Oleuropein Attenuates 6-Hydroxydopamine-Induced Cytotoxicity Through Redox Regulation in Differentiated Dopaminergic Neurons: Potential Involvement of RET-Associated Signalling

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by selective loss of dopamine-containing neurons (DCNs) in the substantia nigra. Oxidative stress and impaired neurotrophic signalling contribute to PD pathogenesis. Oleuropein (Ole), a phenolic compound found in olives and olive leaves, exhibits antioxidant and cytoprotective properties that may counteract neuronal injury. This study investigated the neuroprotective effects of Ole in differentiated dopaminergic neurons (dDCNs) derived from the human ReNcell VM model exposed to 6-hydroxydopamine (6-OHDA). Ole significantly attenuated 6-OHDA-induced cytotoxicity, restoring cell viability following post- and pre-treatment compared with toxin-treated cells. Tyrosine hydroxylase expression was preserved, indicating maintenance of the dopaminergic phenotype. Ole also reduced lipid peroxidation and restored total antioxidant capacity, supporting a role in redox homeostasis. Molecular docking suggested a stable interaction between Ole and the RET receptor tyrosine kinase, suggesting a potential involvement of RET-associated survival signalling pathways that requires further experimental validation. In addition, 6-OHDA altered extracellular vesicle (EV) release and EV-associated transcripts related to Wnt signalling (Wnt3a, Wnt5a, GSK3), while Ole partially restored EV release profiles and EV-associated Wnt signalling-related transcripts. Collectively, these findings indicate that Ole protects dDCNs from oxidative stress and highlight its potential as a neuroprotective agent against dopaminergic neuronal injury.