Rimonabant (SR141716) induces metabolism and acquisition of fertilizing ability in human sperm

Background and purpose: The endocannabinoid system and the cannabinoid CB1 receptor have been identified in human sperm, and it is well known that endocannabinoids have pronounced adverse effects on male and female reproduction. In order to elucidate further the pathophysiological role of the endocannabinoid system in male fertility, we investigated the activity of the CB1 receptor antagonist rimonabant (SR141716) on the fertilizing ability of human sperm. Experimental approach: We evaluated in vitro the effects of rimonabant on motility, survival, capacitation, acrosin activity and metabolism of human sperm. Particularly, capacitation was studied by using three different approaches: intracellular free Ca2+ content assay, cholesterol efflux assay and protein tyrosine phosphorylation analysis. Key results: Rimonabant significantly increased sperm motility and viability through the induction of pAkt and pBcl2, key proteins of cell survival and metabolism, and it induced acrosome reaction and capacitation as well. Rimonabant reduced the triglyceride content of sperm, while enhancing lipase and acyl-CoA dehydrogenase activities, implying an overall lipolytic action in these cells. Rimonabant also affected sperm glucose metabolism by decreasing phosphorylation of glycogen synthase kinase 3 and increasing glucose-6-phosphate dehydrogenase activity, suggesting a role in inducing sperm energy expenditure. Intriguingly, agonism at the CB1 receptor, with an anandamide analogue or a selective inhibitor of fatty acid amide hydrolase, produced opposing effects on human sperm functions. Conclusions and implications: Our data suggest that blockade of the CB1 receptor by rimonabant induces the acquisition of fertilizing ability and stimulates energy expenditure in human sperm.