Sulforaphane activates anti-inflammatory microglia, modulating stress resilience associated with BDNF transcription

Rui Tang1,2, Qian-qian Cao1, Sheng-wei Hu3, Lu-juan He1, Peng-fei Du4, Gang Chen5, Rao Fu6, Fei Xiao7, Yi-rong Sun8, Ji-chun Zhang1, Qi Qi3
1 Department of Physiology, School of Medicine, Jinan University, Guangzhou 510632, China
2 School of Medicine, Xi-an Medicine College, Xi-an 710000, China
3 MOE Key Laboratory of Tumor Molecular Biology, Clinical Translational Center for Targeted Drug, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 510632, China
4 Second Affiliated Hospital of Jiaxing, Jiaxing 4564496, China
5 School of traditional Chinese Medicine, Jinan University, Guangzhou 510632, China
6 Department of Anatomy, School of Medicine (Shenzhen), Sun Yat-sen University, Guangzhou 510080, China
7 Department of Pharmacology, School of Pharmacy, Jinan University, Guangzhou 510632, China
8 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
Correspondence to: Yi-rong Sun:, Ji-chun Zhang:, Qi Qi:,
DOI: 10.1038/s41401-021-00727-z
Received: 30 March 2021
Accepted: 22 June 2021
Advance online: 16 July 2021


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.
Keywords: sulforaphane; Nrf2; BDNF; microglia; stress resilience

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