Protective effects of specific cannabinoid receptor 2 agonist GW405833 on concanavalin A-induced acute liver injury in mice

Abstract

Cannabinoid receptor 2 (CB2R) is highly expressed in immune cells and plays an important role in regulating immune responses. In the current study, we investigated the effects of GW405833 (GW), a specific CB2R agonist, on acute liver injury induced by concanavalin A (Con A). In animal experiments, acute liver injury was induced in mice by injection of Con A (20 mg/kg, i.v.). The mice were treated with GW (20 mg/kg, i.p., 30 min after Con A injection) or GW plus the selective CB2R antagonist AM630 (2 mg/kg, i.p., 15 min after Con A injection). We found that Con A caused severe acute liver injury evidenced by significantly increased serum aminotransferase levels, massive hepatocyte apoptosis, and necrosis, as well as lymphocyte infiltration in liver tissues. Treatment with GW significantly ameliorated Con A-induced pathological injury in liver tissue, decreased serum aminotransferase levels, and decreased hepatocyte apoptosis. The therapeutic effects of GW were prevented by AM630. In cell experiments, we showed that CB2Rs were highly expressed in Jurkat T cells, but little expression in L02 liver cells. Treatment with GW (10−40 μg/mL) dosedependently decreased the viability of Jurkat T cells and induced cell apoptosis, which was reversed by AM630. In the coculture of Jurkat T cells with L02 liver cells, GW dose-dependently protected L02 cells from apoptosis induced by Con A (5 μg/mL). The protective effect of GW was reversed by AM630 (1 μg/mL). Our results suggest that GW protects against Con A-induced acute liver injury in mice by inhibiting Jurkat T-cell proliferation through the CB2Rs.

Nanophytomedicines for the Prevention of Metabolic Syndrome: A Pharmacological and Biopharmaceutical Review

“…These markers were significantly increased in rats treated with atorvastatin, garlic oil and nanoformulation of garlic oil at a concentration of 0.65 mg/kg; while they were decreased in rats treated with nano-encapsulated garlic oil at concentrations of 0.18 and 0.46 ml/kg. Lymphocytic infiltration and necrosis, which indicates liver damage (Huang et al, 2019), were not observed in animals treated with 0.18 and 0.46 ml/kg of nanoemulsion. Hematoxylin and Eosin staining revealed a decrease in vesicular steatosis (presence of numerous vesicle of fat in the liver) at 0.65 ml/kg of the nanoformulation.…”

Low Basal CB2R in Dopamine Neurons and Microglia Influences Cannabinoid Tetrad Effects

“…Using the Cre- loxP system to generate cell-type-specific deletion of CBRs in the hepatocyte, microglia, and dopamine neurons, we show that the application of Cre-loxP recombinant mouse strains unravels hitherto unknown physiological, behavioral and signaling mechanisms associated with CB2R function. For example, the upregulation of CB1R by HFHS diet in hepatocytes has an inverse relationship with the downregulation of CB2R by lipid overload in the co-expressed hepatocytes [ 51 , 52 ]. Therefore, we isolated adult rodent hepatocytes, neurons, and microglia to compare CB2R expression to those of CB1R.…”

Targeting Cannabinoid Receptors: Current Status and Prospects of Natural Products

“…At present, at least three unique synthetic CB2 agonists have reached clinic trials, including GW842166X, S-777469 and JBT-101 from ClinicalTrials.gov [22,70,103]. Anti-convulsant, neuroprotective [106]; antiinflammatory [96,97]; anti-nociceptive [96]; anti-dyskinesia [98]; osteoprotective [97]; alleviating septic lung injury [113] (e) GW-405833 Aminoalkylindole 4772/CB1 3.92/CB2 [24] 0.650 [24] Anti-nociceptive, anti-inflammatory [99]; protective effects on acute liver injury [114] (f) L-759,633…”

“…Rimonabant, AM-251 and AM-281 not only act as antagonists attenuating effects of CB1 agonists, but act as inverse agonists which can by themselves elicit responses in some CB1-containing tissues that are opposite in direction from those elicited by CB1 agonists [117]. More specifically, they appear to produce inverse cannabimimetic effects in at least some tissues by somehow reducing the constitutive Anti-convulsant, neuroprotective [106]; antiinflammatory [96,97]; anti-nociceptive [96]; anti-dyskinesia [98]; osteoprotective [97]; alleviating septic lung injury [113] (e) GW-405833 Aminoalkylindole 4772/CB1 3.92/CB2 [24] 0.650 [24] Anti-nociceptive, anti-inflammatory [99]; protective effects on acute liver injury [114] (f) L-759,633…”

“…More specifically, they appear to produce inverse cannabimimetic effects in at least some tissues by somehow reducing the constitutive activity of CB1. The constitutive activity is understood as the coupling of CB1 to its effector mechanisms that, it is thought, can occur in the absence of exogenously added or endogenously Anti-convulsant, neuroprotective [106]; antiinflammatory [96,97]; anti-nociceptive [96]; anti-dyskinesia [98]; osteoprotective [97]; alleviating septic lung injury [113] (e) GW-405833 Aminoalkylindole 4772/CB1 3.92/CB2 [24] 0.650 [24] Anti-nociceptive, anti-inflammatory [99]; protective effects on acute liver injury [114] (f) L-759,633…”