title: Testicular toxicity induced by a triple neurokinin receptor antagonist in male dogs.
abstract: Mechanism mediating the testicular toxicity induced by CS-003, a triple neurokinin receptor antagonist, was investigated in male dogs. Daily CS-003 administrations showed testicular toxicity, such as a decrease in the sperm number, motility and prostate weight; and an increase in sperm abnormality, accompanying histopathological changes in the testis, epididymis and prostate. A single CS-003 administration suppressed plasma testosterone and LH levels in intact and castrated males. The suppressed LH release was restored by GnRH agonist injection, suggesting that pituitary sensitivity to GnRH is not impaired by CS-003. Treatment with SB223412, a neurokinin 3 receptor antagonist, caused a similar effect to CS-003, such as toxicity in the testis, prostate and epididymis and decreased plasma level of LH and testosterone. In conclusion, CS-003-induced testicular toxicity is caused by the inhibition of neurokinin B/neurokinin 3 receptor signaling probably at the hypothalamic level in male dogs.
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co. Ltd., 717 Horikoshi, Fukuroi, Shizuoka 437-0065, Japan. noritake.ken-ichi.rm@daiichisankyo.co.jp
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Noritake
authors.forename: Junko
authors.initials: J
authors.lastname: Suzuki
authors.forename: Toshiki
authors.initials: T
authors.lastname: Matsuoka
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Makino
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ohnishi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shimomura
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Uenoyama
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tsukamura
authors.forename: Kei-Ichiro
authors.initials: K
authors.lastname: Maeda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sanbuissho
mesh_terms: D000818:Animals; D003499:Cyclic S-Oxides / Q000633:toxicity*; D004285:Dogs; D005640:Follicle Stimulating Hormone / Q000097:blood; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D009025:Morpholines / Q000633:toxicity*; D015287:Neurokinin B / Q000378:metabolism; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D011467:Prostate / Q000187:drug effects / Q000473:pathology; D011804:Quinolines / Q000633:toxicity; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013076:Sperm Count; D013081:Sperm Motility / Q000187:drug effects; D013091:Spermatogenesis / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013737:Testis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013739:Testosterone / Q000097:blood; D013997:Time Factors
chemical_list: C530698:1-(2-(2-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl)ethyl)spiro(benzo(c)thiophene-1(3H),4'-piperidine)-2-oxide; D003499:Cyclic S-Oxides; D009025:Morpholines; D011804:Quinolines; D018042:Receptors, Neurokinin-3; D018039:Receptors, Tachykinin; C106716:SB 223412; D013739:Testosterone; D015287:Neurokinin B; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone