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

Oviedo-Pino V.; Pazos M.; Prunell G.; Ferreiro-Vera C.; Sánchez de Medina V.; Reyes-Parada M.; Ramírez D.; Scorza C.; Echeverry C. · ChemMedChem · 2026

**Background & Methods** This review investigates the neuroprotective mechanisms of cannabidiol (CBD) and cannabigerol (CBG) in primary cerebellar granule neuron cultures exposed to rotenone-induced toxicity. The study employed pharmacological blockade using the sigma-1 receptor (σ1R) antagonist NE-100, complemented by molecular docking and molecular dynamics simulations to characterize ligand-receptor interactions. **Key Findings** • Pharmacological blockade of σ1R with NE-100 completely abolished the neuroprotective effects of both CBD and CBG, establishing σ1R as a functionally essential target for cannabinoid-mediated neuroprotection against mitochondrial damage. • Molecular docking and dynamics simulations confirmed stable binding of CBD and CBG within the σ1R ligand-binding pocket, with neutral cannabinoid forms demonstrating higher predicted binding affinities compared to their acidic precursors (CBDA and CBGA), while NE-100 exhibited the strongest binding affinity. • The neuroprotective mechanisms are independent of canonical cannabinoid receptors (CB1/CB2) and noncanonical targets (TRPV1, PPAR), indicating σ1R-mediated modulation of calcium homeostasis, oxidative stress reduction, and mitochondrial function as the primary protective pathways. **Dosage & Administration** Not reported. Study utilized in vitro culture models without specified dose-response data applicable to clinical use. **Safety & Adverse Effects** Not reported. The study focused on mechanistic investigations in cultured neurons and did not assess adverse effects or toxicity profiles. **Evidence Quality** This is a basic science research article (in vitro study) with moderate evidence limitations. Strengths include rigorous molecular modeling and pharmacological validation through receptor antagonism. Limitations include: (1) restriction to cultured cerebellar granule neurons, limiting generalizability to intact nervous system or other neural populations; (2) use of rotenone as a single toxicity model, which may not represent clinical neurodegeneration; (3) lack of in vivo validation; and (4) absence of dose-response characterization. The findings provide mechanistic support for σ1R as a cannabinoid target but require subsequent animal model and clinical studies to establish therapeutic relevance. This represents preliminary evidence (Level 4) supporting further investigation of CBD and CBG as σ1R ligands for neuroprotection.

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