The Sigma‐1 Receptor as a Novel Target in the Neuroprotective Effects of Cannabidiol and Cannabigerol Against Mitochondrial Damage in Cultured Cerebellar Granule Neurons

Cannabidiol (CBD) and cannabigerol (CBG) are nonpsychotomimetic phytocannabinoids with neuroprotective properties. We have previously reported that CBD and CBG, but not their acidic forms, protect cerebellar granule neurons from rotenone‐induced toxicity. These effects were independent of canonical (i.e., cannabinoid 1 and 2‐receptors) and noncanonical cannabinoid targets (i.e., transient‐receptor potential vanilloid type 1 or peroxisome proliferator‐activated receptor), suggesting alternative mechanisms. The sigma‐1 receptor (σ1R), a chaperone enriched at mitochondria‐associated membranes, regulates Ca 2+ homeostasis, oxidative stress, and mitochondrial function, representing a neuroprotective target. In this study, we investigated the role of σ1R in\ the neuroprotective actions of CBD and CBG using a rotenone‐induced neurotoxicity model in primary neuronal cultures. Pharmacological blockade of σ1R with NE‐100 abolished the neuroprotective effects of both cannabinoids, supporting a σ1R‐dependent mechanism. Consistently, molecular docking and molecular dynamics simulations using the human σ1R structure revealed stable binding of CBD and CBG within the ligand‐binding pocket, involving key residues for receptor recognition. According to the in vitro data, neutral forms showed higher predicted affinities than their acidic counterparts, while NE‐100 exhibited the strongest binding. These findings identify σ1R as a functionally relevant target for CBD and CBG, supporting their neuroprotective effects through modulation of σ1R‐mediated responses.