0000000000267881
AUTHOR
Jarl E. S. Wikberg
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 …
Opposite effects of γ1- and γ2-melanocyte stimulating hormone on regulation of the dopaminergic mesolimbic system in rats
By use of the brain microdialysis technique we show that administration of gamma(1)-melanocyte stimulating hormone (gamma(1)-MSH) into the ventral tegmental area of anaesthetized rats causes an increase in the release of extracellular dopamine and its metabolite 3,4-dihydroxyphenylacetic acid in the nucleus accumbens, while gamma(2)-MSH causes the opposite effect. Moreover, gamma(2)-MSH pre-treatment considerably reduced the gamma(1)-MSH-induced effects. Our findings suggest an opposing action of two gamma-MSH-activated pathways on the mesolimbic dopaminergic system, which could be important in the maintenance of a balanced psychoactivation state.
Subtype selective binding properties of substituted linear melanocyte stimulating hormone analogues
The melanocortin receptors are peptide binding G-protein coupled receptors that play a role in important physiological functions such as energy balance, inflammatory processes and several aspects of reproduction. In this study, we synthesised 11 new linear MSH analogues and tested their binding to the human MC receptors (MC1, MC3, MC4 and MC5) expressed in COS cells. Our results show that introduction of Asp in position 4 similarly affects the binding to the MC1, MC4 and MC5 receptors, but drastically lowers the binding to the MC3 receptor. Arg(5) substitution shows relatively high affinity for the MC4 receptor, while the results also give further support for specific importance of His(6) f…
Pharmacological comparison of rat and human melanocortin 3 and 4 receptors in vitro.
Abstract The melanocortin 3 and 4 receptors are G-protein-coupled receptors found in the hypothalamus with important role in regulation of the energy balance. In this study, we performed pharmacological comparison of the rat and human melancortin (MC) 3 and MC4 receptors. We transiently expressed the genes for these receptors individually in a mammalian cell line and determined the binding affinities to several MSH peptides. The results showed no major difference between the rat and human MC3 receptors while the rat MC4 receptor had higher affinity to several peptides compared with the human MC4 receptor. NDP-, α-, β-, γ-MSH, ACTH(1–24), HS014 and MTII had from 5- to 34-fold higher affinity…
The MC3 receptor binding affinity of melanocortins correlates with the nitric oxide production inhibition in mice brain inflammation model
Melanocortins possess strong anti-inflammatory effects acting in the central nervous system via inhibition of the production of nitric oxide (NO) during brain inflammation. To shed more light into the role of melanocortin (MC) receptor subtypes involved we synthesized and evaluated some novel peptides, modified in the melanocyte-stimulating hormone (MSH) core structure, natural MCs and known MC receptor selective peptides - MS05, MS06. Since the study included both selective, high affinity binders and the novel peptides, it was possible to do the correlation analysis of binding activities and the NO induction-related anti-inflammatory effect of the peptides. beta-MSH, gamma1-MSH, gamma2-MSH…
Effects of alpha-melanotropin C-terminal tripeptide analogues on macrophage NO production.
The C-terminal tripeptide of melanocyte-stimulating hormone, MSH (11-13) (Lys-Pro-Val), possesses strong anti-inflammatory actions, which are mediated via mechanisms that are not fully understood. To shed more light into these mechanisms we have here synthesised and evaluated the activities of L- and D-Val substituted cyclic modifications of MSH (11-13) on nitric oxide (NO) in macrophage RAW 264.7 cells, as well as on binding to melanocortin receptors (MCRs) in B16-F1 and MCR expressing insect cells, and for effects on cAMP. MSH (11-13) and its analogues did neither bind to MCRs nor stimulate cAMP in RAW 264.7 and B16-F1 cells, except H-, which showed a tendency to increase cAMP at high (10…
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 actio…
New Melanocortin 1 Receptor Binding Motif Based on the C-Terminal Sequence of ?-Melanocyte-Stimulating Hormone
The C-terminal tripeptide of the alpha-melanocyte stimulating hormone (alpha-MSH11-13) possesses strong antiinflammatory activity without known cellular target. In order to better understand the structural requirements for function of such motif, we designed, synthesized and tested out Trp- and Tyr-containing analogues of the alpha-MSH11-13. Seven alpha-MSH11-13 analogues were synthesized and characterized for their binding to the melanocortin receptors recombinantly expressed in insect (Sf9) cells, infected with baculovirus carrying corresponding MC receptor DNA. We also tested these analogues on B16-F1 mouse melanoma cells endogenously expressing the MC1 receptor for binding and for abili…
Beta- and gamma-melanocortins inhibit lipopolysaccharide induced nitric oxide production in mice brain.
The pro-opiomelanocortin-derived peptide alpha-melanocyte stimulating hormone (alpha-MSH) mediates many diverse physiological actions, including anti-inflammatory and immunomodulatory effects. However, little is known about the physiological roles of the other melanocortins, beta- and gamma-MSH. Here, we investigated the effects of melanocortin peptides in an in vivo neuroinflammation model. Six hours following intracisternal (i.c.) administration of 10 microg lipopolysaccharide (LPS) to mice a five-fold increase in the nitric oxide (NO) level was seen in the animals' brains, when detected by electron paramagnetic resonance (EPR). All tested melanocortins, alpha-, beta-, gamma1- and gamma2-…