Panaxynol (PAL, also called falcarinol) is widely found in plants of the Umbelliferae family, among which carrots are rich in PAL, so it is proved to be edible. PAL has neuroprotective effects and other pharmacological activities. This study aimed to explore the effects and mechanisms of action of PAL on chronic unpredictable mild stress (CUMS)-induced anxiety and depression in mice. The effects of PAL on behavioral activities in mice were first assessed by a CUMS-induced depression model. The secretion levels of monoamine neurotransmitters and hypothalamic-pituitary-adrenal (HPA) axis-related hormones were measured by ELISA. Western blotting was used to analyze the expression of glucocorticoid receptor (GR), glutamate receptor 1 (GluR1) and synapse-associated protein in the hippocampus. The behavioral experiment results showed that PAL can improve exploratory behavior and activities in mice. Meanwhile, PAL can significantly activate the release of 5-HT/5-HIAA and DA/HVA in the hippocampus. It inhibits the expression of adrenocorticotropic hormone (ACTH), corticosterone (CORT) and corticotrophin-releasing hormone (CRH) in serum and the hypothalamus. The contents of GR, glutamate receptor 1 (GluR1), postsynaptic density-95 (PSD95) and synapsin I protein in the hippocampus significantly increased. Studies have found that PAL can inhibit the hyperfunction of the HPA axis, which may be achieved by regulating HPA axis hormones and GR. Meanwhile, PAL promotes the release of 5-HT and DA in the hippocampus and improves synaptic plasticity in the hippocampus, allowing neurotransmitters to function more effectively. Therefore, PAL may improve anxiety and depression-like effects in mice through the abovementioned effects.

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.