Frontiers in Pharmacology · Published 2026-08-05 · DOI 10.3389/fphar.2026.1895800
Shanglan Qu, Xin Peng, Jieyu Ji, Ershu He, Le Jiang, Ruixue Ma, Hanwei Li, Yanjiao Li, Lijuan Li, Hui-Yin Yow, Sharina Hamzah, Zhiting Gong
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.
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Qu, S., Peng, X., Ji, J., et al. (2026). NDP-MSH rescues LPS-induced neuroinflammation, synaptic deficits, and depressive-like behaviors in mice: involvement of MC1R–cAMP/PKA signaling. Frontiers in Pharmacology. https://doi.org/10.3389/fphar.2026.1895800