title: Modulation of γ2-MSH hepatoprotection by antisense peptides and melanocortin subtype 3 and 4 receptor antagonists.
abstract: Melanocortins, i.e., melanocyte stimulating hormones (MSH) are peptides with strong antiinflammatory effects. The most investigated aspects of γ2-MSH are related to cardiovascular effects and natriuresis, with limited research available about its anti-inflammatory and cytoprotective effects. The aims of this study were: 1) to examine the effects of γ2-MSH and its derivative [D-Trp(8)]-γ2-MSH on the acetaminophen model of liver damage in CBA mice; 2) to evaluate the modulation of γ2-MSH hepatoprotection by melanocortin subtypes 3 and 4 receptor antagonists SHU 9119 and HS 024; 3) to define the importance of central MSH pharmacophore region (HFRW) by using antisense peptides LVKAT and VKAT. In this study, specific antagonists and antisense peptides were used to target central pharmacophore region of γ2-MSH and [D-Trp(8)]-γ2-MSH, enabling the evaluation of hepatoprotection from the standpoint of the receptor and pharmacophore blockade. The criteria for monitoring the effects of the hormones on the liver damage were alanine transaminase, aspartate transaminase activities (U/L), and pathohistological scoring of liver necrosis (scale 0-5). γ2-MSH (0.24 mg/kg) indicated hepatoprotective effects in comparison to control (p < 0.001). In contrast, [D-Trp(8)]-γ2-MSH did not show any hepatoprotective effects. Application of antagonists SHU 9119 and HS 024, and antisense peptides LVKAT and VKAT, also did not show any hepatoprotective effects. In fact, when combined with γ2-MSH, it annulled its hepatoprotective effect. The results provide evidence for hepatoprotective and antiinflammatory effects of the γ2-MSH in the liver.
authors.forename: Petra
authors.initials: P
authors.lastname: Turcic
authors.affiliation: Ruder Boskovic Institute, Bijenicka cesta 54, 10002 Zagreb, Croatia. stambuk@irb.hr.
authors.forename: Nikola
authors.initials: N
authors.lastname: Stambuk
authors.forename: Pasko
authors.initials: P
authors.lastname: Konjevoda
authors.forename: Tomislav
authors.initials: T
authors.lastname: Kelava
authors.forename: Mario
authors.initials: M
authors.lastname: Gabricevic
authors.forename: Ranko
authors.initials: R
authors.lastname: Stojkovic
authors.forename: Gorana
authors.initials: G
authors.lastname: Aralica
mesh_terms: D000082:Acetaminophen; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008808:Mice, Inbred CBA; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D044104:Receptor, Melanocortin, Type 3 / Q000037:antagonists & inhibitors*; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C116098:HS 024; D016376:Oligonucleotides, Antisense; D010456:Peptides, Cyclic; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; C103272:SHU 9119; D000082:Acetaminophen; D009074:Melanocyte-Stimulating Hormones