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Contributions

CX, JY and JL conceived and designed the experiments; CX, JY and YS performed the experiments; CX, JY, XS and JL analyzed the data; CX and JY wrote the paper.

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Correspondence to Chi Xu or Jing-gen Liu.

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Ethical Approval

The current study was performed with the approval of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). All experimental procedures were approved by the Animal Ethics Committee of Zhejiang Chinese Medical University (permission number: IACUC-20220328-09) and conducted according to the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80-23).

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Xu, C., Ye, J., Sun, Y. et al. The Antidepressant Effect of Magnolol on Depression-Like Behavior of CORT-Treated Mice. J Mol Neurosci 74, 3 (2024). https://doi.org/10.1007/s12031-023-02185-0

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