1. Academic Validation
  2. Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodents

Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodents

  • Transl Psychiatry. 2021 Feb 24;11(1):140. doi: 10.1038/s41398-021-01261-6.
Wei Yao  # 1 Song Lin  # 2 Jin Su 3 Qianqian Cao 2 Yueyue Chen 4 Jiaxu Chen 1 Zhentao Zhang 5 Kenji Hashimoto 6 Qi Qi 7 Ji-Chun Zhang 8
Affiliations

Affiliations

  • 1 Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, 510632, Guangzhou, China.
  • 2 Department of Physiology, School of Medicine, Jinan University, 510632, Guangzhou, China.
  • 3 MOE Key Laboratory of Tumor Molecular Biology; Clinical Translational Center for Targeted Drug, Department of Pharmacology, School of Medicine, Jinan University, 510632, Guangzhou, China.
  • 4 Guangzhou Overseas Chinese Hospital of Jinan University, 510632, Guangzhou, China.
  • 5 Department of Neurology, Renmin Hospital of Wuhan University, 430060, Wuhan, China.
  • 6 Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan. hashimoto@faculty.chiba-u.jp.
  • 7 MOE Key Laboratory of Tumor Molecular Biology; Clinical Translational Center for Targeted Drug, Department of Pharmacology, School of Medicine, Jinan University, 510632, Guangzhou, China. qiqikc@jnu.edu.cn.
  • 8 Department of Physiology, School of Medicine, Jinan University, 510632, Guangzhou, China. jczhang@jnu.edu.cn.
  • # Contributed equally.
Abstract

The transcription factor erythroid 2-related factor 2 (Nrf2) and brain-derived neurotrophic factor (BDNF) play a key role in depression. However, the molecular mechanisms underlying the crosstalk between Nrf2 and BDNF in depression remain unclear. We examined whether Nrf2 regulates the transcription of Bdnf by binding to its exon I promoter. Furthermore, the role of Nrf2 and BDNF in the brain regions from mice with depression-like phenotypes was examined. Nrf2 regulated the transcription of Bdnf by binding to its exon I promoter. Activation of Nrf2 by sulforaphane (SFN) showed fast-acting antidepressant-like effects in mice by activating BDNF as well as by inhibiting the expression of its transcriptional repressors (HDAC2, mSin3A, and MeCP2) and revising abnormal synaptic transmission. In contrast, SFN did not affect the protein expression of BDNF and its transcriptional repressor proteins in the medial prefrontal cortex (mPFC) and hippocampus, nor did it reduce depression-like behaviors and abnormal synaptic transmission in Nrf2 knockout mice. In the mouse model of chronic social defeat stress (CSDS), protein levels of Nrf2 and BDNF in the mPFC and hippocampus were lower than those of control and CSDS-resilient mice. In contrast, the protein levels of BDNF transcriptional repressors in the CSDS-susceptible mice were higher than those of control and CSDS-resilient mice. These data suggest that Nrf2 activation increases the expression of Bdnf and decreases the expression of its transcriptional repressors, which result in fast-acting antidepressant-like actions. Furthermore, abnormalities in crosstalk between Nrf2 and BDNF may contribute to the resilience versus susceptibility of mice against CSDS.

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