Natural β‑Dihydroagarofuran-Type Sesquiterpenoids as Cognition-Enhancing and Neuroprotective Agents from Medicinal Plants of the Genus Celastrus

Alzheimer’s disease (AD) is an irreversible, multifaceted, and progressive neurodegenerative disorder. Over the past 30 years, the search for anti-AD drugs has been primarily based on the cholinergic deficiency hypothesis and/or the β-amyloid (Aβ) cascade hypothesis. In this study, we report the identification of 16 new and 38 known β-dihydroagarofuran-type sesquiterpenoids from Celastrus flagellaris and Celastrus angulatus. The β-dihydroagarofuran-type sesquiterpenoids 58, 59, 61, and 63 significantly attenuated scopolamine-induced prolonged escape latency and increased number of errors compared with the control group. At 10 μM, 21 of the 62 tested β-dihydroagarofuran-type sesquiterpenoids rescued Aβ25–35-induced SH-SY5Y cells from viability reduction, which increased the cell viability from 64.6% for the model to more than 74.0%. The majority of the β-dihydroagarofuran-type sesquiterpenoids with ester groups exhibited stronger activity than those with free hydroxy groups or without substituents at the same positions. These results identified a new chemical skeleton as drug lead for the investigation of novel therapeutic agents against AD.