The cannabinoid receptor‐1 antagonist rimonabant inhibits platelet activation and reduces pro‐inflammatory chemokines and leukocytes in Zucker rats

Abstract

Background and purpose: We investigated the effect of rimonabant on inflammation and enhanced platelet reactivity in type 2 diabetic Zucker rats, an experimental model of impaired glucose tolerance and the metabolic syndrome. Experimental approach: Rimonabant (10 mg kg À1 by gavage) was fed for 2 weeks to 3-month-old male obese Zucker rats as an impaired glucose tolerance model and for 10 weeks to 6-month-old male obese Zucker rats as a model of the metabolic syndrome. RANTES (Regulated upon Activation, Normal T cell Expressed, and Secreted) and MCP-1 (monocyte chemotactic protein-1) serum levels were determined by ELISA. Leukocyte populations were quantitatively assessed using a veterinary differential blood cell counter. Platelet activation was assessed by flow-cytometry, platelet aggregation, and adhesion of isolated platelets to immobilized fibrinogen. Key results: RANTES and MCP-1 serum levels were increased in obese vs lean Zucker rats and significantly reduced by longterm treatment with rimonabant, which slowed weight gain in rats with the metabolic syndrome. Neutrophils and monocytes were significantly increased in young and old obese vs lean Zucker rats and lowered by rimonabant. Platelet-bound fibrinogen was significantly enhanced in obese vs lean Zucker rats of both age, and was reduced by rimonabant. Platelets from obese rats were more sensitive to thrombin-induced aggregation and adhesion to fibrinogen, which were both attenuated by rimonabant therapy. Conclusions and implications:We demonstrate positive modulation of circulating neutrophil and monocyte numbers, reduced platelet activation and lower RANTES and MCP-1 levels by rimonabant in Zucker rats. This may potentially contribute to a reduction of cardiovascular risk.

Rimonabant inhibits TNF-α-induced endothelial IL-6 secretion via CB1 receptor and cAMP-dependent protein kinase pathway

“…It has been reported that rimonabant reduced plasma levels of the pro-inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1) and interleukin-12 (IL-12) in LDLR-/-mice fed a Western-type diet [13] . Positive modulation of circulating neutrophil and monocyte numbers, reduced platelet activation and lower levels of MCP-1 and regulated upon activation, normal T cell expressed and secreted (RANTES) by rimonabant in type 2 diabetic Zucker rats have also been reported [14] . we demonstrated that TNF-α-induced IL-6 production, IKKα/ β phosphorylation and IκB-α degradation were significantly attenuated by rimonabant in HUVEC.…”

Activation by 2-arachidonoylglycerol of platelet p38MAPK/cPLA2 pathway

“…Since ROS participate in cell signaling process and their regulation, 2-AG could potentiate its platelet aggregating power increasing ROS formation. Recently it has been demonstrated that antagonism of CB1 receptor depresses platelet activation in a mouse model of type 2 diabetes mellitus and reduces cardiovascular risk by lessening proinflammatory and proatherosclerotic cascades [Schäfer et al, 2008]. Treatment with rimonabant reduced fibrinogen binding, reduced thrombin-induced platelet aggregation and decreasing ADP-stimulated expression of pselectin, a platelet activation marker.…”

Rimonabant, a specific antagonist of the cannabinoid CB1-receptor, prevents lipopolysaccharide-induced endotoxemia in awake guinea pigs

“…The concentration of rimonabant used in this work was similar to that used for other animal experiments 12,30) , and to the concentration approved for use as an antiobe- …”

“…was administered. Rimonabant and LPS concentrations were based on published findings 11,12) . Intestinal tension and blood pressure were measured from 30 min before administration of LPS to 5 h afterward, with readings taken every 30 min.…”