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

Overview

1. School of Pharmacy, Faculty of Health and Medical Sciences, Taylor’s University, Subang Jaya, Selangor, Malaysia
2. School of Medicine, Dali University, Dali, Yunnan, China
3. School of Medicine, Xinjiang College of Science and Technology, Korla, China
4. Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur, Malaysia

Abstract

Introduction: Inflammatory 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.

Methods: Systemic 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).

Results: LPS 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.

Conclusion: This 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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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• doi:10.17632/8rsxrhfp68.1, at the source; found in “Data availability statement”

Data availability statement

The untargeted metabolomics datasets generated and analyzed during the current study are publicly available in the Mendeley Data repository at https://data.mendeley.com/ with the DOI:10.17632/8rsxrhfp68.1 (https://doi.org/10.17632/8rsxrhfp68.1).

Reproduced under the paper's license (CC BY), from the paper cited above.

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Recorded: type, language, journal, volume, pages, dates, 12 authors, 5 keywords, 1 funder, 57 references.

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This paper

Qu, S., Peng, X., Ji, J., He, E., Jiang, L., Ma, R., Li, H., Li, Y., Li, L., Yow, H.-Y., Hamzah, S., & Gong, Z. (2026). NDP-MSH rescues LPS-induced neuroinflammation, synaptic deficits, and depressive-like behaviors in mice: involvement of MC1R-cAMP/PKA signaling. Frontiers in pharmacology, 17, 1895800. https://doi.org/10.3389/fphar.2026.1895800

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