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-Trp8]-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-Trp8]-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-Trp8]-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.