Jurado Coronel, J. C.; Duennwald, M. L.

Oxidative stress and the progressive degeneration of dopaminergic neurons are key features of Parkinsons disease (PD). The intrinsically disordered structure of the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2), which coordinates the main cellular antioxidant response of the body, makes it highly susceptible to misfolding and aggregation under severe oxidative stress, compromising cellular survival. Cannabidiol (CBD) has potent neuroprotective properties, but its exact molecular mechanism within the dopaminergic redox environment remains unclear. In this study, we investigated the protective effects of CBD against 6-hydroxydopamine (6-OHDA)-induced toxicity in both undifferentiated and mature, post-mitotic differentiated SH-SY5Y cells. We found that CBD confers robust Nrf2-dependent neuroprotection against 6-OHDA. Importantly, we uncover a previously unexplored mechanism of neuroprotection by which CBD actively prevents the stress-induced sequestration of Nrf2 into insoluble cytoplasmic inclusions under oxidative stress. We find that CBD keeps Nrf2 in a soluble, functional state, increases Ser40 phosphorylation, restores nuclear localization, and drives the robust transcriptional upregulation of antioxidant enzymes. This targeted activation of Nrf2 effectively reduces intracellular ROS, significantly attenuates mitochondrial fragmentation, and decreases aberrant mitophagic activity. Overall, our results show that rather than merely scavenging reactive oxygen species, CBD directly increases Nrf2 activity during oxidative stress, enabling a sustained cytoprotective response. We thus identify CBD as a highly specific, targeted molecule with a high potential for neuroprotective therapy in PD.