Luo Li, Liu Wenna, Dong Leipeng, Wang Saiying, Wang Qinhui, Jiang Yuting, Zhao Minggao, Liu An, Yang Le
Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Air Force Medical University, Xi'an, 710038, China.
Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, China.
Neurochem Res. 2025 Jan 3;50(1):69. doi: 10.1007/s11064-024-04323-5.
Depression is a common and complex neuropsychiatric disorder affecting people of all ages worldwide, associated with high rates of relapse and disability. Neohesperidin (NEO) is a dietary flavonoid with applications in therapeutics; however, its effects on depressive-like behavior remain unknown. Here, we evaluated the effects of NEO on depressive-like behavior induced by chronic and unpredictable mild stress (CUMS). NEO (25, 50, and 100 mg kg) treatment for two weeks dose-dependently improved CUMS-induced depressive-like behavior measured by the sucrose preference, open field, forced swimming, and tail suspension tests. Moreover, NEO effectively blocked the decrease of superoxide dismutase, catalase, and glutathione peroxidase activity and the increase of malondialdehyde levels, which are markers of oxidative stress. In addition, NEO inhibited microglial activation and the production of proinflammatory cytokines interleukin-1β (IL-1β), IL-6 and tumor necrosis factor α (TNF-α) in the hippocampus and prefrontal cortex. Molecular docking and dynamic simulations showed that NEO has good affinity for NOD-like receptor protein 3 (NLRP3), suggesting that NEO may play an antidepressant role by regulating the NLRP3 signaling pathway. Western blotting results further revealed that the increased expression level of NLRP3 inflammasome components (NLRP3, caspase-1, and ASC) in CUMS mice was significantly reversed by NEO treatment. These results suggest that NEO is a candidate for treating depression and should be considered for further clinical development.
抑郁症是一种常见且复杂的神经精神疾病，影响着全球所有年龄段的人群，与高复发率和致残率相关。新橙皮苷（NEO）是一种具有治疗应用的膳食类黄酮；然而，其对抑郁样行为的影响尚不清楚。在此，我们评估了NEO对慢性不可预测轻度应激（CUMS）诱导的抑郁样行为的影响。NEO（25、50和100毫克/千克）治疗两周剂量依赖性地改善了通过蔗糖偏好、旷场、强迫游泳和悬尾试验测量的CUMS诱导的抑郁样行为。此外，NEO有效阻断了超氧化物歧化酶、过氧化氢酶和谷胱甘肽过氧化物酶活性的降低以及丙二醛水平的升高，这些都是氧化应激的标志物。此外，NEO抑制了海马体和前额叶皮质中微胶质细胞的激活以及促炎细胞因子白细胞介素-1β（IL-1β）、IL-6和肿瘤坏死因子α（TNF-α）的产生。分子对接和动态模拟表明，NEO对NOD样受体蛋白3（NLRP3）具有良好的亲和力，表明NEO可能通过调节NLRP3信号通路发挥抗抑郁作用。蛋白质印迹结果进一步显示，NEO治疗可显著逆转CUMS小鼠中NLRP3炎性小体成分（NLRP3、半胱天冬酶-1和ASC）表达水平的升高。这些结果表明，NEO是治疗抑郁症的候选药物，应考虑进一步进行临床开发。
