Co-treatment With the Herbal Medicine SIP3 and Donepezil Improves Memory and Depression in the Mouse Model of Alzheimer’s Disease

Abstract Background: Alzheimer’s disease (AD) is a lethal progressive neurodegenerative disorder. Currently, many acetylcholinesterase inhibitors, such as donepezil, is widely used for the treatment of AD. However, the efficacy of long-term donepezil use is limited. SIP3, a mixture of Santalum album, Illicium verum, and Polygala tenuifolia, a new formula derived from traditional Korean herbal medicine. In this study, SIP3 were assessed the survival of Drosophila AD model and synergistic effect of SIP3, donepezil co-treatment of AD using APP/PS1 transgenic mice. Methods: In Drosophila AD models, we analyzed the survival, climbing ability and acridine orange (AO) staining. In APP/PS1 mice, at six months of age were randomized into four groups. Then, these groups were orally administered vehicle (for the control), donepezil, low and high doses SIP3 plus Donepezil respectively for six months. The passive avoidance test (PAT) and the Morris water maze (MWM) were analyzed cognitive behavioral changes. In addition, the forced swimming test (FST) and the tail suspension test (TST) were assessed depression-like behavior. To investigate the molecular and cellular mechanisms underlying positive effects of SIP3 on AD, the cerebral cortex transcriptomes were analyzed by RNA sequencing.Results: Using the passive avoidance test (PAT), we analyzed the combination of SIP3 and donepezil improved the learning capabilities and memory of APP/PS1 mice, compared with the group treated with donepezil only, in late stage of AD. In addition, using the Morris water maze (MWM) test, co-treatment with donepezil and a low concentration of SIP3 significantly ameliorated cognitive impairment. Co-administration of SIP3 and donepezil effectively reduced depression-like behavior in the forced swimming and tail suspension tests. Furthermore, RNA sequencing of cerebral cortex transcriptome revealed that gene expression profiles after low dose of SIP3 co-treatment are slightly similar to those of normal phenotype mice than those obtained after donepezil treatment alone. Gene ontology (GO) along with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway have demonstrated that differentially expressed genes were involved in locomotor behavior and neuroactive ligand-receptor interactions. Collectively: our results suggest that co-treatment of low dose of SIP3 and donepezil improves impaired learning, memory, and depression in late stage of AD in mice.