Co-treatment with the herbal medicine SIP3 and donepezil improves memory and depression in the mouse model of Alzheimer's disease

Alzheimer's disease (AD) is a lethal progressive neurodegenerative disorder that has been linked to a deficiency of neurotransmitter, acetylcholine. 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 three herbal extracts from Santalum album, Illicium verum, and Polygala tenuifolia, is a new formula derived from traditional Korean herbal medicine. In this study, we assessed synergistic effect of SIP3 and donepezil co-treatment on symptoms of AD using APP/PS1 transgenic mice. Using the passive avoidance test (PAT), we found that the combination of SIP3 and donepezil improved 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) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses demonstrated that significantly 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.