Post-stroke depression, observed in 30-50% of stroke patients, negatively affects quality of life and mortality. The pathogenesis of post-stroke depression is complex, but heightened reactive oxygen species production and inflammation might be two key factors. We have reported that intracerebral hemorrhage (ICH) in cerebral cortex produces depression-like behavior in young male mice. Here, we found that mice lacking nuclear factor erythroid-derived 2-related factor 2 (Nrf2), a transcription factor that upregulates antioxidant proteins and trophic factors such as brain-derived neurotrophic factor (BDNF), had more severe depression-like behavior than wild-type mice at days 21 to 28 after cortical ICH (c-ICH). Moreover, the expression of Nrf2, heme oxygenase-1, BDNF, and TrkB were significantly decreased in wild-type mice after c-ICH. Interestingly, TP-500 (2 mg/kg), a potent Nrf2 inducer, decreased the inflammatory response and reactive oxygen species production on day 28 after c-ICH and improved depression-like behaviors. TrkB receptor antagonist ANA-12 abolished this anti-depression effect. Depression was more severe in female than in male wild-type mice after ICH, but TP-500 improved depression-like behavior in females. These results suggest that downregulation of Nrf2-BDNF-TrkB signaling contributes to development of post-stroke depression, and that Nrf2 inducer TP-500 might improve depression after c-ICH.

在 30-50% 的中风患者中观察到中风后抑郁症对生活质量和死亡率产生负面影响。中风后抑郁症的发病机制很复杂，但活性氧生成增加和炎症可能是两个关键因素。我们报道了大脑皮层的脑出血 (ICH) 在年轻的雄性小鼠中产生抑郁样行为。在这里，我们发现缺乏核因子红细胞衍生 2 相关因子 2 (Nrf2)（一种上调抗氧化蛋白和脑源性神经营养因子 (BDNF) 等营养因子的转录因子）的小鼠具有比抑郁症更严重的行为。野生型小鼠在皮层 ICH (c-ICH) 后第 21 至 28 天。此外，在 c-ICH 后，野生型小鼠中 Nrf2、血红素加氧酶 1、BDNF 和 TrkB 的表达显着降低。有趣的是，TP-500 (2 mg/kg) 是一种有效的 Nrf2 诱导剂，可在 c-ICH 后第 28 天降低炎症反应和活性氧物质的产生，并改善抑郁样行为。TrkB 受体拮抗剂 ANA-12 消除了这种抗抑郁作用。在 ICH 后，雌性的抑郁症比雄性野生型小鼠更严重，但 TP-500 改善了雌性的抑郁样行为。这些结果表明，Nrf2-BDNF-TrkB 信号的下调有助于卒中后抑郁症的发展，并且 Nrf2 诱导剂 TP-500 可能会改善 c-ICH 后的抑郁症。在 ICH 后，雌性的抑郁症比雄性野生型小鼠更严重，但 TP-500 改善了雌性的抑郁样行为。这些结果表明，Nrf2-BDNF-TrkB 信号的下调有助于卒中后抑郁症的发展，并且 Nrf2 诱导剂 TP-500 可能会改善 c-ICH 后的抑郁症。在 ICH 后，雌性的抑郁症比雄性野生型小鼠更严重，但 TP-500 改善了雌性的抑郁样行为。这些结果表明，Nrf2-BDNF-TrkB 信号的下调有助于卒中后抑郁症的发展，并且 Nrf2 诱导剂 TP-500 可能会改善 c-ICH 后的抑郁症。