Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Neurosciences Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS), Site Pitié-Salpêtrière, Paris, France.
INSERM, U1130, Paris, France.
Mol Psychiatry. 2017 Dec;22(12):1701-1713. doi: 10.1038/mp.2016.144. Epub 2016 Sep 20.
Stressful life events produce a state of vulnerability to depression in some individuals. The mechanisms that contribute to vulnerability to depression remain poorly understood. A rat model of intense stress (social defeat (SD), first hit) produced vulnerability to depression in 40% of animals. Only vulnerable animals developed a depression-like phenotype after a second stressful hit (chronic mild stress). We found that this vulnerability to depression resulted from a persistent state of oxidative stress, which was reversed by treatment with antioxidants. This persistent state of oxidative stress was due to low brain-derived neurotrophic factor (BDNF) levels, which characterized the vulnerable animals. We found that BDNF constitutively controlled the nuclear translocation of the master redox-sensitive transcription factor Nrf2, which activates antioxidant defenses. Low BDNF levels in vulnerable animals prevented Nrf2 translocation and consequently prevented the activation of detoxifying/antioxidant enzymes, ultimately resulting in the generation of sustained oxidative stress. Activating Nrf2 translocation restored redox homeostasis and reversed vulnerability to depression. This mechanism was confirmed in Nrf2-null mice. The mice displayed high levels of oxidative stress and were inherently vulnerable to depression, but this phenotype was reversed by treatment with antioxidants. Our data reveal a novel role for BDNF in controlling redox homeostasis and provide a mechanistic explanation for post-stress vulnerability to depression while suggesting ways to reverse it. Because numerous enzymatic reactions produce reactive oxygen species that must then be cleared, the finding that BDNF controls endogenous redox homeostasis opens new avenues for investigation.
生活压力事件会使某些个体易患抑郁症。导致易患抑郁症的机制仍知之甚少。一种强烈压力的大鼠模型（社交挫败（SD），第一次打击）使 40%的动物易患抑郁症。只有易患动物在第二次应激打击（慢性轻度应激）后才会出现类似抑郁症的表型。我们发现，这种易患抑郁症是由于持续的氧化应激状态引起的，而抗氧化剂治疗可以逆转这种状态。这种持续的氧化应激状态是由于脑源性神经营养因子（BDNF）水平降低引起的，这种状态是易患动物的特征。我们发现，BDNF 持续控制着主要的氧化还原敏感转录因子 Nrf2 的核易位，从而激活抗氧化防御。易患动物的 BDNF 水平低会阻止 Nrf2 的易位，从而阻止解毒/抗氧化酶的激活，最终导致持续的氧化应激产生。激活 Nrf2 的易位可以恢复氧化还原平衡并逆转易患抑郁症的状态。该机制在 Nrf2 缺失的小鼠中得到了证实。这些小鼠表现出高水平的氧化应激，并且天生易患抑郁症，但用抗氧化剂治疗可以逆转这种表型。我们的数据揭示了 BDNF 在控制氧化还原平衡中的新作用，并为应激后易患抑郁症提供了一种机制解释，同时也为逆转这种状态提供了方法。由于许多酶促反应会产生必须清除的活性氧，因此 BDNF 控制内源性氧化还原平衡的发现为进一步研究开辟了新的途径。
