ABSTRACT
We previously reported that pseudoginsenoside-F11 (PF11), an ocotillol-type saponin, significantly ameliorated Alzheimer's disease (AD)-associated cognitive defects in APP/PS1 and SAMP8 mice by inhibiting Aß aggregation and tau hyperphosphorylation, suggesting a potential therapeutic effect of PF11 in the treatment of AD. In the present study we further evaluated the therapeutic effects of PF11 on relieving cognitive impairment in a rat model of sporadic AD (SAD). SAD was induced in rats by bilateral icv infusion of streptozotocin (STZ, 3 mg/kg). The rats were treated with PF11 (2, 4, 8 mg·kg-1·d-1, ig) or a positive control drug donepezil (5 mg·kg-1·d-1, ig) for 4 weeks. Their cognitive function was assessed in the nest building, Y-maze, and Morris water maze tests. We showed that STZ icv infusion significantly affected the cognitive function, tau phosphorylation, and insulin signaling pathway in the hippocampus. Furthermore, STZ icv infusion resulted in significant upregulation of the calpain I/cyclin-dependent protein kinase 5 (CDK5) signaling pathway in the hippocampus. Oral administration of PF11 dose-dependently ameliorated STZ-induced learning and memory defects. In addition, PF11 treatment markedly reduced the neuronal loss, protected the synapse structure, and modulated STZ-induced expression of tau phosphorylation by regulating the insulin signaling pathway and calpain I/CDK5 signaling pathway in the hippocampus. Donepezil treatment exerted similar beneficial effects in STZ-infused rats as the high dose of PF11 did. This study highlights the excellent therapeutic potential of PF11 in managing AD.
Subject(s)
Alzheimer Disease/drug therapy , Cognitive Dysfunction/drug therapy , Ginsenosides/pharmacology , tau Proteins/metabolism , Alzheimer Disease/chemically induced , Animals , Calpain/metabolism , Chromosome Pairing , Disease Models, Animal , Glycogen Synthase Kinase 3 beta/metabolism , Hippocampus/metabolism , Hippocampus/pathology , Hippocampus/ultrastructure , Insulin Receptor Substrate Proteins/metabolism , Male , Maze Learning/drug effects , Morris Water Maze Test/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Wistar , StreptozocinABSTRACT
OBJECTIVES: Xiaochaihutang (XCHT) has antidepressant effects in multiple animal models of depression in our previous studies. But the antidepressant effects and exact mechanisms of XCHT in a rat model of chronic social isolation stress (CSIS) have never been studied. We therefore aimed to investigate the effects of XCHT on depressive/anxiety-related behaviours of CSIS-exposed rats and understand the neurological mechanism involving neurogenesis. METHODS: We established the CSIS model and then investigated the effects of XCHT on behavioural change. HPLC-MS/MS was adopted to quantify neurotransmitter levels in the cerebrospinal fluid (CSF). Immunofluorescence technology was used to study the effects of XCHT on neurogenesis; while expressions of 5-HT1A receptor signalling pathway in the hippocampus were measured using Western blotting. KEY FINDINGS: Xiaochaihutang significantly alleviated depressive/anxiety-like behaviours of CSIS-exposed rats. XCHT significantly regulated levels of monoamine neurotransmitters in the CSF without affecting Glu, GABA and ACh. XCHT also significantly increased neurogenesis in CSIS-exposed rats. Additionally, XCHT reversed CSIS-induced decrease of 5-HT1A receptor expression and promoted the expression of BDNF in the hippocampus. CONCLUSION: Our results suggest that XCHT could significantly regulate the depressive/anxiety-like behaviours induced by CSIS, which are likely attributed to the promotion of hippocampal neurogenesis and neurotrophin expressions through the activation of serotonergic system.
