Studies of involvement of G-protein coupled receptor-3 in cannabidiol effects on inflammatory responses of mouse primary astrocytes and microglia

Abstract

Cannabidiol (CBD) exhibits anti-inflammatory and neuroprotective properties and is suggested to be effective in the pre-clinical and clinical treatment of illnesses of the central nervous system (CNS). Two major types of CNS glial cells, astrocytes and microglia, play critical roles in the development and pathogenesis of CNS diseases. However, the mechanisms by which CBD plays an anti-inflammatory and neuroprotective role for these glial cells have not been fully elucidated. In this study, we examined the effects of CBD on the inflammatory response of mouse primary astrocytes and microglia. We also investigated whether the effect of CBD on cytokine release is mediated by the G protein coupled receptor 3 (GPR3), which was recently identified as a novel receptor for CBD. Our results showed that CBD inhibited inflammatory responses of astrocytes and microglia stimulated with lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) ligand in vitro and in vivo. In addition, CBD reduced the phosphorylation of STAT3 and NF-κB signaling pathways in LPS-stimulated astrocytes. However, the inhibitory effect of CBD on pro-inflammatory cytokine production was independent of GPR3 expression in both types of glial cells. Thus, although CBD is effective in ameliorating the activation of astrocytes and microglia, its mechanism of action still requires further study. Our data support the concept that CBD may have therapeutic potential for neurological disorders that involve neuroinflammation.

Neuroprotection of Cannabidiol, Its Synthetic Derivatives and Combination Preparations against Microglia-Mediated Neuroinflammation in Neurological Disorders

“…A summary of the preclinical evidence of CBD on microglial activation and neuroinflammatory signaling pathways in various neurological disorders is listed in Table 1. In vitro investigations LPS-induced BV-2 microglia [37] Reduced neuroinflammatory cytokines, such as IL-1β, IL-6 and interferon-beta (IFN-β) Downregulated nuclear factor kappa B (NF-kB) signaling pathway LPS-induced microglia and astrocytes (host not specified) [38] Ameliorated activation of microglia and astrocytes, inhibited production of IL-6 from microglia and astrocyte cell line Inhibited phosphorylation of NF-κB and signal transducer and activator of transcription 3 (STAT3) signalling pathways LPS-induced microglia in mice [39] Reduced synthesis of glucose-derived nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) and reduced neuroinflammatory mediators (ROS and TNF-α) Downregulated NF-kB-dependent signaling pathway…”

“…A study from Wu et al (2021) demonstrated that CBD (10 µM) inhibited IL-6, but not TNF-α, in LPS-stimulated mouse primary microglia and astrocytes. Interestingly, their results demonstrated that such action was not dependent on the G protein coupled receptor 3 (GPR3), a member of the G protein-coupled receptor family of transmembrane receptor, in primary mouse astrocytes and microglia [38].…”

Endothelial Cells Mediated by UCP2 Control the Neurogenic‐to‐Astrogenic Neural Stem Cells Fate Switch During Brain Development

“…Astrocytes and microglia are the main cells responsible for the inflammatory responses in the brain. [ 29 ] To determine whether the persistent increase in astrocytes is caused by an inflammatory response, we examined whether endothelial UCP2 deletion affects microglia and inflammation. Immunostaining results showed that the number of IBA1 + and CD68 + (microglia marker) cells was not significantly different between UCP2 WT and UCP2 ECKO mice (Figure S5C–E , Supporting Information), suggesting that endothelial UCP2 deletion had no effect on microglial cells.…”

The role of microglial autophagy in Parkinson’s disease

“…NLY01 (Yun et al, 2018), nilotinib (Wu et al, 2021b), and cannabidiol (Wu et al, 2021a). Zhu et al 10.3389/fnagi.2022.1039780 Frontiers in Aging 06 frontiersin.org treatment of PD through pathways related to microglial activation and neuroinflammation.…”

“…The anti-inflammatory properties of nilotinib may further reduce inflammatory neurotoxicity to protect against DA neuron loss, indicating its potential use in PD ( Wu et al, 2021b ). Cannabidiol (CBD) can inhibit IL-6 release and improve microglial activation, and there is a correlation between CBD-induced signal transducer and activator of transcription 3 (STAT3) and NF-κB phosphorylation, indicating that CBD may have therapeutic potential for treating neurological diseases involving neuroinflammation ( Wu et al, 2021a ; Table 1 ).…”