Cannabinoid CB₂ receptors in human brain inflammation

Abstract

The presence of functional cannabinoid CB 2 receptors in the CNS has provoked considerable controversy over the past few years. Formerly considered as an exclusively peripheral receptor, it is now accepted that it is also present in limited amounts and distinct locations in the brain of several animal species, including humans. Furthermore, the inducible nature of these receptors under neuroinflammatory conditions, in contrast to CB 1 , makes them attractive targets for the development of novel therapeutic approaches. In fact, the undesired psychoactive effects caused by CB 1 activation have largely limited the clinical use of cannabinoid-related compounds that act on these receptors. In this review some recent findings on the antiinflammatory properties of CB 2 receptors are presented, as well as new perspectives that have been obtained based on studies of human postmortem brain samples. In addition, various working hypotheses are also proposed and discussed.

Lipid G Protein-coupled Receptor Ligand Identification Using β-Arrestin PathHunter™ Assay

“…Furthermore, we were encouraged by the fact that transient transfection of receptors into ␤-arrestin-EA parental HEK293 cells gave robust signals, circumventing the need for labor-intensive stable cell line generation and selection. The EC 50 values obtained in the transient ␤-arrestin assay for a subset of receptors were significantly higher than the EC 50 values obtained from other assay formats (Table 1). This appears to be partly due to the low sensitivity resultant from transient transfection method.…”

“…Data Analysis-EC 50 or IC 50 values were obtained by fitting the data with the sigmoidal dose-response curve-fitting tool of the GraphPad Prism software. Eight or twelve different concentrations were usually used and two or three data points per concentration.…”

“…7A). Because the EC 50 values of these compounds appeared to be high in the ␤-arrestin assay, making accurate EC 50 determinations difficult, we also tested these compounds in the aequorin assay. The aequorin assay is a more sensitive assay for G2A, giving lower EC 50 values for all compounds tested.…”

Cannabinoids and Epilepsy

“…Δ9-THC has antioxidant effects in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-and N-methyl-D-aspartate-mediated cytotoxicity models via a CB 1 R-independent mechanism [87]. Cannabinoids reduce neuronal and glial release of the proinflammatory cytokines tumor necrosis factor-α, NO, interleukin (IL)-1 and IL-6 [88][89][90][91][92][93], and increase release of anti-inflammatory cytokines IL-4, IL-10, and IL-1 receptor antagonist (IL-1a) [94,95] via CB1R-and CB2R-dependent mechanisms in neurons and glia [94,95] (reviewed in [96]). Δ9-THC also transiently activates and desensitizes the transient receptor potential (TRP) channels TRPA1, TRPV1, and TRPV2 [97][98][99].…”

Endocannabinoid Systetm: Neuropharmacological Implications

“…It has been demonstrated that in microglia of AD patients, CB1 and CB2 receptor expression is significantly increased, while in basal ganglia and hippocampus neuronal CB1 receptor expression is decreased [58]. Therefore, endocannabinoid system might play an important role in AD pathogenesis [59].…”