Cannabidiol (CBD) and cannabigerol (CBG) protected cultured rat brain cells from toxic injury through a mechanism involving the sigma-1 receptor, according to research published in ChemMedChem and conducted by researchers from the Clemente Estable Biological Research Institute in Uruguay, the University of Concepción and the University of Santiago de Chile in Chile, and Phytoplant Research in Spain.
For the study, scientists exposed cerebellar granule neurons to rotenone, a substance that disrupts mitochondrial function. Mitochondria produce energy needed for cells to function.
Earlier experiments found that CBD and CBG protected these neurons, while their acidic counterparts did not. The protection appeared independent of several previously investigated cannabinoid targets, prompting researchers to examine another mechanism.
The team focused on the sigma-1 receptor, which helps regulate calcium balance, oxidative stress and mitochondrial function.
When researchers blocked that receptor with a compound called NE-100, the protective effects of both cannabinoids disappeared, supporting its involvement in their activity.
Computer simulations using the human sigma-1 receptor also predicted stable binding by CBD and CBG. Their neutral forms showed stronger predicted binding than their acidic counterparts.
The findings identify the sigma-1 receptor as a relevant target for understanding how CBD and CBG protect neurons in this laboratory model.
The study’s full abstract can be found below
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 Ca2+ 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.
