Beta-sitosterol belongs to the group of phytosterols, which are active trace components existing in natural plants, known as the "key of life", and have a steroid nucleus structure similar to cholesterol. Due to the insolubility issue of beta-sitosterol, most pharmacological studies and clinical applications are limited. Therefore, the modification of beta-sitosterol into its derivatives to enhance its pharmacologic activity is viable. In this study, 4 kinds of new beta-sitosterol derivative were obtained by an esterification reaction with beta-sitosterol, organic acids, EDCI and DMAP in dichloromethane. The chemical structures were defined by IR and NMR. Beta-sitosterol and its derivatives were used to carry out antidepressant research in the tail suspension test (TST) and the forced swimming test (FST) in mice. Additionally, the roles of different parts of the central nervous system (CNS) in the antidepressant-like effect of Sit-S, which is one of the beta-sitosterol derivatives, were also investigated. The results showed that the derivatives exhibited a stronger antidepressant activity than beta-sitosterol. Among the derivatives, administration of Sit-S (4 mg kg-1) gave the lowest immobility time in the TST, demonstrating that Sit-S exhibited the strongest antidepressant-like activity. The study into the roles of different parts of the CNS in the antidepressant-like effect of Sit-S showed that agomelatine (40 mg kg-1), haloperidol (0.2 mg kg-1) and bicuculline (4 mg kg-1) reversed the antidepressant effect of Sit-S (4 mg kg-1). This study confirmed the conclusions that beta-sitosterol derivatives broaden the pharmacological effects of beta-sitosterol, Sit-S (4 mg kg-1) exhibits antidepressant-like effects, and this antidepressant-like effect on male adult mice is mediated by the 5-HT, DA and GABA-ergic systems.
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