Department of Pharmacy, Zhongshan Affiliated Hospital of Zhongshan University, Zhongshan, China.
Institute of Clinical Pharmacy and Pharmacology, Jining First People's Hospital, Jining Medical University, Jining, China.
Int Immunopharmacol. 2020 Sep;86:106734. doi: 10.1016/j.intimp.2020.106734. Epub 2020 Jun 27.
Estrogen replacement therapy (ERT) has been proven to relieve menopausal-related mental disorders including depression in postmenopausal women. However, the unsafety of ERT hinders its clinical use. In this study, we would evaluate whether vitamin D (VD), a hormone with optimal safety profile, could relieve the depressive-like symptom in ovariectomized (OVX) rats. Furthermore, we would determine whether vitamin D and 17β-estradiol (E2) exert neurological function through their immunomodulatory effect in OVX rats. Middle-aged female SD rats were randomly divided into four groups, namely, control (SHAM), OVX, OVX + VD, and OVX + E2. Vitamin D (calcitriol, 100 ng/kg) and 17β-estradiol (30 μg/kg) had been daily gavaged in the OVX + VD and OVX + E2 group, respectively. After 10-week administration, vitamin D and 17β-estradiol both showed anti-depressive-like activity in the OVX rats. Using the method of immunofluorescent staining and western blot, vitamin D and 17β-estradiol were demonstrated to upregulate each other's receptors, including VDR, ERα, and ERβ in the hippocampus of OVX rats. Additionally, the upregulation of VDR, calbindin-D28k, and calbindin-D9k suggested that the vitamin D signaling system was amplified by vitamin D and 17β-estradiol. Vitamin D and 17β-estradiol showed neuroprotective effects by decreasing OVX-induced apoptosis and neuronal damage, regulating the AMPK/NF-κB signaling pathway, and reducing the proinflammatory cytokines (IL-1β, IL-6, and TNFα), as well as iNOS and COX-2 in the hippocampus of OVX rats. Collectively, the present study demonstrated that vitamin D and 17β-estradiol could upregulate each other's receptors and regulate the AMPK/NF-κB pathway to relieve the OVX-induced depressive-like state. The results could stimulate translational research towards the vitamin D potential for prevention or treatment of menopause-related depression.
雌激素替代疗法（ERT）已被证明可缓解绝经后妇女与绝经相关的精神障碍，包括抑郁症。然而，ERT 的安全性问题阻碍了其临床应用。在这项研究中，我们将评估维生素 D（VD）——一种安全性极佳的激素——是否可以缓解去卵巢（OVX）大鼠的抑郁样症状。此外，我们还将确定维生素 D 和 17β-雌二醇（E2）是否通过其在 OVX 大鼠中的免疫调节作用发挥神经功能。中年雌性 SD 大鼠被随机分为四组，即对照组（SHAM）、OVX 组、OVX+VD 组和 OVX+E2 组。OVX+VD 和 OVX+E2 组分别每天给予维生素 D（骨化三醇，100ng/kg）和 17β-雌二醇（30μg/kg）灌胃。给药 10 周后，维生素 D 和 17β-雌二醇均显示出抗抑郁样活性。通过免疫荧光染色和 Western blot 方法，证明维生素 D 和 17β-雌二醇可上调 OVX 大鼠海马中的彼此受体，包括 VDR、ERα 和 ERβ。此外，VDR、钙结合蛋白-D28k 和钙结合蛋白-D9k 的上调表明维生素 D 信号系统被维生素 D 和 17β-雌二醇放大。维生素 D 和 17β-雌二醇通过减少 OVX 诱导的凋亡和神经元损伤、调节 AMPK/NF-κB 信号通路以及降低海马中的促炎细胞因子（IL-1β、IL-6 和 TNFα）、iNOS 和 COX-2，发挥神经保护作用。总之，本研究表明，维生素 D 和 17β-雌二醇可以上调彼此的受体，并调节 AMPK/NF-κB 通路，以缓解 OVX 诱导的抑郁样状态。这些结果可能会激发针对维生素 D 预防或治疗绝经相关抑郁症潜力的转化研究。
