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

Zhentao Zhang,Qianqian Cao,Yueyue Chen,Qi Qi,Jiaxu Chen,Song Lin,Kenji Hashimoto,Ji-Chun Zhang,Wei Yao,Jin Su

doi:10.1038/s41398-021-01261-6

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.

Highlights

Introduction The World HealthOrganization estimates that major depressive disorder (MDD) is the most common psychiatric disorder worldwide, which affects more than 264 million individuals of all ages across the globe
We reported that Nrf[2] activator sulforaphane (SFN) showed antidepressant-like effects in the lipopolysaccharide (LPS)-induced and chronic social defeat stress (CSDS) models of depression by stimulating the expression of brain-derived neurotrophic factor (BDNF)[8,10,11], and that Nrf[2] activators such as TBE-31 and MCE-1 showed antidepressant-like effects in LPSinduced model of depression[12]
We examined to explore whether Nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated increases in BDNF affect the expression of Bdnf transcriptional repressors (Fig. 1A–H)

Summary

Introduction

Organization estimates that major depressive disorder (MDD) is the most common psychiatric disorder worldwide, which affects more than 264 million individuals of all ages across the globe. MDD is a major contributor to the global burden of disease[1]. Accumulating evidence suggests a crucial role of Nrf[2] in the pathogenesis of depression[8,9]. We reported that Nrf[2] activator sulforaphane (SFN) showed antidepressant-like effects in the lipopolysaccharide (LPS)-induced and chronic social defeat stress (CSDS) models of depression by stimulating the expression of brain-derived neurotrophic factor (BDNF)[8,10,11], and that Nrf[2] activators such as TBE-31 and MCE-1 showed antidepressant-like effects in LPSinduced model of depression[12].

Methods

Results

Conclusion