Depression after Intracerebral Hemorrhage: Role of Nrf2

脑出血后抑郁：Nrf2 的作用

• 批准号: 9461285
• 负责人: Jian Wang
• 金额: $ 20.44万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9461285
• 关键词: Agmatine; American Heart Association; Animals; Antidepressive Agents; Area; Autologous; Basal Ganglia; Behavior; Bioavailable; Biochemical; Blood; Brain; Brain Injuries; Brain hemorrhage; Brain-Derived Neurotrophic Factor; C57BL/6 Mouse; Cerebral hemisphere hemorrhage; Clinical; Clinical Research; Cognition; Complex; Corpus striatum structure; Data; Depressed mood; Development; Female; Flavanol; Fluoxetine; Frequencies; Fumarates; Gene Targeting; Glutathione; Glutathione Disulfide; Goals; Hemorrhage; Human; Incidence; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1 beta; Interleukin-6; Ischemic Stroke; Knockout Mice; Lead; Lipids; Mental Depression; Modeling; Molecular; Mus; NQO1 gene; Neurological outcome; Neurotrophic Tyrosine Kinase Receptor Type 2; Nuclear; Oral; Outcome; Pathogenesis; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Pilot Projects; Production; Proteins; Quality of life; Reactive Oxygen Species; Recovery of Function; Reporting; Research; Risk; Role; Selective Serotonin Reuptake Inhibitor; Severities; Sex Characteristics; Signal Transduction; Stroke; Sucrose; Swimming; System; TNF gene; Tail Suspension; Testing; Time; Toxic effect; Validation; antidepressant effect; behavior test; clinically relevant; collagenase; cytokine; depressive symptoms; early experience; epicatechin; experience; improved; insight; male; mortality; negative affect; neurobiological mechanism; neuroprotection; new therapeutic target; novel; object recognition; outcome forecast; oxidation; post stroke depression; pre-clinical; preclinical evaluation; preclinical study; preference; sex; stroke survivor; superoxide dismutase 1; transcription factor; young adult

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).

项目概要： 至少有三分之一的中风幸存者患有中风后抑郁症（PSD），这已被证明是 对预后有负面影响。虽然缺血性卒中后PSD已被研究，很少有人知道， 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，发生ICH的患者确实会发生PSD。确定ICH特异性PSD的新药靶点 患者是一个迫切的需求，因为抗抑郁药，特别是选择性血清素再摄取抑制剂， 与出血风险升高、卒中严重程度增加和卒中死亡率增加相关，或 ICH。为了限制脑出血损伤和改善功能恢复，我们研究了临床前脑出血的PSD 模型，并首次表明，小鼠皮质ICH模型产生抑郁样行为。 然而，临床上，ICH最常见于基底神经节，这是一个有助于发展的区域。 的PSD。事实上，我们的初步数据表明，纹状体ICH确实会导致小鼠的抑郁样行为。的 PSD的发病机制复杂，但炎症反应增强，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Nrf 2是一个主因子， ROS和炎症的调节剂。加强这种内源性系统可能提供一种机制， ICH后PSD。我们已经报道了Nrf 2活性在ICH后具有神经保护作用。我们还表明， Nrf 2基因敲除小鼠脑损伤加重与炎症和ROS产生增加有关 并且脑渗透性的Nrf 2诱导剂（-）-表儿茶素提供针对ICH的神经保护。脑源 神经营养因子（BDNF）是Nrf 2的靶基因之一，Nrf 2/BDNF信号通路被证明参与了Nrf 2的表达。 胍丁胺和氟西汀产生的抗抑郁作用。因为神经生物学机制 Nrf 2基因的缺失/激活是否与其他抑郁症亚型的Nrf 2基因的缺失/激活有关， 加重/减轻纹状体ICH后PSD。本R21的总体目标是调查 纹状体脑出血模型可用于研究脑出血后PSD，如果是这样，则可确定Nrf 2/BDNF的作用 在PSD发病机制中起重要作用。在两个具体的目标，我们将测试的假设，失调， Nrf 2/BDNF通路参与了脑出血后PSD的发生发展。目的1将确定纹状体ICH是否 在两种性别的年轻小鼠中产生PSD，Aim 2将确定Nrf 2途径的失调是否 导致ICH后PSD。成功验证了纹状体ICH模型作为一种适当的方法， 研究PSD将为PSD的扩展临床前研究提供依据。这个项目是高度临床化的 相关，代表了首次在纹状体ICH模型中对PSD进行临床前评价。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诱导的PSD是一个研究不足的临床问题，由美国心脏协会（卒中 2017; 48：e30-e43）。