橙皮油素靶向海马色氨酸-犬尿氨酸代谢途径调控大鼠抑郁样行为的研究

橙皮油素（AUR）是自然界中已知最丰富的丙烯氧基香豆素。本实验组前期研究发现，AUR在小鼠抑郁模型中表现出抗抑郁样作用的同时正常化海马COX-2、IL-6和5-HT的表达。提示AUR的抗抑郁作用可能与其调控中枢炎症及单胺类递质相关。TRY-KYN代谢平衡失调由炎症诱导并伴随中枢5-HT的下调，是炎症性抑郁症的一个重要致病特征。本课题拟采用大鼠慢性不可预见性温和应激和脂多糖诱导的炎症性抑郁两种动物模型，应用高效液相分析、分子生物学、免疫荧光组化、蛋白质抗体芯片和行为学等多种技术手段，研究AUR对海马TRY-KYN通路的反应底物、关键酶、下游代谢产物，及该通路的关键调节因子包括小胶质细胞和炎性细胞因子等的影响。阐明AUR是否以靶向海马TRY-KYN代谢通路的某些关键环节，作为其拮抗大鼠抑郁样作用的分子机制，为AUR在未来参与抑郁症的临床药物治疗提供重要的药理学参考依据。

Auraptene (AUR) belongs to the coumarin family, which is also known as 7-geranyloxycoumarin, is the most abundant naturally occurring prenyloxycoumarin and is mostly found in Citrus fruits. The antioxidant, anti-inflammatory and anti-cancer properties of auraptene has been reported, and it been found antidepressant-like effects in our laboratory, in both the forced stress depression models including the forced swimming test (FST) and tail suspension test (TST), and the chronically unpredicted mild stress (CUMS) model in mice, and, furthermore, it down-regulated the expressions of COX-2, IL-6 and increased 5-HT content in hippocampus. It is suggested that the antidepressant effect of AUR may be related to its antagonism to neuroinflammation and regulation of monoamine transmitters, but whether it is a key mechanism is unknown. In addition, the metabolic imbalance of TRY-KYN pathway is considered to be an important pathogenic feature of inflammation-induced depression, the relationship between this pathway and the antidepressant mechanism of AUR aroused our strong interest. In the present research project, we intend to study the effects of AUR on the reaction substrate, key enzymes and downstream metabolites in TRY-KYN pathway, and the microglia immune activity and the related inflammatory factors in hippocampus in rats, using chronically unpredicted mild stress (CUMS) and lipopolysaccharide (LPS)-induced depression model with high performance liquid chromatography, RT-PCR, western blot, immunofluorescence histochemistry, protein antibody chip technology and behavioral methods. We aim to clarify the possible targets mediated by the TRY-KYN metabolic pathway of AUR on the antidepressant-like effect in rats, and provide a new way of medication for clinical depression in the future.