Department of Pharmacy, Zhejiang University Mingzhou Hospital, Ningbo, China.
Department of Pharmacy, Zhejiang Pharmaceutical University, Ningbo, China.
J Cell Mol Med. 2024 Oct;28(20):e70179. doi: 10.1111/jcmm.70179.
The aim of this study was to investigate the role of 17β-estradiol (E2)-mediated oestrogen receptor (ER) in modulating the depressive-like behaviours of ovariectomy (OVX) mice and the associated mechanisms. E2 was administrated in OVX mice. The behaviour and physiological changes of OVX mice including immobility time in tail suspension test (TST) and forced swimming test (FST), levels of serum E2, inflammatory mediators, oxidative stress factors, indoleamine2,3-dioxygenase 1 (IDO1) and the neurotransmitters mediated by IDO1 activation were then recorded. Cell injury models established by lipopolysaccharide (LPS) or HO stimulation in HT22 and BV2 cells were employed to further explore the mechanisms of E2's function. E2 treatment improved OVX-induced increase of immobility time in FST and TST. Meanwhile, E2 ameliorated the changes of inflammatory factors (NF-κB, TNF-α and IL-6), IDO1, IDO1-mediated TRP/KYN pathway and oxidative stress factors (iNOS, MDA, GSH and SOD) in the hippocampus of OVX mice. Interestingly, ERβ inhibitor abolished E2's inhibitory effects on the inflammation and IDO1-mediated TRP/KYN pathway; ERβ inhibitor also abolished E2's anti-oxidative stress effect. In cell experiments, ERβ small interfering RNA (siRNA) pretreatment reversed E2's anti-inflammatory effect on LPS-treated HT22 and BV2 cells and E2's inhibitory effect on IDO1 expression in LPS-treated BV2 cells. ERβ siRNA pretreatment also reversed E2's anti-oxidation effect on HO-treated HT22 cells. E2 exert the antidepressant function in OVX mice via ERβ-modulated suppression of NF-κB-mediated inflammatory pathway, oxidative stress factors and IDO1-mediated TRP/KYN pathway in the hippocampus.
本研究旨在探讨 17β-雌二醇（E2）介导的雌激素受体（ER）在调节去卵巢（OVX）小鼠抑郁样行为中的作用及其相关机制。给 OVX 小鼠给予 E2。记录 OVX 小鼠的行为和生理变化，包括悬尾试验（TST）和强迫游泳试验（FST）中的不动时间、血清 E2 水平、炎症介质、氧化应激因子、吲哚胺 2,3-双加氧酶 1（IDO1）和 IDO1 激活介导的神经递质。采用脂多糖（LPS）或 HO 刺激 HT22 和 BV2 细胞建立细胞损伤模型，进一步探讨 E2 作用的机制。E2 处理改善了 FST 和 TST 中 OVX 诱导的不动时间增加。同时，E2 改善了 OVX 小鼠海马中炎症因子（NF-κB、TNF-α和 IL-6）、IDO1、IDO1 介导的 TRP/KYN 途径和氧化应激因子（iNOS、MDA、GSH 和 SOD）的变化。有趣的是，ERβ 抑制剂消除了 E2 对炎症和 IDO1 介导的 TRP/KYN 途径的抑制作用；ERβ 抑制剂也消除了 E2 的抗氧化应激作用。在细胞实验中，ERβ 小干扰 RNA（siRNA）预处理逆转了 E2 对 LPS 处理的 HT22 和 BV2 细胞的抗炎作用，以及 E2 对 LPS 处理的 BV2 细胞中 IDO1 表达的抑制作用。ERβ siRNA 预处理也逆转了 E2 对 HO 处理的 HT22 细胞的抗氧化作用。E2 通过 ERβ 调节抑制 NF-κB 介导的炎症途径、氧化应激因子和海马中的 IDO1 介导的 TRP/KYN 途径，在 OVX 小鼠中发挥抗抑郁作用。
