The two synthetic cannabinoid compounds 4′‐F‐CBD and HU‐910 efficiently restrain inflammatory responses of brain microglia and astrocytes

Abstract

To study the anti‐inflammatory potential of the two synthetic cannabinoids 4′‐F‐CBD and HU‐910, we used post‐natal brain cultures of mouse microglial cells and astrocytes activated by reference inflammogens. We found that 4′‐F‐CBD and HU‐910 efficiently curtailed the release of TNF‐α, IL‐6, and IL‐1β in microglia and astrocytes activated by the bacterial Toll‐Like Receptor (TLR)4 ligand LPS. Upon LPS challenge, 4′‐F‐CBD and HU‐910 also prevented the activation of phenotypic activation markers specific to microglia and astrocytes, that is, Iba‐1 and GFAP, respectively. In microglial cells, the two test compounds also efficiently restrained LPS‐stimulated release of glutamate, a non‐cytokine inflammation marker for these cells. The immunosuppressive effects of the two cannabinoid compounds were concentration‐dependent and observable between 1 and 10 μM. These effects were not dependent on cannabinoid or cannabinoid‐like receptors. Both 4′‐F‐CBD and HU‐910 were also capable of restraining the inflammogenic activity of Pam3CSK4, a lipopeptide that activates TLR2, and of BzATP, a prototypic agonist of P2X7 purinergic receptors, suggesting that these two cannabinoids could exert immunosuppressive effects against a variety of inflammatory stimuli. Using LPS‐stimulated microglia and astrocytes, we established that the immunosuppressive action of 4′‐F‐CBD and HU‐910 resulted from the inhibition of ROS produced by NADPH oxidase and subsequent repression of NF‐κB‐dependent signaling events. Our results suggest that 4′‐F‐CBD and HU‐910 may have therapeutic utility in pathological conditions where neuroinflammatory processes are prominent.