Lianyungang Hospital of Traditional Chinese Medicine, No. 160, Chaoyang Middle Road, Haizhou District, Lianyungang City, Jiangsu Province, 222004, China.
School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, No. 138, Xianlin Road, Qixia District, Nanjing City, Jiangsu 210023, China.
Phytomedicine. 2024 Jun;128:155433. doi: 10.1016/j.phymed.2024.155433. Epub 2024 Feb 7.
BACKGROUND: Post-stroke depression (PSD) affects approximately one-third of stroke survivors, leading to adverse outcomes in rehabilitation, reduced quality of life, and increased mortality rates. Despite these implications, the underlying causes of PSD remain unclear, posing challenges for prevention and treatment. Echinacoside (ECH), a natural compound with known neuroprotective and antidepressant properties, holds significant therapeutic potential for PSD. However, the precise mechanism of its action remains unknown. PURPOSE: To unravel the specific mechanism through which ECH alleviates PSD by exploring the intricate interplay between ECH and Nrf2, as well as its impact on the BDNF/TrkB signaling axis. STUDY DESIGN AND METHODS: A rat PSD model was established though middle cerebral artery occlusion coupled with chronic unpredictable mild stress, followed by ECH treatment. The rats' depressive state was evaluated using the sucrose preference test and force swimming test. Brain damage was assessed through TTC staining, Nissl staining, and TUNEL assay. The multifaceted mechanism of ECH in PSD was investigated using immunofluorescence, immunohistochemistry, RT-qPCR, dual-luciferase assay, and western blotting. Additionally, the interaction between ECH and Nrf2 was explored through molecular docking and microscale thermophoresis. RESULTS: Our findings unveiled a novel facet of ECH action, demonstrating its unique ability to upregulate Nrf2 through acetylation within the hippocampus of PSD-affected rats (p < 0.05). Moreover, ECH showcased its distinctive potential by enhancing BDNF transcriptional activity, activating the BDNF/TrkB signaling axis, and orchestrating a comprehensive response against oxidative stress and apoptosis, thereby alleviating PSD symptoms in rats (p < 0.05). CONCLUSIONS: This study not only provides insights into the pivotal role of Nrf2 in mediating the BDNF/TrkB axis activation by ECH but also highlights the novelty of ECH's mechanism in addressing PSD. The elucidation of these unique aspects positions ECH as a groundbreaking candidate for further exploration and development in the realm of PSD intervention.
背景： 脑卒中后抑郁（PSD）影响约三分之一的脑卒中幸存者，导致康复不良、生活质量下降和死亡率增加。尽管有这些影响，但 PSD 的根本原因仍不清楚，这给预防和治疗带来了挑战。松果菊苷（ECH）是一种具有已知神经保护和抗抑郁作用的天然化合物，对 PSD 具有重要的治疗潜力。然而，其作用的确切机制尚不清楚。
目的： 通过探讨 ECH 与 Nrf2 之间的复杂相互作用及其对 BDNF/TrkB 信号轴的影响，揭示 ECH 缓解 PSD 的具体机制。
研究设计和方法： 通过大脑中动脉闭塞结合慢性不可预测轻度应激建立大鼠 PSD 模型，然后给予 ECH 治疗。通过蔗糖偏好试验和强迫游泳试验评估大鼠的抑郁状态。通过 TTC 染色、尼氏染色和 TUNEL 测定评估脑损伤。采用免疫荧光、免疫组织化学、RT-qPCR、双荧光素酶报告基因检测和 Western blot 检测 ECH 治疗 PSD 的多方面机制。此外，通过分子对接和微量热泳法研究 ECH 与 Nrf2 之间的相互作用。
结果： 我们的研究结果揭示了 ECH 作用的一个新方面，表明它具有通过乙酰化作用在 PSD 大鼠海马中上调 Nrf2 的独特能力（p < 0.05）。此外，ECH 通过增强 BDNF 的转录活性、激活 BDNF/TrkB 信号轴以及协调对氧化应激和细胞凋亡的全面反应，展示了其独特的潜力，从而缓解了大鼠的 PSD 症状（p < 0.05）。
结论： 本研究不仅深入探讨了 Nrf2 在介导 ECH 激活 BDNF/TrkB 轴中的关键作用，还强调了 ECH 在治疗 PSD 方面的机制新颖性。这些独特方面的阐明使 ECH 成为 PSD 干预领域进一步探索和开发的突破性候选药物。
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