Non-psychotropic Cannabis sativa L. phytocomplex modulates microglial inflammatory response through CB2 receptors-, endocannabinoids- and NF-κB-mediated signaling

Cannabis sativa L. has been emerging for its protective potential in modulating neuroinflammation, a complex process orchestrated among others by the resident immune cells of the central nervous system, microglia. Phytocannabinoids, especially cannabidiol (CBD), terpenes, and other constituents trigger several upstream and downstream microglial intracellular pathways. Here, we investigated the molecular mechanisms of a chemically standardized extract of C. sativa (CSE) compared to its main cannabinoid component, CBD, and terpenoid constituent, β-caryophyllene (CAR), in an in vitro model of neuroinflammation. We evaluated the effect of a pre-treatment with CSE, CBD or CAR on the inflammatory response induced by an exposure to lipopolysaccharide (LPS) in BV-2 microglia. The LPS-induced upregulation of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α, was significantly attenuated by CSE and only partially by CBD. The strong downregulation of CB2 receptors caused by LPS was reverted by CBD and CAR, while the effect of CSE was less evident. In BV-2 cells, CSE phytocomplex exerted an anti-inflammatory activity partially CB2r dependent and related to p38 and JNK MAPKs cascade modulation and ROS production with consequent NF-κB p65 nuclear translocation block. Our data suggest that C. sativa phytocomplex and its multitarget mechanism could represent a novel therapeutic strategy for neuroinflammatory-related diseases.