Functional evaluation of THIQ, a melanocortin 4 receptor agonist, in models of food intake and inflammation.
The central melanocortinergic system plays an important role in regulating different aspects of energy homeostasis and the immunomodulatory response. In the present study, we evaluated the in vivo activities of food intake suppression and anti-inflammatory activity of THIQ, which has been proposed to possess high and selective melanocortin-4 receptor agonistic activity in vitro. The results showed that THIQ (0.1, 0.3 and 1 nmol/rat, intracerebroventricularly) is less effective in reducing food intake and body weights of rats than the non-selective melanocortin receptor agonist melanotan II. Electron paramagnetic resonance measurements in mice brain tissue showed that THIQ at doses of 0.001 and 0.01 nmol/mouse (intracisternally) increased the concentration of nitric oxide, which is not typical for melanocortin receptor agonists. In an experimental brain inflammation model, THIQ only weakly antagonized lipopolysaccharide-induced nitric oxide overproduction in brain tissue at a dose of 0.01 nmol/mouse. Our findings provide new insight into the in vivo pharmacological profile of the in vitro selective melanocortin-4 receptor agonist THIQ and give grounds for caution when interpreting and predicting melanocortin receptor selective agonist activity in vivo.
Muceniece
Ruta
R
Faculty of Medicine, University of Latvia, Riga, Latvia.
Zvejniece
Liga
L
Vilskersts
Reinis
R
Liepinsh
Edgars
E
Baumane
Larisa
L
Kalvinsh
Ivars
I
Wikberg
Jarl E
JE
Dambrova
Maija
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects*; D004578:Electron Spin Resonance Spectroscopy; D007249:Inflammation / Q000188:drug therapy*; D007276:Injections, Intraventricular; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009569:Nitric Oxide / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists*; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*; D000521:alpha-MSH / Q000031:analogs & derivatives / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; C467221:N-(1,2,3,4-tetrahydroisoquinolinium-3-ylcarbonyl)-1-(4-chlorobenzyl)-2-(4-cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl)piperidin-1-yl)-2-oxoethylamine; D010456:Peptides, Cyclic; D044105:Receptor, Melanocortin, Type 4; D044005:Tetrahydroisoquinolines; D014230:Triazoles; C079282:melanotan-II; D009569:Nitric Oxide; D000521:alpha-MSH