Cannabidiol Protects Dopaminergic-like Neurons against Paraquat- and Maneb-Induced Cell Death through Safeguarding DJ-1CYS¹⁰⁶ and Caspase 3 Independently of Cannabinoid Receptors: Relevance in Parkinson's Disease

Parkinson's disease (PD), a progressive neurodegenerativemovement disorder, has reached pandemic status worldwide. This neurologicdisorder is caused primarily by the specific deterioration of dopaminergic(DAergic) neurons in the substantia nigra pars compacta (SNc). Unfortunately,there are no therapeutic agents that slow or delay the disease progression.Herein, menstrual stromal cell-derived dopamine-like neurons (DALNs)intoxicated with paraquat (PQ(2+))/maneb (MB) were used asa model system to elucidate the mechanism by which CBD protects theneural cell from apoptosis in vitro. According toimmunofluorescence microscopy, flow cytometry, cell-free assay, andmolecular docking analysis, we demonstrate that CBD offers protectionto DALNs against PQ(2+) (1 mM)/MB (50 mu M)-induced oxidativestress (OS) by simultaneously (i) decreasing reactive oxygen species(ROS: O-2 (center dot-), H2O2), (ii) maintaining the mitochondrial membrane potential (Delta psi(m)), (iii) directly binding to stress sensor protein DJ-1, therebyblunting its oxidation from DJ-1CYS(106)-SH into DJ-1CYS(106)-SO3, and (iv) directly binding to pro-apoptoticprotease protein caspase 3 (CASP3), thereby disengaging neuronal dismantling.Furthermore, the protective effect of CBD on DJ-1 and CASP3 was independentof CB1 and CB2 receptor signaling. CBD also re-established the Ca2+ influx in DALNs as a response to dopamine (DA) stimuli underPQ(2+)/MB exposure. Because of its powerful antioxidant andantiapoptotic effects, CBD offers potential therapeutic utility inthe treatment of PD.