Work

Cannabidiol releases CB1R from A2AR repression in ischemic stroke

Year: 2025

Type: article

Abstract: Cannabidiol (CBD) is a phytocannabinoid with potential in one of the most prevalent syndromes occurring at birth, the hypoxia of the neonate. CBD targets a variety of proteins, adenosine A 2A R and cannabinoid CB 1 R receptors included. These two receptors may interact to form heteromers (A 2A R-CB 1 R Hets) that are also a target of CBD. Thus, we aimed to assess whether the expression and function of A 2A R–CB 1 R-Hets is affected by CBD in animal models of hypoxia of the neonate and in glucose- and oxygen deprived (GOD) neurons and microglial cells. Results indicated that the formation of A 2A R-CB 1 R heteromers increased A 2A R affinity for its selective agonist CGS21680. Moreover, resonance energy transfer assays showed that CBD and cannabigerol (CBG) affected the structure of the heteromer. Regarding functionallity, CBD partially bloked A 2A R induced signalling in transfected HEK-293 T cells, while it recovered CB 1 R signalling in glucose/oxygen-deprived neurons and microglial cells. The expression of A 2A R-CB 1 R Hets increased in GOD neurons and microglial cells. This increase was counteracted with a pre-treatment with CBD and CBG. Importantly, in brain sections of a hypoxia/ischemia animal model, administration of CBD led to a significant reduction in the expression of A 2A R-CB 1 R Hets. In conclusion, CBD effects in the hypoxia of the neonate can be mediated by A 2A R-CB 1 R complex. CBD partially blocks A 2A R signalling while potentiates the neuroprotective effect of CB 1 R in hypoxic-ischemic conditions.

Source: Neurobiology of Disease

DOI: 10.1016/j.nbd.2025.107131