Title

 

Authors

L. Minutoli¹, D. Altavilla¹ , A. Bitto¹, P. Antonuccio², N. Irrera¹, C. Romeo², A.P. Caputi¹ and F. Squadrito¹
 

¹Dept. of Experimental and Clinical Medicine and Pharmacology, Section of Pharmacology, School of Medicine, University of Messina, Italy

²Dept of Medical and Surgical Pediatric Sciences, School of Medicine, University of Messina, Italy

 

 

Abstract

Vagus nerve innervates the testis. Melanocortins trigger a vagus nerve-mediated cholinergic-anti-inflammatory pathway, by acting at brain melanocortin receptors. We tested whether pharmacological activation of brain melanocortin 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 (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 melanocortin MC₄ receptor antagonist HS024. Immediately after reperfusion, rats were ip treated with saline or the melanocortin analog [Nle⁴,D-Phe⁷]α-melanocyte-stimulating hormone (NDP-α-MSH, 340 µg/kg). We evaluated testicular IL-6 and TNF-α by Western Blot, 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 days 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. Following 24-h reperfusion, in TI/R saline-treated rats there was a 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 days 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 MC₄ receptor agonists might be therapeutic candidates for the management of testicular torsion.