Insights into the inhibitory mechanism of skullcapflavone II against α-synuclein aggregation and its mediated cytotoxicity.
Int J Biol Macromol
; 209(Pt A): 426-440, 2022 Jun 01.
Article
in En
| MEDLINE
| ID: mdl-35398391
ABSTRACT
The dangerous self-assembled and infectious seeds of α-synuclein (αSN) play primary roles in Parkinson's disease. Accordingly, the inhibition of αSN fibrillation and elimination of toxic aggregates are the main therapeutic strategies. Skullcapflavone II (S.FII), a compound isolated from S. pinnatifida, has shown multiple neuroprotective features. Herein, we demonstrated that S.FII inhibited αSN aggregation with IC50 of 7.2 µM. It increased nucleation time and decreased fibril elongation rate and the species formed in the presence of S.FII were unable to act as seeds. Additionally, S.FII inhibited both secondary nucleation and seeding of αSN and disaggregated the mature preformed fibrils as well. The species formed in the presence of S.FII showed less toxicity. It also preserved neurite length and dopamine content of SH-SY5Y cells and attenuated the inflammatory responses in mixed glial cells. The Localized Surface Plasmon Resonance (LSPR) analysis indicated that S.FII interacts with αSN. Docking simulation studies on αSN fibrils revealed that S.FII could interact with the key residues of the salt bridges and glutamine ladder, which might lead to the destruction of fibril's structures. We also showed that S.FII passes through the blood-brain barrier in vitro and in vivo. Overall, these findings elucidate the neuroprotective roles of S.FII in reducing αSN pathogenicity.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Parkinson Disease
/
Alpha-Synuclein
Limits:
Humans
Language:
En
Journal:
Int J Biol Macromol
Year:
2022
Document type:
Article
Affiliation country:
Irán