Beta-MSH inhibits brain inflammation via MC(3)/(4) receptors and impaired NF-kappaB signaling.
The anti-inflammatory effects of melanocortin peptides have been demonstrated in different inflammation models. This is the first report describing the molecular mechanisms for the beta-MSH-induced suppression of bacterial lipopolisaccharide (LPS)-caused brain inflammation. We found that beta-MSH suppresses LPS-induced nuclear translocation of the transcription factor NF-kappaB, and inhibits the expression of inducible nitric oxide synthase, and the following nitric oxide overproduction in the brain, in vivo. Moreover, administering the preferentially MC(4) receptor selective antagonist HS014 blocked completely these effects, suggesting a tentative MC(4) receptor mediated mechanism of action for the beta-MSH. However, as HS014 shows quite low selectivity vis-à-vis the MC(3) receptor, a role for the MC(3) receptor cannot be excluded. In conclusion, our results show that beta-MSH is capable of inhibiting brain inflammation via activation of melanocortin receptors, of the subtypes 4 and/or 3.
Muceniece
Ruta
R
Faculty of Medicine, University of Latvia, Sarlotes St. 1a, Riga, LV-1001, Latvia. rutam@latnet.lv
Zvejniece
Liga
L
Kirjanova
Olga
O
Liepinsh
Edgars
E
Krigere
Liga
L
Vilskersts
Reinis
R
Baumane
Larisa
L
Gordjusina
Valentina
V
Kalvinsh
Ivars
I
Wikberg
Jarl E S
JE
Dambrova
Maija
M
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004660:Encephalitis / Q000139:chemically induced / Q000188:drug therapy*; D006728:Hormones / Q000627:therapeutic use*; D007120:Immunochemistry / Q000379:methods; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D044104:Receptor, Melanocortin, Type 3 / Q000502:physiology*; D044105:Receptor, Melanocortin, Type 4 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D019824:beta-MSH / Q000627:therapeutic use*
C116098:HS 024; D006728:Hormones; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010456:Peptides, Cyclic; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D019824:beta-MSH; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II