Antidepressant-like Effects Of Fuzi And Its Mechanisms

Fuzi, a traditional Chinese medicinal plant, has various pharmacological effects. Crude exacts of Fuzi has a good therapeutic effect on overcoming depressive symptoms, but its active ingredients have not been uncovered until now. Polysaccharides and alkaloids make up two of the most important components of Fuzi. Alkaloids in Fuzi can boost morale and improve confidence. While acute administration of Fuzi polysaccharide could decrease immobility time in normal mice, which showed that Fuzi polysaccharide has antidepressant-like behavioral effects. However, antidepressant-like action of Fuzi alkaloids and polysaccharides remains less well understood. In this work, we focus on the antidepressant-like effects and mechanisms of Fuzi alkaloids and polysaccharides by the manner of behavior pharmacology, biochemistry and bioinformatics.Fuzi total alkaloids and polysaccharides of Fuzi were extracted by traditional methods with some modifications. Fuzi total alkaloids were isolated by ultrasonic extraction, organic solvent extraction and silica gel column chromatography. Then HPLC-ESI-MS was employed to analysis the composition of Fuzi total alkaloids. Fuzi polysaccharides were prepared by hot water extraction, ethanol precipitation and destarch. To discuss the antidepressant-like effect of Fuzi alkaloid and polysaccharide, ovariectomized mice model and immobilization stress mice model were established. Both Fuzi alkaloid and polysaccharide were administered by repeated intragastric way.The antidepressant-like effect of Fuzi alkaloid and their dose-effect relations were investigated through the forced swim test and open field test. Repeated administration of Fuzi alkaloid for 7 days decreased immobility time in both normal mice and ovariectomized mice. However, the antidepressant-like behavioral effects were not simply due to locomotor hyperactivity. It was confirmed that 10mg/kg/day is an optimal dosage of the intragastric administration for Fuzi alkaloid in normal mice, while it is 30mg/kg/day for in ovariectomized mice. Western blotting and ELISA assays showed that Fuzi total alkaloid enhanced the ratio of phospho-CREB/CREB(cAMP response element-binding protein) and BDNF protein in the frontal cortex and hippocampus of ovariectomized mice. These results indicated that the CREBBDNF pathway may be involved in the antidepressant mechnism of Fuzi alkaloid in ovariectomized mice. Further studies showed that differentially expressed genes existed in the frontal cortex and hippocampus of ovariectomized mice. The pathways of these genes mainly enriched in neuroactive ligand-receptor, cytokine-cytokine receptor interaction and ovarian steroidogenesis. Behavioral studies were carried out by repeated administration of Fuzi polysaccharides in a dose of 100 mg/kg/day. Decreased immobility time was abserved on 14 th day in normal mice, while 21 days in immobilization stress model mice. These antidepressant-like behavioral effects were not simply due to locomotor hyperactivity. Western blotting and ELISA assays showed that administration of Fuzi polysaccharides increased BDNF protein level in the frontal cortex and hippocampus of normal mice. These results indicated that the increasing of BDNF may be involved in antidepressant like action of Fuzi polysaccharides. Taken together, our study confirmed the antidepressant-like effects of Fuzi alkaloids and polysaccharides. The relative antidepressive mechanisms were covered for the first time. The active ingredient in Fuzi alkaloids and polysaccharides and the genes involved in the regulation of antidepressant effect are under investigation in our laborotary.