Optimized integration of fluoxetine and 7, 8-dihydroxyflavone as an efficient therapy for reversing depressive-like behavior in mice during the perimenopausal period

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 st...

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Published in:Progress in neuro-psychopharmacology & biological psychiatry 2020-07, Vol.101, p.109939-109939, Article 109939
Main Authors: Amin, Nashwa, Xie, Shiyi, Tan, Xiaoning, Chen, Yili, Ren, Qiannan, Botchway, Benson O.A., Hu, Shaohua, Ma, Yongchun, Hu, Zhiying, Fang, Marong
Format: Article
Language:English
Subjects:
Autophagy
Brain-derived neurotrophic factor (BDNF)
Inflammation
Perimenopausal depression
Tropomyosin-related kinase B
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Summary: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. •Fluoxetine and 7,8-DHF treatment might be mediated by BDNF/ TrkB and PI3K/Akt/mTOR signaling pathways.•ANA-12 can act as a therapeutic agent for patients having an increased level of BDNF-TrkB.•Fluoxetine and 7,8-DHF improve the behavioral function during the perimenopausal period.•The combined therapy could attenuate the inhibition of NeuN and Iba-1 expression in the hippocampus.
ISSN:0278-5846
1878-4216
DOI:10.1016/j.pnpbp.2020.109939