Biol. Pharm. Bull. 29(12) 2399—2403 (2006)

It is well known that abnormality of neuroendocrine function plays an important role in the occurrence of depression. The hypothalamic-pituitary-adrenal (HPA) axis is one of the important neuroendocrine axes, and enhanced activity of this axis is considered a key neurobiological alteration in major depression. Corticotropin-releasing factor (CRF), the major physiological regulator of the HPA system, is believed to contribute to several depressive symptoms, and augmentation of the pituitary, and elevated cortisol levels in serum have been observed in depressive disorders. Recent studies have showed there is a close relationship between activation of the cytokine system and the HPA axis in major depression. Cytokines are intercellular messengers in the immune system, they regulate the inflammatory response by interaction with specific receptors and are capable of triggering cellular responses. Cytokines regulate immune responses, possibly through activation of the HPA axis, while the HPA axis activity is related to behavioral lateralization and brain asymmetry. Some researchers reported that interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a) regulated not only the inflammatory process, but also mediated a variety of CNS-mediated responses and neuroendocrine activity. Icariin (Fig. 1) is one of the major active flavonoids isolated from Epimedium brevicornum MAXIM (Berberidaceae). Icariin and E. brevicornum have a wide range of pharmacological activities, including regulating the cardiovascular system, stimulating neurite growth and enhancing the estrogenic activity which possess the osteogenic differentiation. Clinical evidence suggested that E. brevicornum could improve depressive symptoms after stroke. Recently, our laboratory demonstrated antidepressant actions of icariin and total flavonoid extracts from E. brevicornum in animal behavior despair models of mice. Furthermore, icariin administration attenuated the swim stress-induced elevation in serum CRF and cortisol levels in mice. The aim of this study was to further confirm the antidepressant-like effects of icariin in a chronic mild stress (CMS) model of depression in Sprague-Dawley rats, which causes behavioral changes in rodents that parallel symptoms of depression, and to investigate whether icariin influences the HPA axis function and serum cytokine levels in the stressed animals in order to discuss its antidepressant mechanism.