alpha-synuclein and acteoside

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. At present, the incidence rate of PD is increasing worldwide, there is no effective cure available so far, and currently using drugs are still limited in efficacy due to serious side effects. Acteoside (ACT) is an active ingredient of many valuable medicinal plants, possesses potential therapeutic effects on many pathological conditions. In this study, we dissected the neuroprotection effects of ACT on PD and its potential molecular mechanism in our PD model pathology based on network pharmacology prediction and experimental assays. Network pharmacology and bioinformatics analysis demonstrated that ACT has 381 potential targets; among them 78 putative targets associated with PD were closely related to cellular autophagy and apoptotic processes. Our experimental results showed that ACT exerted significant neuroprotection effects on Rotenone (ROT) -induced injury of neuronal cells and Drosophila melanogaster (D. melanogaster). Meanwhile, ACT treatment induced autophagy in both neuronal cell lines and fat bodies of D. melanogaster. Furthermore, ACT treatment decreased ROT induced apoptotic rate and reactive oxygen species production, increased mitochondrial membrane potentials in neuronal cells, and promoted clearance of α-synuclein (SNCA) aggregations in SNCA overexpressed cell model through the autophagy-lysosome pathway. Interestingly, ACT treatment significantly enhanced mitophagy and protected cell injury in neuronal cells. Taken together, ACT may represent a potent stimulator of mitophagy pathway, thereby exerts preventive and therapeutic effects against neurodegenerative diseases such as PD by clearing pathogenic proteins and impaired cellular organelles like damaged mitochondria in neurons.

Topics: Adenylate Kinase; alpha-Synuclein; Animals; Apoptosis; Autophagy; Cell Line, Tumor; Cell Survival; Computational Biology; Drosophila melanogaster; Glucosides; HEK293 Cells; Humans; Longevity; Membrane Potential, Mitochondrial; Models, Biological; Motor Activity; Neurons; Neuroprotective Agents; Parkinson Disease; Phenols; Rats; Reactive Oxygen Species; Rotenone

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.

Topics: alpha-Synuclein; Animals; Caspase 3; Disease Models, Animal; Glucosides; Humans; Microtubule-Associated Proteins; Molecular Dynamics Simulation; Parkinson Disease; Phenols; Protein Binding; Rats; Rats, Sprague-Dawley; Rotenone