The mechanisms underlying the pathophysiology of depression remain elusive, and the development of novel, effective antidepressant drugs remains necessary. A dihydroquinoline analog of agomelatine (AGO), N-(2-(7-methoxy-3,4-dihydroisoquinolin-1-yl)ethyl)acetamide hydrochloride (NMDEA), was synthesized by employing a scaffold-hopping strategy in our previous study. In this study, NMDEA was demonstrated to attenuate depression-related behaviors in mice models of chronic unpredictable mild stress (CUMS), using a sucrose preference test, a forced swimming test, and a tail suspension test. However, the antidepressant mechanism of NMDEA appears to differ from that for AGO. Based on the analysis of fecal microbiota from mice, stress can alter the richness of the gut bacterial community, increasing the expression of immune-modulating microbiota, such as Clostridia, and decreasing the expression of probiotic bacteria, such as Lactobacillus. Treatment with NMDEA was able to recover the richness and to regulate the dysbiosis among bacterial species. Several studies have demonstrated that the gut microbiota population can induce inflammatory processes. To explore the effects of NMDEA on the suppression of pro-inflammatory factors, we used Western blotting to analyze the levels of interleukin 1 beta (IL-1β), interleukin 6 (IL-6), p65, and inducible nitric oxide synthase (iNOS). NMDEA suppressed the activation of IL-1β and IL-6, in the hippocampus, and IL-1β, IL-6, p65, and iNOS, in lipopolysaccharide (LPS)-induced BV-2 cells. These results suggested that NMDEA may affect the microbiota-inflammasome-brain axis, regulating relevant neuro-inflammatory markers and gut microbiota. Our data also suggested that using small molecules to modify the gut microbiota population or alter inflammasome signaling may represent a new therapeutic opportunity for the mitigation of depression.

抑郁症的病理生理机制仍然难以捉摸，开发新的、有效的抗抑郁药物仍然是必要的。阿戈美拉汀 (AGO) 的二氢喹啉类似物，N-(2-(7-methoxy-3,4-dihydroisoquinolin-1-yl)ethyl)acetamide hydrochloride (NMDEA) 在我们之前的研究中采用支架跳跃策略合成。在这项研究中，使用蔗糖偏好测试、强迫游泳测试和悬尾测试证明 NMDEA 可以减轻慢性不可预测轻度压力 (CUMS) 小鼠模型中的抑郁相关行为。然而，NMDEA 的抗抑郁机制似乎与 AGO 不同。根据对小鼠粪便微生物群的分析，压力可以改变肠道细菌群落的丰富度，增加免疫调节微生物群（如梭状芽孢杆菌）的表达，并降低益生菌（如乳酸杆菌）的表达. 用 NMDEA 治疗能够恢复丰富度并调节细菌物种之间的生态失调。几项研究表明，肠道微生物群可以诱导炎症过程。为了探索 NMDEA 对促炎因子抑制的影响，我们使用蛋白质印迹法分析了白细胞介素 1 β (IL-1β)、白细胞介素 6 (IL-6)、p65 和诱导型一氧化氮合酶 (iNOS ）。NMDEA 抑制海马中 IL-1β 和 IL-6 的激活，以及脂多糖 (LPS) 诱导的 BV-2 细胞中 IL-1β、IL-6、p65 和 iNOS 的激活。这些结果表明，NMDEA 可能影响微生物群-炎症小体-脑轴，调节相关的神经炎症标志物和肠道微生物群。