Depression after Intracerebral Hemorrhage: Role of Nrf2

项目总结： 至少三分之一的中风幸存者患有中风后抑郁(PSD)，这已被证明是 对预后有负面影响。尽管已经对缺血性卒中后的PSD进行了研究，但对其发病机制知之甚少。 与脑出血(ICH)相关的抑郁或抑郁情绪的频率和严重程度。 然而，经历过脑出血的患者确实会患上PSD。确定针对脑出血的PSD的新药物靶点 患者是迫切需要的，因为抗抑郁药物，特别是选择性5-羟色胺再摄取抑制剂， 与出血风险增加、卒中严重程度增加和卒中或 我也是。为了限制脑出血的损伤和改善功能恢复，我们研究了临床前脑出血患者的PSD。 模型，并首次表明小鼠大脑皮层脑出血模型会产生抑郁样行为。 然而，在临床上，脑出血最常发生在基底节，这是一个有助于发育的区域。 PSD的人。事实上，我们的试验数据表明，纹状体脑出血确实会导致小鼠出现抑郁样行为。这个 PSD的发病机制很复杂，但炎症反应增强和活性氧增加 物种(ROS)的产生可能是两个关键的生化因素。转录因子Nrf2是主因子 ROS和炎症的调节者。增强这种内生系统可能会提供一种机制，以减少 脑出血后PSD。我们已经报道了脑出血后Nrf2的活性具有神经保护作用。我们还表明， Nrf2基因敲除小鼠脑损伤加重与炎症和ROS产生增加有关 而且，脑透性、NRF2诱导剂(-)-表儿茶素提供了对脑出血的神经保护。脑源性 神经营养因子(BDNF)是Nrf2的靶基因之一，Nrf2/BDNF信号转导被证明参与了Nrf2信号转导 在胍丁胺和氟西汀所产生的抗抑郁药样作用中。因为神经生物机制 PSD可能与其他抑郁症亚型不同，目前尚不清楚Nrf2是否缺失/激活 加重/减轻纹状体脑出血后的PSD。此R21的总体目标是调查是否 纹状体脑出血模型可用于研究脑出血后的PSD，如果是的话，则可以确定Nrf2/BDNF的作用 PSD发病机制中的途径。在两个特定的目标中，我们将检验这一假设，即 Nrf2/BDNF通路参与脑出血后PSD的发生发展。目标1将确定纹状体脑出血 在幼鼠中产生PSD，无论性别，目标2将确定Nrf2途径的失调 对脑出血后的PSD有贡献。纹状体脑出血模型的成功验证是一种适当的方法 调查PSD将为扩大PSD的临床前研究提供理论基础。该项目具有高度的临床应用价值。 这是首次在纹状体脑出血模型中对PSD进行的临床前评估。结果将提供 深入了解脑出血后PSD的分子机制，并将确定和验证新的治疗靶点 ICH诱发的PSD，美国心脏协会(卒中)发现的一个未被充分研究的临床问题 2017；48：E30-E43)。

PROJECT SUMMARY: At least one-third of stroke survivors suffer from post-stroke depression (PSD), which has been shown to negatively affect prognosis. Although PSD after ischemic stroke has been studied, very little is known about the frequency and severity of depression or depressed mood associated with intracerebral hemorrhage (ICH). However, patients who experience ICH do develop PSD. Identifying new drug targets for PSD specific for ICH patients is a pressing need because antidepressants, particularly selective serotonin reuptake inhibitors, are associated with an elevated risk of bleeding, increased stroke severity, and increased mortality from stroke or ICH. In an effort to limit ICH injury and improve functional recovery, we have investigated PSD in preclinical ICH models and shown for the first time that the mouse cortical ICH model produces depression-like behavior. Clinically, however, ICH occurs most commonly in the basal ganglia, an area that contributes to the development of PSD. Indeed, our pilot data showed that striatal ICH does lead to depression-like behavior in mice. The pathogenesis of PSD is complex, but a heightened inflammatory response and increased reactive oxygen species (ROS) production might be two key biochemical factors. The transcription factor Nrf2 is a master regulator of ROS and inflammation. Enhancing this endogenous system might provide a mechanism to reduce PSD after ICH. We have reported that Nrf2 activity is neuroprotective after ICH. We have also shown that the exacerbation of brain injury in Nrf2 knockout mice is associated with increased inflammation and ROS production and that the brain-permeable, Nrf2 inducer (–)-epicatechin offers neuroprotection against ICH. Brain-derived neurotrophic factor (BDNF) is one of the Nrf2 target genes, and Nrf2/BDNF signaling was shown to be involved in the antidepressant-like effect produced by agmatine and fluoxetine. Because the neurobiologic mechanisms of PSD may differ from those of other depression subtypes, it is unknown whether deletion/activation of Nrf2 exacerbates/mitigates PSD after striatal ICH. The overall objective of this R21 is to investigate whether the striatal ICH model can be used to investigate PSD after ICH, and if so, to determine the role of the Nrf2/BDNF pathway in the pathogenesis of PSD. In two specific aims, we will test the hypothesis that dysregulation of the Nrf2/BDNF pathway contributes to the development of PSD after ICH. Aim 1 will determine whether striatal ICH produces PSD in young mice of both sexes, and Aim 2 will determine whether dysregulation of the Nrf2 pathway contributes to PSD after ICH. Successful validation of the striatal ICH model as an appropriate approach to investigate PSD will provide the rationale for expanded preclinical studies on PSD. This project is highly clinically relevant and represents the first preclinical evaluation of PSD in a striatal ICH model. The results will provide insight into the molecular mechanisms of PSD after ICH and will identify and validate new therapeutic targets for ICH-induced PSD, an under-investigated clinical problem identified by the American Heart Association (Stroke 2017; 48: e30-e43).