Institute of Neuroscience and Gastrointestinal Laboratory, The children's Hospital, Zhejiang University School of Medicine, Hangzhou, China; Department of Zoology, Faculty of Science, Aswan University, Egypt.
The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China.
Prog Neuropsychopharmacol Biol Psychiatry. 2020 Jul 13;101:109939. doi: 10.1016/j.pnpbp.2020.109939. Epub 2020 Apr 1.
Fluoxetine (FLX) has been considered as an effective anti-depressant drug. Besides, previous studies reported reasonable anti-depressant effects for 7, 8-dihydroxyflavone (7, 8 DHF). However, the combination of FLX and 7, 8 DHF in a well-established depression model has not been explored. In this study, we demonstrate that the 7, 8 DHF can improve the anti-depressant efficacy of FLX in a chronic unpredictable mild stress (CUMS)-induced depression during the perimenopausal period. The corresponding mechanism of FLX+7, 8 DHF therapy and the effect of ANA-12 are also investigated. Moreover, the influences of 7, 8 DHF (5 mg/kg/day), FLX (18 mg/kg/day), and ANA-12 (0.5 mg/kg/day) on a depressive-like behavior are displayed. Inflammatory, autophagic and apoptotic changes of hippocampus and cortex are examined by using western blot, immunofluorescence, and Real-Time Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) techniques. The protein levels of phosphatidylinositol 3 kinase (PI3K)/ protein kinase B (Akt)/mechanistic target of rapamycin (mTOR)/phosphorylated extracellular signal-regulated kinase1/2 (p-ErK 1/2)/brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) of hippocampus and cortex are assessed by western blot. The combined FLX and 7, 8 DHF treatment can significantly improve depressive-like behavior in sucrose preference and forced swimming tests accompanied by a noticeable upregulation of autophagy, neuronal nuclei (NeuN), ionized calcium-binding adaptor molecule 1 (Iba1) expressions, and PI3K/Akt/ mTOR/ p-ErK 1/2 signaling pathways. Besides, an obvious increase of the brain-derived neurotrophic factor (BDNF) and TrkB levels are observed with down-regulated inflammation and apoptosis. These findings suggest that the integrated FLX and 7, 8 DHF holds a potential as an efficient treatment to ameliorate depressive-like behavior in perimenopausal patients.
氟西汀（FLX）已被认为是一种有效的抗抑郁药。此外，先前的研究报告称，7,8-二羟基黄酮（7,8-DHF）具有合理的抗抑郁作用。然而，FLX 和 7,8-DHF 在既定的抑郁模型中的联合应用尚未得到探索。在这项研究中，我们证明 7,8-DHF 可以改善围绝经期慢性不可预测轻度应激（CUMS）诱导的抑郁中 FLX 的抗抑郁疗效。还研究了 FLX+7,8-DHF 治疗的相应机制和 ANA-12 的作用。此外，还展示了 7,8-DHF（5mg/kg/天）、FLX（18mg/kg/天）和 ANA-12（0.5mg/kg/天）对抑郁样行为的影响。通过 Western blot、免疫荧光和实时定量逆转录聚合酶链反应（RT-qPCR）技术检查海马体和皮质的炎症、自噬和细胞凋亡变化。通过 Western blot 评估海马体和皮质中磷酸肌醇 3 激酶（PI3K）/蛋白激酶 B（Akt）/雷帕霉素靶蛋白（mTOR）/磷酸化细胞外信号调节激酶 1/2（p-ErK 1/2）/脑源性神经营养因子（BDNF）/原肌球蛋白相关激酶 B（TrkB）的蛋白水平。FLX 和 7,8-DHF 联合治疗可显著改善蔗糖偏好和强迫游泳试验中的抑郁样行为，同时明显上调自噬、神经元核（NeuN）、离子钙结合衔接蛋白 1（Iba1）表达和 PI3K/Akt/mTOR/p-ErK 1/2 信号通路。此外，观察到脑源性神经营养因子（BDNF）和 TrkB 水平明显增加，炎症和细胞凋亡减少。这些发现表明，整合的 FLX 和 7,8-DHF 具有改善围绝经期患者抑郁样行为的潜力。
