Chaihu-Shugan-San Ameliorated Osteoporosis of Mice with Depressive Behavior Caused by Chronic Unpredictable Mild Stress via Repressing Neuroinflammation and HPA Activity.
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Abstract
Objective: Depression and osteoporosis are usually concurrent health problems. This study aimed to explore the development of osteoporosis in depressive mice model and investigate the beneficial effects of the classical herbal formula Chaihu-Shugan-San (CHSG) on the brain and bone.
Methods: CHSG powder was prepared by spray-drying following extraction with water. The fingerprint of CHSG was analyzed using liquid chromatography. The depressive-like model was established by chronic unpredictable mild stress (CUMS) in female mice. The depressive behaviors and trabecular bone properties (measured by micro-CT) were detected at 2, 4, 6, and 8 weeks of CUMS. RT-PCR, immunoblotting and immunofluorescence were applied to measure expression of inflammatory cytokines and morphology of microglias in the hippocampus. Biochemical measurements and histological staining on the adrenal gland were carried out to assess the activity of hypothalamic-pituitary-adrenal (HPA) axis. Histological staining, three-point bending strength, and the expression of regulators involved in bone metabolism were determined.
Results: The treatment with CHSG for 8 weeks could ameliorate depressive behaviors, and down-regulate mRNA expression and tissue content of inflammatory factors IL-1β and IL-6 in hippocampus of CUMS mice. The inhibition of CHSG on neuroinflammation might be attributed to its repression of activity in microglias and NLRP3-triggered inflammation pathway. The serum of rats dramatically alleviated LPS-induced phosphorylation of nuclear NFκB (P65) and IκBα and up-regulation of IL-1β and IL-6 proteins in microglia BV2 cells. CUMS induced over-activity of HPA axis shown by the elevation in serum level of ACTH and corticosterone and in area percentage of zona fasciculata, intriguingly, CHSG reversed those changes in HPA system, ameliorated the reduction in mechanical strength and bone mineral density, and regulated bone metabolism factors of CUMS mice.
Conclusion: The chronic stress-induced depression resulted in bone disorders developing to osteoporosis. Chaihu-Shugan-San exerted beneficial effects on skeletal tissue by ameliorating neuroinflammation and HPA over-activity of mice with depression.
目的：抑郁症和骨质疏松症通常是并发的健康问题。本研究旨在探讨抑郁症小鼠骨质疏松症的发展情况，并探讨柴胡疏肝散（CHSG）对脑、骨的有益作用。方法：水提取后喷雾干燥制备CHSG粉末。采用液相色谱法对其指纹图谱进行分析。采用慢性不可预测轻度应激法（CUMS）建立雌性小鼠抑郁样模型。在CUMS的第2、4、6和8周检测抑郁行为和骨小梁特性（通过micro-CT测量）。采用RT-PCR、免疫印迹法和免疫荧光法检测海马炎性细胞因子表达及小胶质细胞形态。采用肾上腺生化测定和组织学染色评价下丘脑-垂体-肾上腺（HPA）轴的活性。测定组织学染色、三点弯曲强度和参与骨代谢调节因子的表达。结果：CHSG治疗8周可改善CUMS小鼠抑郁行为，下调海马炎症因子IL-1β、IL-6 mRNA表达及组织含量。CHSG对神经炎症的抑制作用可能与其抑制小胶质细胞和nlrp3触发的炎症通路的活性有关。大鼠血清显著缓解lps诱导的核nf - κ b （P65）和i - κ b α磷酸化以及IL-1β和IL-6蛋白上调。CUMS诱导HPA轴过度活动，表现为血清ACTH和皮质酮水平升高以及束状带面积百分比升高，CHSG逆转了HPA系统的变化，改善了机械强度和骨密度的降低，调节了CUMS小鼠的骨代谢因子。结论：慢性应激性抑郁可导致骨质疏松症。柴虎疏肝散通过改善抑郁症小鼠的神经炎症和HPA过度活性对骨组织有有益作用。
期刊介绍：
Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications.
The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas.
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Personalized medicine and pharmacogenomics
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