Diverse ecdysterones show different effects on amyloid-β42 aggregation but all uniformly inhibit amyloid-β42-induced cytotoxicity.
Amyloid-β (Aβ) plays a pivotal role in Alzheimer's disease (AD) pathogenesis and in toxic mechanisms such as oxidative stress, mitochondrial dysfunction, calcium turbulence, and apoptosis induction. Therefore, interfering with Aβ aggregation has long been one of the most promising strategies for AD treatment. Ecdysterones (ECRs) are steroidal hormones in insects and terrestrial plants that have high structural diversity and multiple beneficial pharmacological activities. Here, we studied the effects of six ECRs on Aβ aggregation and cytotoxicity. Two ECRs with an acetoxyl group at the 2 or 3 position and saturated chains as side groups showed apparent promotion of Aβ42 fibrilization, resulting in less Aβ42 oligomers in the samples. Another three with unsaturated side chains clearly inhibited Aβ aggregation and disaggregated preformed fibrils, but increased the Aβ42 oligomer levels. Nevertheless, our MTT results showed that all ECRs tested inhibited Aβ42-induced cytotoxicity. This protective activity may be partly attributable to ECR-mediated amelioration of A&beta42-induced release of reactive oxygen species. Taken together, our findings suggest that ECRs, a series of natural compounds in many plants and insects, have therapeutic potential in AD and that the deduced structure-activity relationships may be beneficial in drug design for the treatment of AD and other amyloidoses.
Yang
Shi-Gao
SG
Tsinghua University School of Medicine, Haidian District, Beijing, China.
Zhang
Xi
X
Sun
Xiao-Sia
XS
Ling
Tie-Jun
TJ
Feng
Ying
Y
Du
Xue-Ying
XY
Zhao
Min
M
Yang
Yang
Y
Xue
Di
D
Wang
Li
L
Liu
Rui-Tian
RT
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity*; D045744:Cell Line, Tumor; D004441:Ecdysterone / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity*; D017510:Protein Folding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); D004441:Ecdysterone