Activation of cannabinoid receptor 2 inhibits LPS-induced neuroinflammation via PI3K/Akt signaling pathway in mice

Abstract

Abstract Parkinson's disease (PD) is a common neurodegenerative disease characterized by selective loss of dopaminergic neurons in the substantia nigra (SN) and neuroinflammation mediated by overactivated microglia and astrocytes. Cannabinoid receptor 2 (CB2R) is primarily present on peripheral immune cells and microglia, exerts a significant immunomodulatory effect. However, its antineuroinflammatory effects and the precise mechanism are still unclear. Therefore, this study attempts to investigate the effect of CB2R on neuroinflammation and the underlying mechanisms. Mice were injected with Lipopolysaccharide (LPS) into both sides of the SN using a stereotactic injection method to establish neuroinflammatory model. Pole test and rotarod test were performed to examine the ability of balance and motor coordination of mice. Immunohistochemistry (IHC) and immunofluorescence (IF) were performed on brain tissue sections to observe of tyrosine hydroxylase (TH), Iba1 and GFAP. RT-PCR was examined for inflammatory factors TNF-α, IL-6, IL-1β, iNOS and COX-2. The expression of PI3K/AKT signaling pathway-related proteins was examined by Western blot. Our studies showed that CB2R agonist (JWH133) protected dopaminergic neurons and improve motor dysfunction by inhibiting the activation of glial cells and the release of pro-inflammatory mediators in SN of mice induced by LPS. Furthermore, JWH133 also restored the phosphorylation of PI3K and Akt, which was downregulated by LPS in SN. However, CB2R knockout mice aggravated the loss of dopaminergic neurons and the decline of motor function. After CB2R knockout, the number of activated glial cells was significantly increased, and the expression of pro-inflammatory mediators was increased. The results suggested that activation of CB2R ameliorated LPS-induced neuroinflammation through the PI3K/Akt pathway.