Cannabidiol prevents LPS‐induced microglial inflammation by inhibiting ROS/NF‐κB‐dependent signaling and glucose consumption

Abstract

We used mouse microglial cells in culture activated by lipopolysaccharide (LPS, 10 ng/ml) to study the anti‐inflammatory potential of cannabidiol (CBD), the major nonpsychoactive component of cannabis. Under LPS stimulation, CBD (1–10 μM) potently inhibited the release of prototypical proinflammatory cytokines (TNF‐α and IL‐1β) and that of glutamate, a noncytokine mediator of inflammation. The effects of CBD were predominantly receptor‐independent and only marginally blunted by blockade of CB2 receptors. We established that CBD inhibited a mechanism involving, sequentially, NADPH oxidase‐mediated ROS production and NF‐κB‐dependent signaling events. In line with these observations, active concentrations of CBD demonstrated an intrinsic free‐radical scavenging capacity in the cell‐free DPPH assay. Of interest, CBD also prevented the rise in glucose uptake observed in microglial cells challenged with LPS, as did the inhibitor of NADPH oxidase apocynin and the inhibitor of IκB kinase‐2, TPCA‐1. This indicated that the capacity of CBD to prevent glucose uptake also contributed to its anti‐inflammatory activity. Supporting this view, the glycolytic inhibitor 2‐deoxy‐d‐glucose (2‐DG) mimicked the antioxidant/immunosuppressive effects of CBD. Interestingly, CBD and 2‐DG, as well as apocynin and TPCA‐1 caused a reduction in glucose‐derived NADPH, a cofactor required for NADPH oxidase activation and ROS generation. These different observations suggest that CBD exerts its anti‐inflammatory effects towards microglia through an intrinsic antioxidant effect, which is amplified through inhibition of glucose‐dependent NADPH synthesis. These results also further confirm that CBD may have therapeutic utility in conditions where neuroinflammatory processes are prominent.

Cannabinoids as Key Regulators of Inflammasome Signaling: A Current Perspective

“…To further confirm the role of the inflammasome in liver inflammation, the authors studied the effect of CBD on an LPS + ATP treated mouse macrophage cell line, confirming with in vivo data that the expressions of NLRP3, ASC, IL-1β, NF-κB, and caspase-1 were lower in CBD-treated cells ( 195 ). Mouse microglial cells treated with LPS to simulate neuroinflammatory conditions exhibited a robust activation of pro-inflammatory cytokine repertoire, and CBD (1–10 μM) was able to suppress the secretion of IL-1β and inhibit the NF-κB signaling pathway ( 196 ). A similar reduction in the secretion of IL-1β by CBD (10 μM) was also reported by another independent report ( 197 ).…”

Contributive Role of TNF-α to L-DOPA-Induced Dyskinesia in a Unilateral 6-OHDA Lesion Model of Parkinson’s Disease

“…Similarly, two tetracycline derivatives doxycycline and COL-3 that possess anti-inflammatory properties, efficiently inhibited dyskinesia in L-DOPA-treated parkinsonian rats (Bortolanza et al, 2020). We also found that co-administration of the TRPV-1 ion channel antagonist capsazepine (CPZ) with cannabidiol (CBD), a cannabis derivative with well-reported antiinflammatory properties (Napimoga et al, 2009;Campos et al, 2012;Mori et al, 2017;Sonego et al, 2018;Dos-Santos-Pereira et al, 2020) improves abnormal involuntary movements induced by L-DOPA in a hemiparkinsonian dyskinetic mouse model (Dos-Santos-Pereira et al, 2016;Junior et al, 2020). Coherent with these observations, abnormal involuntary movements were exacerbated by peripheral administration of the bacterial inflammogen lipopolysaccharide (LPS) in preclinical models of dyskinesia (Mulas et al, 2016).…”

Vitamin D3 and K2 and their potential contribution to reducing the COVID-19 mortality rate

“…Other dietary supplementations to consider are: (1) lipoic acid has been shown to inhibit pro-inflammatory IL-6 and IL-17 production ( Salinthone et al, 2010 ); (2) omega-3 fatty acids that are anti-inflammatory and reduce kinase excretion. Consume as a supplement or in form of cod liver oil or fatty fish (such as salmon) once or twice per week ( Vasquez, 2016 ); (3) Cannabidiol (CBD) that promotes anti-inflammatory IL-10 secretion ( Joffre et al, 2020 ) while preventing LPS‐induced microglial inflammation ( dos-Santos-Pereira et al, 2020 ); and (4) Green Tea, since epigallocatechin-3-gallate is the most biologically active catechin in green tea. It reduces Th17 cells and increases regulatory T-cells ( Byun et al, 2014 ).…”