Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, 510632, Guangzhou, China.
Department of Physiology, School of Medicine, Jinan University, 510632, Guangzhou, China.
Transl Psychiatry. 2021 Feb 24;11(1):140. doi: 10.1038/s41398-021-01261-6.
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.
转录因子红细胞 2 相关因子 2（Nrf2）和脑源性神经营养因子（BDNF）在抑郁症中发挥关键作用。然而，Nrf2 和 BDNF 之间相互作用的分子机制在抑郁症中仍不清楚。我们研究了 Nrf2 是否通过结合其外显子 I 启动子来调节 Bdnf 的转录。此外，还研究了具有抑郁样表型的小鼠大脑区域中 Nrf2 和 BDNF 的作用。Nrf2 通过结合其外显子 I 启动子来调节 Bdnf 的转录。通过激活 Nrf2 ，萝卜硫素（SFN）通过激活 BDNF 以及抑制其转录抑制物（HDAC2、mSin3A 和 MeCP2）的表达并修正异常的突触传递，在小鼠中表现出快速抗抑郁样作用。相比之下，SFN 不会影响内侧前额叶皮层（mPFC）和海马体中 BDNF 及其转录抑制蛋白的蛋白质表达，也不会减少 Nrf2 敲除小鼠的抑郁样行为和异常突触传递。在慢性社会挫败应激（CSDS）的小鼠模型中，mPFC 和海马体中的 Nrf2 和 BDNF 蛋白水平低于对照和 CSDS 抗性小鼠。相比之下，CSDS 易感小鼠中 BDNF 转录抑制因子的蛋白水平高于对照和 CSDS 抗性小鼠。这些数据表明，Nrf2 激活增加了 Bdnf 的表达并降低了其转录抑制因子的表达，从而产生快速抗抑郁样作用。此外，Nrf2 和 BDNF 之间相互作用的异常可能导致对 CSDS 的抵抗力和易感性。
