Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Neurotherapeutics. 2019 Apr;16(2):404-415. doi: 10.1007/s13311-018-00680-6.
Reduced estradiol levels are associated with depression in women during the transition to and after menopause. A considerable number of studies focusing on the theme of treating depression through the activation of erythropoietin (EPO)-induced signaling pathways have been published. Venlafaxine is an approved antidepressant drug that inhibits both serotonin and norepinephrine transporters. The aim of the present study was to investigate the effects of venlafaxine on the depressive-like behaviors and serum estradiol levels in female rats following ovariectomy (OVX) and the possible roles of EPO-induced signaling pathways. Venlafaxine (10 mg/kg/day) was orally administered to OVX rats over a period of 4 weeks using two different treatment regimens: either starting 24 h or 2 weeks after OVX. Venlafaxine showed a superior efficacy in inducing antidepressant-like effects after an acute treatment (24 h post-OVX) than after the delayed treatment (2 weeks post-OVX) and was characterized by a decreased immobility time in the forced swimming test. In parallel, venlafaxine induced EPO and EPO receptor mRNA expression and increased levels of phospho-Janus kinase 2 (p-JAK2), phospho-signal transducer and activator of transcription 5, and phospho-extracellular signal-regulated kinase 1/2 in the hippocampus of OVX rats. Meanwhile, rats exhibited a marked reduction in the hippocampal Bax/Bcl2 ratio, caspase-3 activity, and tumor necrosis factor alpha levels after venlafaxine treatment. Venlafaxine also increased the hippocampal brain-derived neurotrophic factor and serum estradiol levels. Based on these findings, venlafaxine exerts a neuroprotective effect on OVX rats that is at least partially attributed to the activation of EPO/EPOR/JAK2 signaling pathways, anti-apoptotic activities, anti-inflammatory activities, and neurotrophic activities, as well as an increase in serum estradiol level. Graphical Abstract ᅟ.
雌激素水平降低与女性绝经前后的抑郁有关。已经发表了相当数量的研究关注通过激活促红细胞生成素（EPO）诱导的信号通路来治疗抑郁症的主题。文拉法辛是一种批准用于治疗抑郁症的药物，可抑制 5-羟色胺和去甲肾上腺素转运体。本研究旨在探讨文拉法辛对卵巢切除（OVX）后雌性大鼠抑郁样行为和血清雌二醇水平的影响，以及 EPO 诱导的信号通路的可能作用。文拉法辛（10mg/kg/天）以两种不同的治疗方案经口给予 OVX 大鼠，持续 4 周：OVX 后 24 小时或 2 周开始给药。文拉法辛在急性治疗（OVX 后 24 小时）后诱导抗抑郁样作用的效果优于延迟治疗（OVX 后 2 周），表现为强迫游泳试验中不动时间减少。平行地，文拉法辛诱导 EPO 和 EPO 受体 mRNA 表达，并增加 JAK2 磷酸化（p-JAK2）、信号转导和转录激活因子 5 磷酸化和细胞外信号调节激酶 1/2 磷酸化水平在 OVX 大鼠海马中。同时，文拉法辛治疗后大鼠海马 Bax/Bcl2 比值、半胱天冬酶-3 活性和肿瘤坏死因子-α水平明显降低。文拉法辛还增加了海马脑源性神经营养因子和血清雌二醇水平。基于这些发现，文拉法辛对 OVX 大鼠具有神经保护作用，至少部分归因于 EPO/EPOR/JAK2 信号通路的激活、抗凋亡活性、抗炎活性和神经营养活性以及血清雌二醇水平的增加。
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