title: Melanocortin 4 receptor activation protects against testicular ischemia-reperfusion injury by triggering the cholinergic antiinflammatory pathway.
abstract: Melanocortins (MC) trigger a vagus nerve-mediated cholinergic-antiinflammatory pathway projecting to the testis. We tested whether pharmacological activation of brain MC receptors might protect the testis from the damage induced by ischemia-reperfusion. Adult male rats were subjected to 1-h testicular ischemia, followed by 24-h reperfusion [testicular ischemia-reperfusion (TI/R)]. Before TI/R, groups of animals were subjected to bilateral cervical vagotomy, or pretreated with the nicotinic acetylcholine receptor antagonist chlorisondamine or the selective MC(4) receptor antagonist HS024. Immediately after reperfusion, rats were ip treated with saline or the MC analog [Nle(4),D-Phe(7)]α-melanocyte-stimulating hormone (NDP-α-MSH) (340 μg/kg). We evaluated testicular IL-6 and TNF-α by Western blot analysis and organ damage by light microscopy. Some experimental groups were prepared for neural efferent activity recording along the vagus nerve starting 30 min after treatment with NDP-α-MSH or saline, and for a 30-min period. Additional groups of TI/R rats were treated for 30 d with saline, NDP-α-MSH, chlorisondamine plus NDP-α-MSH, or HS024 plus NDP-α-MSH to evaluate spermatogenesis, organ damage, and the apoptosis machinery. After a 24-h reperfusion, in TI/R saline-treated rats, there was an increase in IL-6 and TNF-α expression and a marked damage in both testes. NDP-α-MSH inhibited IL-6 and TNF-α expression, decreased histological damage, and increased neural efferent activity. Furthermore, NDP-α-MSH administration for 30 d greatly improved spermatogenesis, reduced organ damage, and inhibited apoptosis. All positive NDP-α-MSH effects were abrogated by vagotomy, chlorisondamine, or HS024. Our data suggest that selective MC(4) receptor agonists might be therapeutic candidates for the management of testicular torsion.
authors.affiliation: Section of Pharmacology, Department of Experimental and Clinical Medicine and Pharmacology, University of Messina, 98125 Messina, Italy.
authors.forename: Letteria
authors.initials: L
authors.lastname: Minutoli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bitto
authors.forename: Francesco
authors.initials: F
authors.lastname: Squadrito
authors.forename: Natasha
authors.initials: N
authors.lastname: Irrera
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Rinaldi
authors.forename: Piero Antonio
authors.initials: PA
authors.lastname: Nicotina
authors.forename: Salvatore
authors.initials: S
authors.lastname: Arena
authors.forename: Carlo
authors.initials: C
authors.lastname: Magno
authors.forename: Herbert
authors.initials: H
authors.lastname: Marini
authors.forename: Luca
authors.initials: L
authors.lastname: Spaccapelo
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ottani
authors.forename: Daniela
authors.initials: D
authors.lastname: Giuliani
authors.forename: Carmelo
authors.initials: C
authors.lastname: Romeo
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guarini
authors.forename: Pietro
authors.initials: P
authors.lastname: Antonuccio
authors.forename: Domenica
authors.initials: D
authors.lastname: Altavilla
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D007249:Inflammation / Q000517:prevention & control*; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D015427:Reperfusion Injury / Q000517:prevention & control*; D013091:Spermatogenesis / Q000187:drug effects; D013737:Testis / Q000098:blood supply* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014630:Vagus Nerve / Q000502:physiology*; D000521:alpha-MSH / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D015850:Interleukin-6; D044105:Receptor, Melanocortin, Type 4; D014409:Tumor Necrosis Factor-alpha; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-