■Chaihushugansan(CSS),舒缓肝脏和缓解抑郁的经典配方,已被确定在雌性小鼠中产生快速的抗抑郁样作用。然而,CSS抗抑郁药的性别优势和潜在机制尚不清楚。
目的:在本研究中,我们专注于揭示CSS在抗抑郁药中的性别优势以及介导这种优势的特定神经元机制。
方法:尾部悬吊试验(TST),强迫游泳试验(FST)和蔗糖偏好试验(SPT)用于评估雌性和雄性慢性不可预测轻度应激(CUMS)小鼠模型中CSS的抑郁表型或抗抑郁样作用。RNA测序用于筛选CSS抗抑郁药性别优势的特定靶标。用RT-PCR和酶联免疫吸附法检测特异性分子的表达,荷尔蒙,和海马中的炎症因子。使用海马病毒过度激活和药物阻断来检测CSS抗抑郁药性别优势与相关靶标之间的相关性。
结果:在本研究中,雌性和雄性小鼠在暴露CUMS3周后均表现出抑郁表型,包括TST中的不动时间显著增加,SPT中的蔗糖偏好率降低.然而,急性给予CSS(2,4g/kg)仅在2小时后的雌性小鼠或非雄性小鼠中改善了抑郁表型。此外,只有雌性小鼠暴露CUMS3周后,TCRN的表达才增加,在2小时后的单次给药后,CSS也将其逆转,但雄性小鼠没有改变。大鼠海马雌激素受体β(Erβ)的表达,在雌性CUMS小鼠模型中,促炎因子(IL-1β和TNF-α)和抗炎因子(IL-10、TGF-β和IL-1Rα)均异常,这些都是由CSS规范化的。此外,AAV-TCRN/+对海马TCRN的过度激活阻断了雌性小鼠CSS的抗抑郁样作用和海马Erβ的上调。然而,Erβ的抑制减弱了CSS的抗抑郁样作用和CSS对促炎因子(IL-1β和TNF-α)的抑制,对海马TCAN和抗炎因子(IL-10和TGF-β)无任何影响。
结论:研究表明,CSS在雌性小鼠中具有抗抑郁优势,这取决于抑制海马TC2N然后激活Erβ,进一步抑制促炎因子的释放产生抗抑郁作用,为CSS在临床应用中的指导提供了依据,开发具有性别差异的抑郁症药物的新思路和目标。
UNASSIGNED: Chaihushugan san (CSS), a classic formula for soothing the liver and relieving depression, has been identified to produce rapid antidepressant-like effects in female mice. However, the gender predominance and underlying mechanisms of CSS\'s antidepressant remain unclear.
OBJECTIVE: In this study, we focused on unraveling the gender predominance of CSS in antidepressant and the specific neuronal mechanisms that mediate this predominance.
METHODS: Tail suspension test (TST), forced swimming test (FST) and sucrose preference test (SPT) were used to evaluate depressive phenotypes or antidepressant-like effects of CSS in female and male chronic unpredictable mild stress (CUMS) mice model. RNA-sequencing was used to screen specific target for CSS antidepressant gender dominance. RT-PCR and elisa were used to detect the expressions of specific molecule, hormones, and inflammatory factors in the hippocampus. hippocampal viral overactivation and pharmacological blockade were used to detect the correlation between CSS antidepressant gender dominance and related targets.
RESULTS: In the present study, both female and male mice displayed depressive phenotypes including significant increasing immobility time in TST and reducing sucrose preference ratio in SPT after exposing CUMS for 3 weeks. However, acute administration of CSS (2, 4 g/kg) improved the depressive phenotypes only in female mice or not male mice at 2 h later. Moreover, the expressions of TC2N were increased only in female mice after exposing CUMS for 3 weeks, which were also reversed by CSS after a single administration 2 h later, but no alterations in male mice. The hippocampal expressions of estrogen receptor β (Erβ), pro-inflammatory factors (IL-1β and TNF-α) and anti-inflammatory factors (IL-10, TGF-β and IL-1Rα) were all abnormal in female CUMS mice model, which were all normalized by CSS. Furthermore, overactivation of hippocampal TC2N by AAV-TC2N+/+ blocked the antidepressant-like effects of CSS and the up-regulation of hippocampal Erβ in female mice. However, inhibition of Erβ blunted the antidepressant-like effects of CSS and CSS\'s suppression of pro-inflammatory factors (IL-1β and TNF-α), which had no any effect on hippocampal TC2N and anti-inflammatory factors (IL-10 and TGF-β).
CONCLUSIONS: The study revealed that CSS had antidepressant superiority in female mice depending on inhibiting hippocampal TC2N and then activating Erβ, further inhibiting the release of pro-inflammatory factors to produce antidepressant effects, which provided a basis for the guidance of CSS in clinical application, new ideas and targets for the development of drugs for depression with gender differences.