Abstract
Sulforaphane (SFN) is an organic isothiocyanate and an NF-E2-related factor-2 (Nrf2) inducer that exerts prophylactic effects on depression-like behavior in mice. However, the underlying mechanisms remain poorly understood. Brain-derived neurotrophic factor (BDNF), a neurotrophin, is widely accepted for its antidepressant effects and role in stress resilience. Here, we show that SFN confers stress resilience via BDNF upregulation and changes in abnormal dendritic spine morphology in stressed mice, which is accompanied by rectifying the irregular levels of inflammatory cytokines. Mechanistic studies demonstrated that SFN activated Nrf2 to promote BDNF transcription by binding to the exon I promoter, which is associated with increased Nrf2, and decreased methyl-CpG binding protein-2 (MeCP2), a transcriptional suppressor of BDNF, in BV2 microglial cells. Furthermore, SFN inhibited the pro-inflammatory phenotype and activated the anti-inflammatory phenotype of microglia, which was associated with increased Nrf2 and decreased MeCP2 expression in microglia of stressed mice. Hence, our findings support that Nrf2 induces BDNF transcription via upregulation of Nrf2 and downregulation of MeCP2 in microglia, which is associated with changes in the morphology of damaged dendritic spines in stressed mice. Meanwhile, the data presented here provide evidence for the application of SFN as a candidate for the prevention and intervention of depression.
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References
Zhang Y, Talalay P, Cho CG, Posner GH. A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proc Natl Acad Sci USA. 1992;89:2399–403.
Kobayashi E, Suzuki T, Yamamoto M. Roles Nrf2 plays in myeloid cells and related disorders. Oxid Med Cell Longev. 2013;2013:529219.
Suzuki T, Yamamoto M. Molecular basis of the Keap1-Nrf2 system. Free Radic Biol Med. 2015;88:93–100.
Phillips C. Brain-derived neurotrophic factor, depression, and physical activity: making the neuroplastic connection. Neural Plast. 2017;2017:7260130.
Rana T, Behl T, Sehgal A, Srivastava P, Bungau S. Unfolding the role of BDNF as a biomarker for treatment of depression. J Mol Neurosci. 2020. https://doi.org/10.1007/s12031-020-01754-x.
Rosa PB, Bettio LEB, Neis VB, Moretti M, Kaufmann FN, Tavares MK, et al. Antidepressant-like effect of guanosine involves activation of AMPA receptor and BDNF/TrkB signaling. Purinergic Signal. 2021;17:285–301.
Zhang JC, Yao W, Dong C, Yang C, Ren Q, Ma M, et al. Prophylactic effects of sulforaphane on depression-like behavior and dendritic changes in mice after inflammation. J Nutr Biochem. 2017;39:134–44.
Yao W, Zhang JC, Ishima T, Dong C, Yang C, Ren Q, et al. Role of Keap1-Nrf2 signaling in depression and dietary intake of glucoraphanin confers stress resilience in mice. Sci Rep. 2016;6:30659.
Yao W, Lin S, Su J, Cao Q, Chen Y, Chen J, et al. Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodents. Transl Psychiatry. 2021;11:140.
Yirmiya R, Rimmerman N, Reshef R. Depression as a microglial disease. Trends Neurosci. 2015;38:637–58.
Deng SL, Chen JG, Wang F. Microglia: a central player in depression. Curr Med Sci. 2020;40:391–400.
Santos LE, Beckman D, Ferreira ST. Microglial dysfunction connects depression and Alzheimer’s disease. Brain Behav Immun. 2016;55:151–65.
Tang Y, Le W. Differential roles of M1 and M2 microglia in eurodegenerative diseases. Mol Neurobiol. 2016;53:1181–94.
Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci. 2013;16:1211–8.
Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci. 2009;29:13435–44.
Zhou XL, Spittau B, Krieglstein K. TGF beta signalling plays an important role in IL4-induced alternative activation of microglia. J Neuroinflamm. 2012;9:210.
Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 2007;8:57–69.
Han Y, Zhang LJ, Wang QZ, Zhang DD, Zhao QY, Zhang JQ, et al. Minocycline inhibits microglial activation and alleviates depressive-like behaviors in male adolescent mice subjected to maternal separation. Psychoneuroendocrinology. 2019;107:37–45.
Li C, Zhao B, Lin C, Gong Z, An X. TREM2 inhibits inflammatory responses in mouse microglia by suppressing the PI3K/NF-kappaB signaling. Cell Biol Int. 2019;43:360–72.
Golden SA, Covington HE, Berton O, Russo SJ. A standardized protocol for repeated social defeat stress in mice. Nat Protoc. 2011;6:1183–91.
Zhang JC, Yao W, Dong C, Yang C, Ren Q, Ma M, et al. Comparison of ketamine, 7,8-dihydroxyflavone, and ANA-12 antidepressant effects in the social defeat stress model of depression. Psychopharmacology (Berl). 2015;232:4325–35.
Wang ZH, Gong K, Liu X, Zhang Z, Sun X, Wei ZZ, et al. C/EBPbeta regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer’s disease. Nat Commun. 2018;9:1784.
Wu Z, Xia Y, Wang Z, Su Kang S, Lei K, Liu X, et al. C/EBPbeta/delta-secretase signaling mediates Parkinson’s disease pathogenesis via regulating transcription and proteolytic cleavage of alpha-synuclein and MAOB. Mol Psychiatry. 2020;26:568–85.
Popescu IR, Le KQ, Palenzuela R, Voglewede R, Mostany R. Marked bias towards spontaneous synaptic inhibition distinguishes non-adapting from adapting layer 5 pyramidal neurons in the barrel cortex. Sci Rep. 2017;7:14959.
Vogelzangs N, Duivis HE, Beekman AT, Kluft C, Neuteboom J, Hoogendijk W, et al. Association of depressive disorders, depression characteristics and antidepressant medication with inflammation. Transl Psychiatry. 2012;2:e79.
Haroon E, Chen X, Li Z, Patel T, Woolwine BJ, Hu XP, et al. Increased inflammation and brain glutamate define a subtype of depression with decreased regional homogeneity, impaired network integrity, and anhedonia. Transl Psychiatry. 2018;8:189.
Pfau ML, Russo SJ. Peripheral and central mechanisms of stress resilience. Neurobiol Stress Neurobiol Stress. 2015;1:66–79.
Menard C, Pfau ML, Hodes GE, Russo SJ. Immune and neuroendocrine mechanisms of stress vulnerability and resilience. Neuropsychopharmacology. 2017;42:62–80.
Martinowich K, Hattori D, Wu H, Fouse S, He F, Hu Y, et al. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science. 2003;302:890–3.
Zhang J, Rong P, Zhang L, He H, Zhou T, Fan Y, et al. IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis. Sci Adv. 2021;7. https://doi.org/10.1126/sciadv.abb9888.
Mohammadi M, Manaheji H, Maghsoudi N, Danyali S, Baniasadi M, Zaringhalam J. Microglia dependent BDNF and proBDNF can impair spatial memory performance during persistent inflammatory pain. Behav Brain Res. 2020;390:112683.
Kobayashi A, Kang MI, Watai Y, Tong KI, Shibata T, Uchida K, et al. Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1. Mol Cell Biol. 2006;26:221–9.
Kometsi L, Govender K, Mofo Mato EP, Hurchund R, Owira PMO. By reducing oxidative stress, naringenin mitigates hyperglycaemia-induced upregulation of hepatic nuclear factor erythroid 2-related factor 2 protein. J Pharm Pharmacol. 2020;72:1394–404.
Shirai Y, Fujita Y, Hashimoto K. Effects of the antioxidant sulforaphane on hyperlocomotion and prepulse inhibition deficits in mice after phencyclidine administration. Clin Psychopharmacol Neurosci. 2012;10:94–8.
Shirai Y, Fujita Y, Hashimoto R, Ohi K, Yamamori H, Yasuda Y, et al. Dietary Intake of sulforaphane-rich broccoli sprout extracts during juvenile and adolescence can prevent phencyclidine-induced cognitive deficits at adulthood. PLoS ONE. 2015;10:e0127244.
Bjorkholm C, Monteggia LM. BDNF–a key transducer of antidepressant effects. Neuropharmacology. 2016;102:72–9.
Castrén E. Neurotrophins and psychiatric disorders. Handb Exp Pharmacol. 2014;220:461–79.
Hashimoto K. Brain‐derived neurotrophic factor as a biomarker for mood disorders: an historical overview and future directions. Psychiatry Clin Neurosci. 2010;64:341–57.
Hashimoto K. Rapid-acting antidepressant ketamine, its metabolites and other candidates: a historical overview and future perspective. Psychiatry Clin Neurosci. 2019;73:613–27.
Hashimoto K. Molecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine. Biochem Pharmacol. 2020;177:113935.
Hashimoto K, Shimizu E, Iyo M. Critical role of brain-derived neurotrophic factor in mood disorders. Brain Res Brain Res Rev. 2004;45:104–14.
Lindholm JS, Castrén E. Mice with altered BDNF signaling as models for mood disorders and antidepressant effects. Front Behav Neurosci. 2014;8:143.
Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron. 2002;34:13–25.
Zhang JC, Yao W, Hashimoto K. Brain-derived neurotrophic factor (BDNF)-TrkB signaling in inflammation-related depression and potential therapeutic targets. Curr Neuropharmacol. 2016;14:721–31.
Kim JM, Stewart R, Kim SW, Yang SJ, Shin IS, Kim YH, et al. Interactions between life stressors and susceptibility genes (5-HTTLPR and BDNF) on depression in Korean elders. Biol Psychiatry. 2007;62:423–8.
Karege F, Vaudan G, Schwald M, Perroud N, La Harpe R. Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs. Brain Res Mol Brain Res. 2005;136:29–37.
Yang B, Ren Q, Zhang JC, Chen QX, Hashimoto K. Altered expression of BDNF, BDNF pro-peptide and their precursor proBDNF in brain and liver tissues from psychiatric disorders: rethinking the brain-liver axis. Transl Psychiatry. 2017;7:e1128.
Banerjee R, Ghosh AK, Ghosh B, Bhattacharyya S, Mondal AC. Decreased mRNA and protein expression of BDNF, NGF, and their receptors in the hippocampus from suicide: an analysis in human postmortem brain. Clin Med Insights Pathol. 2013;6:1–11.
Sheldrick A, Camara S, Ilieva M, Riederer P, Michel TM. Brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) levels in post-mortem brain tissue from patients with depression compared to healthy individuals—a proof of concept study. Eur Psychiatry. 2017;46:65–71.
Yang B, Yang C, Ren Q, Zhang JC, Chen QX, Shirayama Y, et al. Regional differences in the expression of brain-derived neurotrophic factor (BDNF) pro-peptide, proBDNF and preproBDNF in the brain confer stress resilience. Eur Arch Psychiatry Clin Neurosci. 2016;266:765–9.
Zhang JC, Yao W, Dong C, Han M, Shirayama Y, Hashimoto K. Keap1-Nrf2 signaling pathway confers resilience versus susceptibility to inescapable electric stress. Eur Arch Psychiatry Clin Neurosci. 2018;268:865–70.
Ishii T, Mann GE. When and how does brain-derived neurotrophic factor activate Nrf2 in astrocytes and neurons? Neural Regen Res. 2018;13:803–4.
Bouvier E, Brouillard F, Molet J, Claverie D, Cabungcal JH, Cresto N, et al. Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression. Mol Psychiatry. 2017;22:1701–13.
Zhang JC, Wu J, Fujita Y, Yao W, Ren Q, Yang C, et al. Antidepressant effects of TrkB ligands on depression-like behavior and dendritic changes in mice after inflammation. Int J Neuropsychopharmacol. 2014;18:pyu077.
Magarinos AM, Li CJ, Gal Toth J, Bath KG, Jing D, Lee FS, et al. Effect of brain-derived neurotrophic factor haploinsufficiency on stress-induced remodeling of hippocampal neurons. Hippocampus. 2011;21:253–64.
Govindarajan A, Rao BSS, Nair D, Trinh M, Mawjee N, Tonegawa S, et al. Transgenic brain-derived neurotrophic factor expression causes both anxiogenic and antidepressant effects. Proc Natl Acad Sci USA. 2006;103:13208–13.
Jazwa A, Rojo AI, Innamorato NG, Hesse M, Fernandez-Ruiz J, Cuadrado A. Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism. Antioxid Redox Signal. 2011;14:2347–60.
Acknowledgements
The authors are thankful to Dr. Li Zhang (Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University) for providing the Thy1-YFP mice. We would like to thank Editage (www.editage.com) for English language editing. This work was supported by the National Natural Science Foundation of China (81973341 to QQ), the Fundamental Research Funds for the Central Universities (11620425 to JCZ; 21620426 to QQ), the Science and Technology Program of Guangzhou (202002030010 to QQ), Science and Technology Jiaxing (Grant No: 2017AY33030 to PFD), and the Natural Science Foundation of Guangdong Province (No. 2019A1515010936 to FX).
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JCZ, QQ, and YRS conceived the project, designed the experiments, analyzed the data, and wrote the manuscript. RT, SWH, and QQC performed the social defeat stress model, behavior study, Western blot, immunofluorescence, and ELSA for the in vivo study. LJH and PFD performed the luciferase assay, ChIP assay, Western blot, and immunofluorescence for the in vitro study. GC, RF, and FX assisted with data analysis and interpretation, and critically read the manuscript.
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Tang, R., Cao, Qq., Hu, Sw. et al. Sulforaphane activates anti-inflammatory microglia, modulating stress resilience associated with BDNF transcription. Acta Pharmacol Sin 43, 829–839 (2022). https://doi.org/10.1038/s41401-021-00727-z
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DOI: https://doi.org/10.1038/s41401-021-00727-z
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