Abstract
Aim:
Major depressive disorder (MDD) is a debilitating mental disorder associated with dysfunction of the neurotransmitter-neuroendocrine system and neuroinflammatory responses. Salvianolic acid B (SalB) has shown a variety of pharmacological activities, including anti-inflammatory, antioxidant and neuroprotective effects. In this study, we examined whether SalB produced antidepressant-like actions in a chronic mild stress (CMS) mouse model, and explored the mechanisms underlying the antidepressant-like actions of SalB.
Methods:
Mice were subjected to a CMS paradigm for 6 weeks. In the last 3 weeks the mice were daily administered SalB (20 mg·kg−1·d−1, ip) or a positive control drug imipramine (20 mg·kg−1·d−1, ip). The depressant-like behaviors were evaluated using the sucrose preference test, the forced swimming test (FST), and the tail suspension test (TST). The gene expression of cytokines in the hippocampus and cortex was analyzed with RT-PCR. Plasma corticosterone (CORT) and cerebral cytokines levels were assayed with an ELISA kit. Neural apoptosis and microglial activation in brain tissues were detected using immunofluorescence staining.
Results:
Administration of SalB or imipramine reversed the reduced sucrose preference ratio of CMS-treated mice, and significantly decreased their immobility time in the FST and TST. Administration of SalB significantly decreased the expression of pro-inflammatory cytokines IL-1β and TNF-α, and markedly increased the expression of anti-inflammatory cytokines IL-10 and TGF-β in the hippocampus and cortex of CMS-treated mice, and normalized their elevated plasma CORT levels, whereas administration of imipramine did not significantly affect the imbalance between pro- and anti-inflammatory cytokines in the hippocampus and cortex of CMS-treated mice. Finally, administration of SalB significantly decreased CMS-induced apoptosis and microglia activation in the hippocampus and cortex, whereas administration of imipramine had no significant effect on CMS-induced apoptosis and microglia activation in the hippocampus and cortex.
Conclusion:
SalB exerts potent antidepressant-like effects in CMS-induced mouse model of depression, which is associated with the inhibiting microglia-related apoptosis in the hippocampus and the cortex.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Kessler RC, Merikangas KR, Wang PS . Prevalence, comorbidity, and service utilization for mood disorders in the United States at the beginning of the twenty-first century. Annu Rev Clin Psycho 2007; 3: 137–58.
World Health Organization (2012) Media Centre Fact Sheet No 369. http://www.who.int/mediacentre/factsheets/fs369/en/.
Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM . Neurobiology of depression. Neuron 2002; 34: 13–25.
Berton O, Nestler EJ . New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 2006; 7: 137–51.
Entsuah AR, Huang H, Thase ME . Response and remission rates in different subpopulations with major depressive disorder administered venlafaxine, selective serotonin reuptake inhibitors, or placebo. J Clin Psychiat 2001; 62: 869–77.
Hansen RA, Gartlehner G, Lohr KN, Gaynes BN, Carey TS . Efficacy and safety of second-generation antidepressants in the treatment of major depressive disorder. Ann Intern Med 2005; 143: 415–26.
Mills NT, Scott JG, Wray NR, Cohen-Woods S, Baune BT . Research Review: The role of cytokines in depression in adolescents: a systematic review. J Child Psychol Psyc 2013; 54: 816–35.
Piser TM . Linking the cytokine and neurocircuitry hypotheses of depression: A translational framework for discovery and development of novel anti-depressants. Brain Behav Immun 2010; 24: 515–24.
Anisman H, Merali Z, Hayley S . Neurotransmitter, peptide and cytokine processes in relation to depressive disorder: Comorbidity between depression and neurodegenerative disorders. Prog Neurobiol 2008; 85: 1–74.
Huang YS, Coupland NJ, Lebel RM, Carter R, Seres P, Wilman AH, et al. Structural changes in hippocampal subfields in major depressive disorder: a high-field magnetic resonance imaging study. Biol Psychiatr 2013; 74: 62–8.
Makhija K, Karunakaran S . The role of inflammatory cytokines on the aetiopathogenesis of depression. Aust Nz J Psychiat 2013; 47: 828–39.
Miller AH . Depression and immunity: a role for T cells? Brain Behav Immun 2010; 24: 1–8.
Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW . From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008; 9: 46–57.
Choi SH, Aid S, Kim HW, Jackson SH, Bosetti F . Inhibition of NADPH oxidase promotes alternative and anti-inflammatory microglial activation during neuroinflammation. J Neurochem 2012; 120: 292–301.
Pan YJ, Cheng IC, Yeh LL, Cho YM, Feng J . Utilization of traditional Chinese medicine in patients treated for depression: a population-based study in Taiwan. Complement Ther Med 2013; 21: 215–23.
Xue WD, Zhou X, Yi N, Jiang LH, Tao WW, Wu RJ, et al. Yueju Pill rapidly induces antidepressant-like effects and acutely enhances BDNF expression in mouse brain. Evid-Based Compl Alt 2013.
Wang SX, Hu LM, Gao XM, Guo H, Fan GW . Anti-inflammatory activity of salvianolic acid B in microglia contributes to its neuroprotective effect. Neurochem Res 2010; 35: 1029–37.
Liu CS, Cheng Y, Hu JF, Zhang W, Chen NH, Zhang JT . Comparison of antioxidant activities between salvianolic acid B and Ginkgo biloba extract (EGb 761). Acta Pharmacol Sin 2006; 27: 1137–45.
Du GH, Qiu Y, Zhang JT . Salvianolic acid B protects the memory functions against transient cerebral ischemia in mice. J Asian Nat Prod Res 2000; 2: 145–52.
Zhang N, Kang TG, Xia Y, Wen QP, Zhang XD, Li HY, et al. Effects of salvianolic acid B on survival, self-renewal and neuronal differentiation of bone marrow derived neural stem cells. Eur J Pharmacol 2012; 697: 32–9.
Zhang YJ, Wu L, Zhang QL, Li J, Yin FX, Yuan Y . Pharmacokinetics of phenolic compounds of Danshen extract in rat blood and brain by microdialysis sampling. J Ethnopharmacol 2011; 136: 129–36.
McArthur R, Borsini F . Animal models of depression in drug discovery: A historical perspective. Pharmacol Biochem Be 2006; 84: 436–52.
Micale V, Kucerova J, Sulcova A . Leading compounds for the validation of animal models of psychopathology. Cell Tissue Res 2013; 354: 309–30.
Feng Y, You ZL, Yan S, He G, Chen YB, Gou XJ, et al. Antidepressant-like effects of Salvianolic acid B in the mouse forced swim and tail suspension tests. Life Sci 2012; 90: 1010–14.
Zhao QY, Peng C, Wu XH, Chen YB, Wang C, You ZL . Maternal sleep deprivation inhibits hippocampal neurogenesis associated with inflammatory response in young offspring rats. Neurobiol Dis 2014; 68: 57–65.
Porsolt RD, Lepichon M, Lalfre M . Behavioral despair revisited–a citation-classic commentary on depression — a new animal-model sensitive to antidepressant treatments. Life Sci 1993; (20): 9.
Zomkowski AD, Santos AR, Rodrigues AL . Putrescine produces antidepressant-like effects in the forced swimming test and in the tail suspension test in mice. Prog Neuro-psychopharmacol Biol Psychiatr 2006; 30: 1419–25.
Seok JH, Kim LS, Hong N, Hong HJ, Kim SJ, Kang HJ, et al. Psychological and neuroendocrinological characteristics associated with depressive symptoms in breast cancer patients at the initial cancer diagnosis. Gen Hosp Psychiat 2010; 32: 503–8.
Hill MN, Hellemans KGC, Verma P, Gorzalka BB, Weinberg J . Neurobiology of chronic mild stress: parallels to major depression. Neurosci Biobehav R 2012; 36: 2085–117.
Schweizer MC, Henniger MS, Sillaber I . Chronic mild stress (CMS) in mice: of anhedonia, 'anomalous anxiolysis' and activity. PLoS One 2009; 4: e4326.
Snaith P . Anhedonia — a neglected symptom of psychopathology. Psychol Med 1993; 23: 957–66.
Cryan JF, Valentino RJ, Lucki I . Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci Biobehav R 2005; 29: 547–69.
Trief PM, Cibula D, Delahanty LM, Weinstock RS . Depression, stress, and weight loss in individuals with metabolic syndrome in SHINE, a DPP Translation Study. Obesity 2014; 22: 2532–8.
Raison CL, Capuron L, Miller AH . Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 2006; 27: 24–31.
Chen YH, Du GH, Zhang JT . Salvianolic acid B protects brain against injuries caused by ischemia-reperfusion in rats. Acta Pharmacol Sin 2000; 21: 463–6.
Blume J, Douglas SD, Evans DL . Immune suppression and immune activation in depression. Brain Behav Immun 2011; 25: 221–9.
Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Critchley HD . Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol Psychiatr 2009; 66: 407–14.
You ZL, Luo CM, Zhang WZ, Chen YB, He JJ, Zhao QY, et al. Pro- and anti-inflammatory cytokines expression in rat's brain and spleen exposed to chronic mild stress: involvement in depression. Behav Brain Res 2011; 225: 135–41.
Lee HY, Kim YK . Transforming growth factor-beta 1 and major depressive disorder with and without attempted suicide: Preliminary study. Psychiatr Res 2010; 178: 92–6.
Voorhees JL, Tarr AJ, Wohleb ES, Godbout JP, Mo XK, Sheridan JF, et al. Prolonged restraint stress increases IL-6, reduces IL-10, and causes persistent depressive-like behavior that is reversed by recombinant IL-10. PLoS One 2013; 8: e58488.
Rosenblat JD, Cha DS, Mansur RB, McIntyre RS . Inflamed moods: A review of the interactions between inflammation and mood disorders. Prog neuro-psychopharmacol Biol Psychiatr 2014; 53: 23–34.
Powell TR, Tansey KE, Breen G, Farmer AE, Craig IW, Uher R, et al. ATP-binding cassette sub-family F member 1 (ABCF1) is identified as a putative therapeutic target of escitalopram in the inflammatory cytokine pathway. J Psychopharmacol 2013; 27: 609–15.
Wainwright SR, Galea LAM . The neural plasticity theory of depression: assessing the roles of adult neurogenesis and PSA-NCAM within the hippocampus. Neural Plast 2013; 2013: 805497.
Raone A, Cassanelli A, Scheggi S, Rauggi R, Danielli B, De Montis MG . Hypothalamus-pituitary-adrenal modifications consequent to chronic stress exposure in an experimental model of depression in rats. Neuroscience 2007; 146: 1734–42.
Wu JF, Du JA, Xu CQ, Le JJ, Xu YZ, Liu BJ, et al. Icariin attenuates social defeat-induced down-regulation of glucocorticoid receptor in mice. Pharmacol Biochem Be 2011; 98: 273–8.
Chen C, Wang Y, Zhang J, Ma L, Gu J, Ho G . Contribution of neural cell death to depressive phenotypes of streptozotocin-induced diabetic mice. Disease Models Mechanism 2014; 7: 723–30.
Lee S, Lee J, Kim S, Park JY, Lee WH, Mori K, et al. A dual role of lipocalin 2 in the apoptosis and deramification of activated microglia. J Immunol 2007; 179: 3231–41.
Yan N, Liu Y, Liu S, Cao S, Wang F, Wang Z, et al. Fluoride-induced neuron apoptosis and expressions of inflammatory factors by activating microglia in rat brain. Mol Neurobiol 2016; 53: 4449–60.
Wang Y, Subramanian P, Shen D, Tuo J, Becerra SP, Chan CC . Pigment epithelium-derived factor reduces apoptosis and pro-inflammatory cytokine gene expression in a murine model of focal retinal degeneration. ASN Neuro 2013; 5: e00126.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (No 81571174), the Open Research Fund of State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources (No 2015003), and Key Technologies R&D Program of Sichuan Province (No 2013SZ0011, 2015SZ0058-5). We are grateful to Ms Xiong WAN for her help in copyediting.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Zhang, Jq., Wu, Xh., Feng, Y. et al. Salvianolic acid B ameliorates depressive-like behaviors in chronic mild stress-treated mice: involvement of the neuroinflammatory pathway. Acta Pharmacol Sin 37, 1141–1153 (2016). https://doi.org/10.1038/aps.2016.63
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/aps.2016.63
Keywords
This article is cited by
-
Salvianolic acid B ameliorates retinal deficits in an early-stage Alzheimer’s disease mouse model through downregulating BACE1 and Aβ generation
Acta Pharmacologica Sinica (2023)
-
Neuroinflammation as an etiological trigger for depression comorbid with inflammatory bowel disease
Journal of Neuroinflammation (2022)
-
Microglia in depression: an overview of microglia in the pathogenesis and treatment of depression
Journal of Neuroinflammation (2022)
-
New monoamine antidepressant, hypidone hydrochloride (YL-0919), enhances the excitability of medial prefrontal cortex in mice via a neural disinhibition mechanism
Acta Pharmacologica Sinica (2022)
-
Ginsenoside Rb1 induces a pro-neurogenic microglial phenotype via PPARγ activation in male mice exposed to chronic mild stress
Journal of Neuroinflammation (2021)
