辛弗林对CUMS大鼠抑郁样行为和血清代谢组学的影响

目的 通过观察分析大鼠慢性应激引起的行为学和血清代谢组变化以及辛弗林抗抑郁的有效治疗，发现潜在的抗抑郁新药先导化合物和生物标志物。方法 将24只大鼠分为正常组、模型组和辛弗林组。模型组为6周慢性温和不可预知应激(CUMS)模型大鼠，用体质量变化、糖水偏好、开场实验作为抑郁评估指标，后2周辛弗林(Syn 20 mg/kg)干预治疗后采集大鼠血清进行气相色谱-质谱联用(GC-MS/MS)测定，研究CUMS大鼠血清内源性代谢物变化，以及辛弗林的干预作用，寻找其抗抑郁潜在的先导化合物和生物标志物，并找到相关靶向代谢通路。结果 辛弗林干预后，在增加CUMS大鼠体质量、提高糖水偏好率、增加开场运动总距离和理毛次数的同时，还能逆转CUMS大鼠血清中磷酸乙醇胺、苯甲酸、胆固醇、谷氨酸等14种代谢物的变化使其趋于正常组，并发现谷氨酰胺和谷氨酸的代谢、缬氨酸和异亮氨酸的生物合成等9条主要牵涉辛弗林的靶向代谢通路。结论 辛弗林可能通过调节谷氨酰胺和谷氨酸的代谢、缬氨酸和异亮氨酸的生物合成等生物学途径发挥对CUMS大鼠抑郁样行为的调正作用。 

Effects of Synephrine on Depression-Like Behavior and Serum Metabonomics in CUMS Rats

OBJECTIVE To identify potential anti-depressant lead compounds and biomarkers， through observing the behavioral and serum metabolome changes induced by chronic stress in rats. METHODS Twenty-four rats were randomly divided into three groups including normal， model and treatment groups. Six-week of chronic unpredictable mild stress (CUMS) of rats were chosen as chronic depressed model. Weight change， sucrose water preference and opening test were used as indicators of depression assessment. Synephrine (Syn 20 mg/kg) was gavaged once a day in late two weeks. After two weeks of intervention， the serum of rats was collected， and GC-MS/MS were used to detect the changes of endogenous metabolites in rat serum and the drug therapy， to discover potent anti-depressant lead compound， biomarker and relative pathway. RESULTS Synephrine alleviated depression-like behavior and changed 14 metabolites including ethanolamine phosphate， benzoic acid， cholesterol and glutamic acid in CUMS rat serum. Nine targeted metabolic pathways involving synephrine， such as glutamine and glutamate metabolism， valine and isoleucine biosynthesis， were discovered. CONCLUSION Synephrine may be against depression-like behavior mainly via regulating mechanism and biosynthesis from glutamate， valine and isoleucine.