NDP-MSH rescues LPS-induced neuroinflammation, synaptic deficits, and depressive-like behaviors in mice: involvement of MC1R-cAMP/PKA signaling.

Qu S, Peng X, Ji J, He E, Jiang L, Ma R, Li H, Li Y, Li L, Yow HY, Hamzah S, Gong Z

Frontiers in pharmacology5 Aug 2026

PMID42621255PMCIDPMC13487505DOI10.3389/fphar.2026.1895800PepBankPUB-42621255

Summary

IntroductionInflammatory processes contribute significantly to the pathophysiology of depression. Although the melanocortin system is well known to regulate inflammation, the specific contribution of melanocortin 1 receptor (MC1R) and its endogenous ligand, α-melanocyte-stimulating hormone (α-MSH), to inflammation-associated depression remains unclear.MethodsSystemic lipopolysaccharide (LPS) administration was used to establish an inflammation-associated depression model in mice. Depressive-like behaviors, synaptic functions, and metabolic alterations were evaluated using behavioral tests, patch-clamp recordings, and untargeted metabolomic profiling. To examine the functional involvement of MC1R, adeno-associated virus (AAV)-mediated selective Mc1r overexpression was performed in the medial prefrontal cortex (mPFC).ResultsLPS administration induced depressive-like behaviors in mice, accompanied by microglial activation and a significant reduction in MC1R expression in the prefrontal cortex (PFC). Treatment with MC1R endogenous ligand α-MSH mimetic Nle4-DPhe7-α-MSH (NDP-MSH) markedly attenuated LPS-induced depressive-like behaviors, enhanced MC1R, postsynaptic density protein 95 (PSD95), glutamate receptor 1 (GluA1) and protein kinase A (PKA) phosphorylation. PKA inhibitor H89-mediated inhibition of the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway partially but robustly abolishes the behavioral, anti-inflammatory, and synaptic protective effects of NDP-MSH. Additionally, untargeted metabolomics confirmed that NDP-MSH effectively corrected LPS-induced metabolic dysregulation, a therapeutic effect that was robustly suppressed by H89; this metabolic remodeling was closely associated with purine metabolism, pantothenate, and coenzyme A biosynthesis. Critically, AAV-mediated Mc1r overexpression in the mPFC was sufficient to rescue LPS-induced depressive-like phenotypes.ConclusionThis study highlights MC1R-related signaling in the PFC as an important contributor to inflammation-associated depression and suggests that NDP-MSH alleviates inflammation-associated depressive-like behaviors in association with melanocortin signaling involving MC1R and downstream cAMP/PKA activation.

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

Results from this study11

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

01AnimalAnimal study (in vivo)Efficacy outcome
In mice given lipopolysaccharide, NDP-MSH markedly attenuated depressive-like behaviors.
In plain wordsIn mice with inflammation-linked depression-like behavior, NDP-MSH clearly reduced those behaviors.
Peptide
Melanotan I (afamelanotide)
Outcome
DecreaseLPS-induced depressive-like behaviors
Study
mousen: not reported in source
LPS-induced inflammation-associated depression model
Outcome group
Anxiety and mood · Mental health and mood
Studied dose
Dose not stated
Source sentences
Summary
Treatment with MC1R endogenous ligand α-MSH mimetic Nle4-DPhe7-α-MSH (NDP-MSH) markedly attenuated LPS-induced depressive-like behaviors, enhanced MC1R, postsynaptic density protein 95 (PSD95), glutamate receptor 1 (GluA1) and protein kinase A (PKA) phosphorylation.
1 context sentence(design, population, supporting numbers)
Summary · context
Systemic lipopolysaccharide (LPS) administration was used to establish an inflammation-associated depression model in mice.
Show in the study text Report a problemFND-4262125501
02AnimalAnimal study (in vivo)Mechanism
In mice given lipopolysaccharide, NDP-MSH treatment enhanced MC1R expression.
In plain wordsIn mice given an inflammatory trigger, NDP-MSH raised levels of its target receptor MC1R.
Peptide
Melanotan I (afamelanotide)
Outcome
IncreaseMC1R expression
Study
mousen: not reported in source
LPS-induced inflammation-associated depression model
Outcome group
Receptor activity and mechanism · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
Treatment with MC1R endogenous ligand α-MSH mimetic Nle4-DPhe7-α-MSH (NDP-MSH) markedly attenuated LPS-induced depressive-like behaviors, enhanced MC1R, postsynaptic density protein 95 (PSD95), glutamate receptor 1 (GluA1) and protein kinase A (PKA) phosphorylation.
1 context sentence(design, population, supporting numbers)
Summary · context
Systemic lipopolysaccharide (LPS) administration was used to establish an inflammation-associated depression model in mice.
Show in the study text Report a problemFND-4262125502
03AnimalAnimal study (in vivo)Mechanism
In mice given lipopolysaccharide, NDP-MSH treatment enhanced postsynaptic density protein 95 (PSD95).
In plain wordsIn mice given an inflammatory trigger, NDP-MSH raised a protein that supports brain cell connections.
Peptide
Melanotan I (afamelanotide)
Outcome
IncreasePSD95 expression
Study
mousen: not reported in source
LPS-induced inflammation-associated depression model
Outcome group
Receptor activity and mechanism · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
Treatment with MC1R endogenous ligand α-MSH mimetic Nle4-DPhe7-α-MSH (NDP-MSH) markedly attenuated LPS-induced depressive-like behaviors, enhanced MC1R, postsynaptic density protein 95 (PSD95), glutamate receptor 1 (GluA1) and protein kinase A (PKA) phosphorylation.
1 context sentence(design, population, supporting numbers)
Summary · context
Systemic lipopolysaccharide (LPS) administration was used to establish an inflammation-associated depression model in mice.
Show in the study text Report a problemFND-4262125503
04AnimalAnimal study (in vivo)Mechanism
In mice given lipopolysaccharide, NDP-MSH treatment enhanced glutamate receptor 1 (GluA1).
In plain wordsIn mice given an inflammatory trigger, NDP-MSH raised levels of a brain glutamate receptor.
Peptide
Melanotan I (afamelanotide)
Outcome
IncreaseGluA1 expression
Study
mousen: not reported in source
LPS-induced inflammation-associated depression model
Outcome group
Receptor activity and mechanism · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
Treatment with MC1R endogenous ligand α-MSH mimetic Nle4-DPhe7-α-MSH (NDP-MSH) markedly attenuated LPS-induced depressive-like behaviors, enhanced MC1R, postsynaptic density protein 95 (PSD95), glutamate receptor 1 (GluA1) and protein kinase A (PKA) phosphorylation.
1 context sentence(design, population, supporting numbers)
Summary · context
Systemic lipopolysaccharide (LPS) administration was used to establish an inflammation-associated depression model in mice.
Show in the study text Report a problemFND-4262125504
05AnimalAnimal study (in vivo)Mechanism
In mice given lipopolysaccharide, NDP-MSH treatment enhanced protein kinase A (PKA) phosphorylation.
In plain wordsIn mice given an inflammatory trigger, NDP-MSH increased activation of the PKA signal.
Peptide
Melanotan I (afamelanotide)
Outcome
IncreasePKA phosphorylation
Study
mousen: not reported in source
LPS-induced inflammation-associated depression model
Outcome group
Receptor activity and mechanism · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
Treatment with MC1R endogenous ligand α-MSH mimetic Nle4-DPhe7-α-MSH (NDP-MSH) markedly attenuated LPS-induced depressive-like behaviors, enhanced MC1R, postsynaptic density protein 95 (PSD95), glutamate receptor 1 (GluA1) and protein kinase A (PKA) phosphorylation.
1 context sentence(design, population, supporting numbers)
Summary · context
Systemic lipopolysaccharide (LPS) administration was used to establish an inflammation-associated depression model in mice.
Show in the study text Report a problemFND-4262125505
06AnimalAnimal study (in vivo)Mechanism
In mice given lipopolysaccharide, untargeted metabolomics showed that NDP-MSH corrected LPS-induced metabolic dysregulation.
In plain wordsIn mice given an inflammatory trigger, NDP-MSH corrected changes in body chemistry caused by the trigger.
Peptide
Melanotan I (afamelanotide)
Outcome
Not applicableLPS-induced metabolic dysregulation
Study
mousen: not reported in source
LPS-induced inflammation-associated depression model
Outcome group
Receptor activity and mechanism · Metabolic and weight
Studied dose
Dose not stated
Source sentences
Summary
Additionally, untargeted metabolomics confirmed that NDP-MSH effectively corrected LPS-induced metabolic dysregulation, a therapeutic effect that was robustly suppressed by H89; this metabolic remodeling was closely associated with purine metabolism, pantothenate, and coenzyme A biosynthesis.
1 context sentence(design, population, supporting numbers)
Summary · context
Systemic lipopolysaccharide (LPS) administration was used to establish an inflammation-associated depression model in mice.
Show in the study text Report a problemFND-4262125506

Studies that did not test the peptide alone5

In this study, Melanotan I (afamelanotide) was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Melanotan I (afamelanotide).

07AnimalNot a test of Melanotan I (afamelanotide) aloneAnimal study (in vivo)Mechanism
In mice given lipopolysaccharide, the PKA inhibitor H89 partially but robustly abolished the behavioral effects of NDP-MSH.
In plain wordsIn mice given an inflammatory trigger, blocking the PKA pathway with H89 largely removed the behavioral benefit of NDP-MSH.
Peptide
Melanotan I (afamelanotide)
Outcome
DecreaseH89 block of NDP-MSH behavioral effect
Study
mousen: not reported in source
LPS-induced inflammation-associated depression model
Outcome group
Anxiety and mood · Mental health and mood
Source sentences
Summary
PKA inhibitor H89-mediated inhibition of the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway partially but robustly abolishes the behavioral, anti-inflammatory, and synaptic protective effects of NDP-MSH.
1 context sentence(design, population, supporting numbers)
Summary · context
Systemic lipopolysaccharide (LPS) administration was used to establish an inflammation-associated depression model in mice.
In this study, Melanotan I (afamelanotide) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Melanotan I (afamelanotide).
Show in the study text Report a problemFND-4262125507
08AnimalNot a test of Melanotan I (afamelanotide) aloneAnimal study (in vivo)Mechanism
In mice given lipopolysaccharide, the PKA inhibitor H89 partially but robustly abolished the anti-inflammatory effects of NDP-MSH.
In plain wordsIn mice given an inflammatory trigger, blocking the PKA pathway with H89 largely removed the anti-inflammatory benefit of NDP-MSH.
Peptide
Melanotan I (afamelanotide)
Outcome
DecreaseH89 block of NDP-MSH anti-inflammatory effect
Study
mousen: not reported in source
LPS-induced inflammation-associated depression model
Outcome group
Inflammation markers · Immune and inflammation
Source sentences
Summary
PKA inhibitor H89-mediated inhibition of the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway partially but robustly abolishes the behavioral, anti-inflammatory, and synaptic protective effects of NDP-MSH.
1 context sentence(design, population, supporting numbers)
Summary · context
Systemic lipopolysaccharide (LPS) administration was used to establish an inflammation-associated depression model in mice.
In this study, Melanotan I (afamelanotide) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Melanotan I (afamelanotide).
Show in the study text Report a problemFND-4262125508
09AnimalNot a test of Melanotan I (afamelanotide) aloneAnimal study (in vivo)Mechanism
In mice given lipopolysaccharide, the PKA inhibitor H89 partially but robustly abolished the synaptic protective effects of NDP-MSH.
In plain wordsIn mice given an inflammatory trigger, blocking the PKA pathway with H89 largely removed the brain-connection protection from NDP-MSH.
Peptide
Melanotan I (afamelanotide)
Outcome
DecreaseH89 block of NDP-MSH synaptic protective effect
Study
mousen: not reported in source
LPS-induced inflammation-associated depression model
Outcome group
Neuroprotection · Nervous system and cognition
Source sentences
Summary
PKA inhibitor H89-mediated inhibition of the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway partially but robustly abolishes the behavioral, anti-inflammatory, and synaptic protective effects of NDP-MSH.
1 context sentence(design, population, supporting numbers)
Summary · context
Systemic lipopolysaccharide (LPS) administration was used to establish an inflammation-associated depression model in mice.
In this study, Melanotan I (afamelanotide) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Melanotan I (afamelanotide).
Show in the study text Report a problemFND-4262125509
10AnimalNot a test of Melanotan I (afamelanotide) aloneAnimal study (in vivo)Mechanism
In mice given lipopolysaccharide, the PKA inhibitor H89 robustly suppressed the metabolic correction by NDP-MSH.
In plain wordsIn mice given an inflammatory trigger, blocking the PKA pathway with H89 removed the metabolic correction by NDP-MSH.
Peptide
Melanotan I (afamelanotide)
Outcome
DecreaseH89 block of NDP-MSH metabolic correction
Study
mousen: not reported in source
LPS-induced inflammation-associated depression model
Outcome group
Receptor activity and mechanism · Metabolic and weight
Source sentences
Summary
Additionally, untargeted metabolomics confirmed that NDP-MSH effectively corrected LPS-induced metabolic dysregulation, a therapeutic effect that was robustly suppressed by H89; this metabolic remodeling was closely associated with purine metabolism, pantothenate, and coenzyme A biosynthesis.
1 context sentence(design, population, supporting numbers)
Summary · context
Systemic lipopolysaccharide (LPS) administration was used to establish an inflammation-associated depression model in mice.
In this study, Melanotan I (afamelanotide) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Melanotan I (afamelanotide).
Show in the study text Report a problemFND-4262125510
11AnimalNot a test of Melanotan I (afamelanotide) aloneAnimal study (in vivo)Efficacy outcome
In mice given lipopolysaccharide, AAV-mediated Mc1r overexpression in the medial prefrontal cortex rescued depressive-like phenotypes.
In plain wordsIn mice given an inflammatory trigger, adding extra MC1R gene copies to a brain area reversed depression-like behavior.
Peptide
Melanotan I (afamelanotide)
Outcome
DecreaseMc1r overexpression and depressive-like phenotypes
Study
mousen: not reported in source
LPS-induced inflammation-associated depression model
Outcome group
Anxiety and mood · Mental health and mood
Source sentences
Summary
Critically, AAV-mediated Mc1r overexpression in the mPFC was sufficient to rescue LPS-induced depressive-like phenotypes.
2 context sentences(design, population, supporting numbers)
Summary · context
To examine the functional involvement of MC1R, adeno-associated virus (AAV)-mediated selective Mc1r overexpression was performed in the medial prefrontal cortex (mPFC).
Summary · context
Systemic lipopolysaccharide (LPS) administration was used to establish an inflammation-associated depression model in mice.
In this study, Melanotan I (afamelanotide) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Melanotan I (afamelanotide).
Show in the study text Report a problemFND-4262125511

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

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
13 Oct 2026, 21:44 UTC
Study results updated
Version 1
13 Oct 2026, 16:31 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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Keywords

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