Abstract：
Post-stroke depression (PSD) is a complication of cerebrovascular disease, which can increase mortality after stroke. CRH is one of the main signaling peptides released after activation of the hypothalamic-pituitary-adrenal (HPA) axis in response to stress. It affects synaptic plasticity by regulating inflammation, oxidative stress and autophagy in the central nervous system. And the loss of spines exacerbates depression-like behavior. Therefore, synaptic deficits induced by CRH may be related to post-stroke depression. However, the underlying mechanism remains unclear. The Keap1-Nrf2 complex is one of the core components of the antioxidant response. As an autophagy associated protein, p62 participates in the Keap1-NrF2 pathway through its Keap1 interaction domain. Oxidative stress is involved in the feedback regulation between Keap1-Nrf2 pathway and p62.However, whether the relationship between CRH and the Keap1-Nrf2-p62 pathway is involved in PSD remains unknown. This study found that serum levels of CRH in 22 patients with PSD were higher than those in healthy subjects. We used MCAO combined with CUMS single-cage SD rats to establish an animal model of PSD. Animal experiments showed that CRHR1 antagonist prevented synaptic loss in the hippocampus of PSD rats and alleviated depression-like behavior. CRH induced p62 accumulation in the prefrontal cortex of PSD rats through CRHR1. CRHR1 antagonist inhibited Keap1-Nrf2-p62 pathway by attenuating oxidative stress. In addition, we found that abnormal accumulation of p62 induces PSD. It alleviates depression-like behavior by inhibiting the expression of p62 and promoting the clearance of p62 in PSD rats. These findings can help explore the pathogenesis of PSD and design targeted treatments for PSD.
摘要：
卒中后抑郁(PSD)是脑血管疾病的并发症,这可以增加中风后的死亡率。CRH是下丘脑-垂体-肾上腺（HPA）轴激活后响应应激释放的主要信号肽之一。它通过调节炎症影响突触可塑性，氧化应激和自噬在中枢神经系统。脊柱的丧失加剧了抑郁样的行为。因此,CRH诱发的突触缺陷可能与卒中后抑郁有关.然而,潜在机制尚不清楚.Keap1-Nrf2复合物是抗氧化反应的核心成分之一。作为自噬相关蛋白，p62通过其Keap1相互作用域参与Keap1-NrF2途径。氧化应激参与Keap1-Nrf2通路和p62之间的反馈调节。然而,CRH与Keap1-Nrf2-p62通路是否参与PSD的关系尚不清楚.这项研究发现，22例PSD患者的血清CRH水平高于健康受试者。采用MCAO联合CUMS单笼SD大鼠建立PSD动物模型。动物实验表明，CRHR1拮抗剂可预防PSD大鼠海马突触丢失，减轻抑郁样行为。CRH经由过程CRHR1引诱p62在PSD年夜鼠前额叶皮层积聚。CRHR1拮抗剂通过减弱氧化应激抑制Keap1-Nrf2-p62通路。此外,我们发现p62的异常积累引起PSD。它通过抑制p62的表达和促进p62的清除减轻PSD大鼠的抑郁样行为。这些发现有助于探索PSD的发病机制和设计针对PSD的靶向治疗方法。
