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.