Salsubstolins A-G, Highly Oxygenated Germacrane-Type Sesquiter-penoids from Salvia substolonifera and Their Anti-Alzheimer’s Disease Activity

Many species of genus Salvia (Lamiaceae) are important edible spices and medicinal plants with a long history. In this study, seven undescribed germacrane-type sesquiterpenoids, salsubstolins A-G (1−7), together with four known sesquiterpenoids (8−11), were isolated from the 95% ethanol extract of the whole plants of Salvia substolonifera via bioactivity-guided isolation. Their chemical structures and absolute configurations were confirmed by extensive spectroscopic methods including HRESIMS, IR, NMR, electronic circular dichroism calculations, and single-crystal X-ray diffraction. The anti-Alzheimer’s disease (AD) activity of compounds 1−11 was evaluated using Caernorhabditis elegans AD pathological model. The results showed that both extracts and compound 2 significantly delayed the paralysis of the transgenic C. elegans strain CL4176. Compound 2 was taken as the preferred compound to investigate its molecular mechanism against AD. Further studies showed that 2 significantly reduced the number of Aβ deposition spots and down-regulated the expression of Aβ mRNA. Furthermore, the activation of insulin/insulin-like growth factor signaling-1 (IIS) pathway was observed with daf-16, skn-1 and hsf-1 showing significant upregulation, meanwhile, the expression of vps-34 and bec-1, which are related to autophagy system, were increased. In conclusion, these results suggest that 2 may exert anti-AD effect by inhibiting Aβ deposition through the IIS pathway and autophagy pathway.