Acteoside Binds to Caspase-3 and Exerts Neuroprotection in the Rotenone Rat Model of Parkinson's Disease

• Published in: PloS one Vol. 11; no. 9; p. e0162696
• Main Authors: Yuan, Jiawen, Ren, Jinpeng, Wang, Ying, He, Xiao, Zhao, Yuwu
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15.09.2016; Public Library of Science (PLoS)
• Subjects: alpha-Synuclein - metabolism; Animals; Apoptosis; Basal ganglia; Biology and Life Sciences; Caspase; Caspase 3 - metabolism; Caspase-3; Central nervous system diseases; Chemical bonds; Computer simulation; Degeneration; Disease; Disease Models, Animal; Dopamine; Dopamine receptors; Glucosides - metabolism; Humans; Hydrogen; Hydrogen bonding; Hydrogen bonds; Laboratories; Medicine and Health Sciences; Microtubule-associated protein 2; Microtubule-Associated Proteins - metabolism; Molecular docking; Molecular dynamics; Molecular Dynamics Simulation; Movement disorders; Neuroblastoma; Neurodegeneration; Neurodegenerative diseases; Neurology; Neurons; Neuroprotection; Oral administration; Parkinson disease; Parkinson Disease - prevention & control; Parkinson's disease; Phenols - metabolism; Physical Sciences; Protein Binding; Proteins; Rats; Rats, Sprague-Dawley; Research and Analysis Methods; Rodents; Rotenone; Rotenone - adverse effects; Signaling; Simulation; Studies; Substantia nigra; Synuclein
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0162696

Parkinson's disease (PD) is characterized by the progressive degeneration of the dopaminergic neurons in the substantia nigra (SN) region. Acteoside has displayed multiple biological functions. Its potential role against PD and the underlying signaling mechanisms are largely unknown. Here, we showed that oral administration of acteoside significantly attenuated parkinsonism symptoms in rotenone-induced PD rats. Further, acteoside inhibited rotenone-induced α-synuclein, caspase-3 upregulation and microtubule-associated protein 2 (MAP2) downregulation in PD rats. The molecular docking and molecular dynamics (MD) simulation results indicated that acteoside may directly bind to and inhibit caspase-3. Acteoside formed hydrogen bonds with at least six residues of caspase-3: ThrA177, SerA178, GlyA238, SerB339, ArgB341 and TrpB348. In addition, a pi-pi interaction was formed between acteoside and caspase-3's HisA237, which might further stabilize the complex. MD simulation results demonstrated that the binding affinity of the caspase-3-acteoside complex was higher than that of caspase-3 and its native ligand inhibitor. Together, we show that acteoside binds to caspase-3 and exerts neuroprotection in the rotenone rat model of PD.