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 neurodegenerative movement disorder, has reached pandemic status worldwide. This neurologic disorder 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 (PQ²⁺)/maneb (MB) were used as a model system to elucidate the mechanism by which CBD protects the neural cell from apoptosis in vitro. According to immunofluorescence microscopy, flow cytometry, cell-free assay, and molecular docking analysis, we demonstrate that CBD offers protection to DALNs against PQ²⁺ (1 mM)/MB (50 μM)-induced oxidative stress (OS) by simultaneously (i) decreasing reactive oxygen species (ROS: O₂^•-, H₂O₂), (ii) maintaining the mitochondrial membrane potential (ΔΨ_m), (iii) directly binding to stress sensor protein DJ-1, thereby blunting its oxidation from DJ-1CYS¹⁰⁶-SH into DJ-1CYS¹⁰⁶-SO₃, and (iv) directly binding to pro-apoptotic protease protein caspase 3 (CASP3), thereby disengaging neuronal dismantling. Furthermore, the protective effect of CBD on DJ-1 and CASP3 was independent of CB1 and CB2 receptor signaling. CBD also re-established the Ca²⁺ influx in DALNs as a response to dopamine (DA) stimuli under PQ²⁺/MB exposure. Because of its powerful antioxidant and antiapoptotic effects, CBD offers potential therapeutic utility in the treatment of PD.