Cannabinol β‑O-Glucoside Inhibitors of the Keap1-Nrf2 Interaction: A Novel Therapeutic Strategy for Parkinson's Disease.

Oxidative stress and xenobiotic exposure disrupt redox homeostasis and contribute to neurodegenerative disease progression. The Keap1-Nrf2-ARE pathway is a key antioxidant defense mechanism, in which Nrf2 activates cytoprotective gene expression. Because disrupting the Keap1-Nrf2 interaction can enhance antioxidant responses, we assessed modified Cannabis sativa cannabinoids bearing C- and O-β-d-glucosides as potential Keap1 inhibitors. Building on our earlier fractionation and derivatization work, these compounds were evaluated for binding to the Keap1 BTB and KDC domains and for activation of Nrf2-mediated responses using in vitro and in silico methods. In a Parkinson's disease model, CS-11 (4a) showed the strongest neuroprotective effect, with an EC50 of 100 nM. Treatment significantly increased cytoprotective gene expression, indicating enhanced Nrf2 transcriptional activity. CS-11 (4a) also restored tyrosine hydroxylase levels and protected dopaminergic neurons from cell death. Computational analyses supported its Keap1-targeting activity, identifying CS-11 (4a) as a promising Parkinson's disease therapeutic candidate.