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.