title: AF-2364 is a prospective spermicide candidate.
abstract: AbstractInhibition of sperm motility has recently become a promising target for male contraceptive development. AF-2364, an analogue of Lonidamine (LND), had a contraceptive effect when orally administered to adult Sprague-Dawley rats. LND can also target mitochondria to inhibit oxygen consumption and block energy metabolism in tumour cells. However, there are no reports of the effects of AF-2364 on human sperm function. Herein we describe the action of AF-2364 on human sperm in vitro, as well as the mechanisms involved. AF-2364 specifically blocked human sperm motility in vitro. Further experiments revealed that AF-2364 can target sperm mitochondrial permeability transition (MPT) pores to induce the loss of sperm mitochondrial membrane potential (DeltaPsim) and decrease ATP generation; however, no significant changes in the cytoskeletal network or the human sperm proteome were detected after exposure to AF-2364. Incubation of AF-2364 with other human or mouse cell lines indicated that the spermicidal effect at the lower concentration was specific. In summary, the spermicidal effect of AF-2364 involves direct action on sperm MPT pores, and this compound should be further investigated as a new spermicide candidate.
authors.affiliation: Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Xiang-Xiang
authors.initials: XX
authors.lastname: Chen
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Wang
authors.forename: Yun-Dong
authors.initials: YD
authors.lastname: Mao
authors.forename: Zuo-Min
authors.initials: ZM
authors.lastname: Zhou
authors.forename: Jia-Hao
authors.initials: JH
authors.lastname: Sha
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D004359:Drug Therapy, Combination; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D029589:Seminal Plasma Proteins / Q000032:analysis; D013081:Sperm Motility / Q000187:drug effects; D013089:Spermatocidal Agents / Q000494:pharmacology*; D013094:Spermatozoa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism
chemical_list: C432482:1-(2,4-dichlorobenzyl)indazole-3-carbohydrazide; D006834:Hydrazines; D007191:Indazoles; D029589:Seminal Plasma Proteins; D013089:Spermatocidal Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; D016572:Cyclosporine; D000255:Adenosine Triphosphate; C022616:thiazolyl blue