Setmelanotide, a Novel, Selective Melanocortin Receptor-4 Agonist Exerts Anti-inflammatory Actions in Astrocytes and Promotes an Anti-inflammatory Macrophage Phenotype.

Kamermans A, Verhoeven T, van Het Hof B, Koning JJ, Borghuis L, Witte M, van Horssen J, de Vries HE, Rijnsburger M

Frontiers in immunology4 Oct 2019Cited by 30 (Europe PMC)

PMID31636637PMCIDPMC6788433DOI10.3389/fimmu.2019.02312PepBankPUB-31636637

Summary

To date, available treatment strategies for multiple sclerosis (MS) are ineffective in preventing or reversing progressive neurologic deterioration, creating a high, and unmet medical need. One potential way to fight MS may be by limiting the detrimental effects of reactive astrocytes, a key pathological hallmark for disease progression. One class of compounds that may exert beneficial effects via astrocytes are melanocortin receptor (MCR) agonists. Among the MCR, MC4R is most abundantly expressed in the CNS and several rodent studies have described that MC4R is-besides neurons-expressed by astrocytes. Activation of MC4R in astrocytes has shown to have potent anti-inflammatory as well as neuroprotective effects in vitro, suggesting that this could be a potential target to ameliorate ongoing inflammation, and neurodegeneration in MS. In this study, we set out to investigate human MC4R expression and analyze its downstream effects. We identified MC4R mRNA and protein to be expressed on astrocytes and observed increased astrocytic MC4R expression in active MS lesions. Furthermore, we show that the novel, highly selective MC4R agonist setmelanotide ameliorates the reactive phenotype in astrocytes in vitro and markedly induced interleukin-6 and -11 production, possibly through enhanced cAMP response element-binding protein (CREB) phosphorylation. Notably, stimulation of human macrophages with medium from astrocytes that were exposed to setmelanotide, skewed macrophages toward an anti-inflammatory phenotype. Taken together, these findings suggest that targeting MC4R on astrocytes might be a novel therapeutic strategy to halt inflammation-associated neurodegeneration in MS.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study5

5 results from studies that gave the peptide. No result from this study comes from people.

01LabIn vitro (cells)Mechanism
In astrocytes in vitro, setmelanotide ameliorated the reactive phenotype.
In plain wordsIn cells, setmelanotide reduced the reactive phenotype of astrocytes.
Peptide
Setmelanotide
Outcome
DecreaseReactive astrocyte phenotype
Study
humann: not reported in source
Astrocytes
Outcome group
Inflammation markers · Immune and inflammation
Studied dose
Dose not stated
Source sentences
Summary
Furthermore, we show that the novel, highly selective MC4R agonist setmelanotide ameliorates the reactive phenotype in astrocytes in vitro and markedly induced interleukin-6 and -11 production, possibly through enhanced cAMP response element-binding protein (CREB) phosphorylation.
Show in the study text Report a problemFND-3163663701
02LabIn vitro (cells)Mechanism
In astrocytes in vitro, setmelanotide markedly increased interleukin-6 production.
In plain wordsIn cells, setmelanotide increased interleukin-6 production in astrocytes.
Peptide
Setmelanotide
Outcome
IncreaseInterleukin-6 production
Study
humann: not reported in source
Astrocytes
Outcome group
Immune response · Immune and inflammation
Studied dose
Dose not stated
Source sentences
Summary
Furthermore, we show that the novel, highly selective MC4R agonist setmelanotide ameliorates the reactive phenotype in astrocytes in vitro and markedly induced interleukin-6 and -11 production, possibly through enhanced cAMP response element-binding protein (CREB) phosphorylation.
Show in the study text Report a problemFND-3163663702
03LabIn vitro (cells)Mechanism
In astrocytes in vitro, setmelanotide markedly increased interleukin-11 production.
In plain wordsIn cells, setmelanotide increased interleukin-11 production in astrocytes.
Peptide
Setmelanotide
Outcome
IncreaseInterleukin-11 production
Study
humann: not reported in source
Astrocytes
Outcome group
Immune response · Immune and inflammation
Studied dose
Dose not stated
Source sentences
Summary
Furthermore, we show that the novel, highly selective MC4R agonist setmelanotide ameliorates the reactive phenotype in astrocytes in vitro and markedly induced interleukin-6 and -11 production, possibly through enhanced cAMP response element-binding protein (CREB) phosphorylation.
Show in the study text Report a problemFND-3163663703
04LabIn vitro (cells)Mechanism
In astrocytes in vitro, setmelanotide effects possibly involved enhanced CREB phosphorylation.
In plain wordsIn cells, setmelanotide effects in astrocytes possibly involved increased CREB phosphorylation.
Peptide
Setmelanotide
Outcome
IncreaseCREB phosphorylation
Study
humann: not reported in source
Astrocytes
Outcome group
Receptor activity and mechanism · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
Furthermore, we show that the novel, highly selective MC4R agonist setmelanotide ameliorates the reactive phenotype in astrocytes in vitro and markedly induced interleukin-6 and -11 production, possibly through enhanced cAMP response element-binding protein (CREB) phosphorylation.
Show in the study text Report a problemFND-3163663704
05LabIn vitro (cells)Mechanism
In human macrophages, medium from setmelanotide-exposed astrocytes promoted an anti-inflammatory phenotype.
In plain wordsIn cells, medium from setmelanotide-exposed astrocytes promoted an anti-inflammatory phenotype in human macrophages.
Peptide
Setmelanotide
Outcome
IncreaseMacrophage anti-inflammatory phenotype
Study
humann: not reported in source
Human macrophages exposed to astrocyte-conditioned medium
Outcome group
Immune response · Immune and inflammation
Studied dose
Dose not stated
Source sentences
Summary
Notably, stimulation of human macrophages with medium from astrocytes that were exposed to setmelanotide, skewed macrophages toward an anti-inflammatory phenotype.
Show in the study text Report a problemFND-3163663705

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Registered trials1

Trials this study reports on, or that list this study as a reference. Registry data from ClinicalTrials.gov.

1 trial · 1 ongoing · source ClinicalTrials.gov (opens in a new tab)

RecruitingPhase 4NCT07674290

Real-World Effects of MC4R Agonist Therapy in BBS and Severe Genetic Obesity

Tom Hühnen = 2001 Jan 2023 to est. 31 Dec 2030

Bardet Biedl Syndrome (BBS) · Bardet Biedl Syndrome · Bardet-Biedl Syndrome (BBS) · Alstrom Syndrome

Trial page ClinicalTrials.govUpdated 29 Jun 2026

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
28 Oct 2026, 02:03 UTC
Study results updated
Version 1
27 Oct 2026, 16:36 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

PepBank is a research reference. Talk to a doctor before you use any peptide.