Energetic metabolism and human sperm motility: impact of CB₁ receptor activation.
It has been reported that the endocannabinoid anandamide (AEA) exerts an adverse effect on human sperm motility, which has been ascribed to inhibition of mitochondrial activity. This seems to be at variance with evidence suggesting a major role of glycolysis in supplying ATP for sperm motility; furthermore, the role of AEA-binding receptors in mediating mitochondrial inhibition has not yet been explored. In this study, human sperm exposure to Met-AEA (methanandamide, nonhydrolyzable analog of AEA) in the micromolar range significantly decreased mitochondrial transmembrane potential (ΔΨm), similarly to rotenone, mitochondrial complex I inhibitor. The effect of Met-AEA (1 μm) was prevented by SR141716, CB(1) cannabinoid receptor antagonist, but not by SR144528, CB(2) antagonist, nor by iodoresiniferatoxin, vanilloid receptor antagonist. The effect of Met-AEA did not involve activation of caspase-9 or caspase-3 and was reverted by washing. In the presence of glucose, sperm exposure either to Met-AEA up to 1 μm or to rotenone for up to 18 h did not affect sperm motility. At higher doses Met-AEA produced a CB(1)-independent poisoning of spermatozoa, reducing their viability. Under glycolysis blockage, 1 μm Met-AEA, similarly to rotenone, dramatically abolished sperm motility, an effect that was prevented by SR1 and reverted by washing. In conclusion, CB(1) activation induced a nonapoptotic decrease of ΔΨm, the detrimental reflection on sperm motility of which could be revealed only under glycolysis blockage, unless very high doses of Met-AEA, producing CB(1)-independent sperm toxicity, were used. The effects of CB(1) activation reported here contribute to elucidate the relationship between energetic metabolism and human sperm motility.
Barbonetti
A
A
Department of Internal Medicine, University of L'Aquila, L'Aquila, Italy.
Vassallo
M R C
MR
Fortunato
D
D
Francavilla
S
S
Maccarrone
M
M
Francavilla
F
F
D001892:Camphanes / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000077285:Rimonabant; D012402:Rotenone / Q000008:administration & dosage / Q000494:pharmacology; D013081:Sperm Motility / Q000502:physiology*; D013094:Spermatozoa / Q000378:metabolism*; D014475:Uncoupling Agents / Q000008:administration & dosage / Q000494:pharmacology
D001892:Camphanes; D004224:Diterpenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C110630:SR 144528; D014475:Uncoupling Agents; C468130:iodoresiniferatoxin; D012402:Rotenone; D005947:Glucose; D000077285:Rimonabant