Rimonabant (SR141716) induces metabolism and acquisition of fertilizing ability in human sperm.
OBJECTIVE
The endocannabinoid system and the cannabinoid CB(1) 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 CB(1) receptor antagonist rimonabant (SR141716) on the fertilizing ability of human sperm.


METHODS
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 Ca(2+) content assay, cholesterol efflux assay and protein tyrosine phosphorylation analysis.


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 CB(1) receptor, with an anandamide analogue or a selective inhibitor of fatty acid amide hydrolase, produced opposing effects on human sperm functions.


CONCLUSIONS
Our data suggest that blockade of the CB(1) receptor by rimonabant induces the acquisition of fertilizing ability and stimulates energy expenditure in human sperm.
Aquila
S
S
Department of Pharmaco-Biology, Centro Sanitario, University of Calabria, Italy.
Guido
C
C
Santoro
A
A
Gazzerro
P
P
Laezza
C
C
Baffa
M F
MF
Andò
S
S
Bifulco
M
M
D000176:Acrosin / Q000378:metabolism; D020101:Acrosome Reaction / Q000187:drug effects; D042964:Acyl-CoA Dehydrogenase / Q000378:metabolism; D001095:Arachidonic Acids / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D004734:Energy Metabolism / Q000187:drug effects*; D005306:Fertilization / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D008049:Lipase / Q000378:metabolism; D008297:Male; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077285:Rimonabant; D013075:Sperm Capacitation / Q000187:drug effects; D013081:Sperm Motility / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects* / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D014443:Tyrosine
D001095:Arachidonic Acids; D063388:Endocannabinoids; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D014280:Triglycerides; D014443:Tyrosine; D002784:Cholesterol; D005954:Glucosephosphate Dehydrogenase; D042964:Acyl-CoA Dehydrogenase; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D008049:Lipase; D000176:Acrosin; D005947:Glucose; D000077285:Rimonabant; D002118:Calcium; C078814:anandamide