State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, People's Republic of China.
Psychoneuroendocrinology. 2010 Feb;35(2):272-83. doi: 10.1016/j.psyneuen.2009.06.020. Epub 2009 Jul 23.
Chronic mild stress (CMS) is suggested to develop dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) stress circuit. Icariin, a major constituent of flavonoids isolated from Epimedium brevicornum, has been previously confirmed to rescue the HPA axis abnormalities in animal models of depression. However, antidepressant treatment of icariin on corticotropin-releasing factor (CRF) system within the LHPA stress circuit and its interaction with serotonergic receptor are still seldom studied in CMS model of animals. The present study further investigated the effects of CMS procedure and subsequent icariin treatment on mRNA and protein levels of CRF, CRF receptor 1 (CRFR1) and CRF binding protein (CRFBP), as well as sucrose intake in rats. Moreover, the levels of cyclic adenosine 3',5'-monophosphate (cAMP) response element binding protein (CREB), glucocorticoid receptor (GR) and 5-hydroxytryptamine 1A receptor (5-HTR1A) in hypothalamus, hippocampus and frontal cortex were simultaneously evaluated for their participations in CRF system in this model. We found that CMS procedure significantly increased CRF expression levels in the brain regions, and decreased GR and 5-HTR1A in hippocampus and frontal cortex, with sucrose intake reduction representing the hedonic deficit in rats. Icariin restored these alterations in CMS rats. These results confirmed the hypothesis that icariin exerted antidepressant-like effect via its regulation of central CRF system. And hippocampus was suggested as an important neural area controlling the LHPA stress circuit in icariin-treated CMS rats. These findings for the first time proved that the potential molecular mechanism of antidepressant action of icariin was targeted on the interaction of the LHPA stress circuit and serotonergic function in CMS rats.
慢性轻度应激（CMS）被认为会导致边缘下丘脑-垂体-肾上腺（LHPA）应激回路的失调。淫羊藿苷是从淫羊藿中分离出的黄酮类化合物的主要成分，先前已被证实可在抑郁症动物模型中挽救 HPA 轴异常。然而，关于 CMS 模型中 LHPA 应激回路内的促肾上腺皮质释放因子（CRF）系统和其与 5-羟色胺能受体的相互作用的淫羊藿苷的抗抑郁治疗仍很少被研究。本研究进一步探讨了 CMS 程序和随后的淫羊藿苷治疗对 CRF、CRF 受体 1（CRFR1）和 CRF 结合蛋白（CRFBP）的 mRNA 和蛋白水平以及大鼠蔗糖摄入量的影响。此外，还同时评估了下丘脑、海马和前额皮质中环腺苷酸 3'，5'-单磷酸（cAMP）反应元件结合蛋白（CREB）、糖皮质激素受体（GR）和 5-羟色胺 1A 受体（5-HTR1A）的水平，以研究它们在该模型中对 CRF 系统的参与。我们发现，CMS 程序显著增加了大脑区域的 CRF 表达水平，并降低了海马体和前额皮质中的 GR 和 5-HTR1A，同时伴随着大鼠快感缺失的蔗糖摄入量减少。淫羊藿苷恢复了 CMS 大鼠的这些改变。这些结果证实了淫羊藿苷通过调节中枢 CRF 系统发挥抗抑郁样作用的假设。并且海马体被认为是控制 CMS 大鼠 LHPA 应激回路的重要神经区域。这些发现首次证明了淫羊藿苷的抗抑郁作用的潜在分子机制是针对 CMS 大鼠 LHPA 应激回路和 5-羟色胺能功能的相互作用。
