Rimonabant (SR141716) exerts anti-proliferative and immunomodulatory effects in human peripheral blood mononuclear cells.
OBJECTIVE
Rimonabant (SR141716) is the first selective cannabinoid receptor CB(1) antagonist described. Along with its anti-obesity action, emerging findings show potential anti-proliferative and anti-inflammatory action of SR141716 in several in vitro and in vivo models. In this study we have investigated the anti-proliferative and immunomodulatory effects of SR141716 in human peripheral blood mononuclear cells (PBMCs).


METHODS
We have evaluated in vitro the effect of SR141716 in human PBMCs stimulated with different mitogens. Cell proliferation was assessed by (3)H-thymidine incorporation. Cell cycle, cell death and apoptosis were analysed by flow cytometry. Protein expression was investigated by Western blot.


RESULTS
SR141716 significantly inhibited the proliferative response of PBMCs and this effect was accompanied by block of G(1)/S phase of the cell cycle without induction of apoptosis and cell death. SR141716 used in combination with 2-methyl-arachidonyl-2'-fluoro-ethylamide (Met-F-AEA), a stable analogue of the endogenous cannabinoid anandamide, showed synergism rather than antagonism of the inhibition of cell proliferation. The immunomodulatory effects of SR141716 were associated with increased expression of IkappaB, phosphorylated AKT (p-AKT) and decreased expression of NF-kappaB, p-IkappaB, p-ERK, COX-2 and iNOS.


CONCLUSIONS
Our findings suggest SR141716 is a novel immunomodulatory drug with anti-inflammatory properties.
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001095:Arachidonic Acids / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D016193:G1 Phase / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D016196:S Phase / Q000187:drug effects
C443759:2-methylarachidonyl-2'-fluoroethylamide; D000893:Anti-Inflammatory Agents; D001095:Arachidonic Acids; D020672:I-kappa B Proteins; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D051057:Proto-Oncogene Proteins c-akt; D000077285:Rimonabant