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Cited by 122Intracerebral and Subarachnoid Hemorrhage ResearchNeuroinflammation and Neurodegeneration MechanismsTraumatic Brain Injury and Neurovascular Disturbances

Activation of melanocortin receptor 4 with RO27-3225 attenuates neuroinflammation through AMPK/JNK/p38 MAPK pathway after intracerebral hemorrhage in mice

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Chen, Shengpan, Zhao, Lianhua, Sherchan, Prativa, Ding, Yan, Yu, Jing, Nowrangi, Derek, Tang, Jiping, Xia, Ying +1 more·2018·Journal of Neuroinflammation
DOI 10.1186/s12974-018-1140-6PMC PMC5896146
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Abstract

BACKGROUND: Neuroinflammation plays an important role in the pathogenesis of intracerebral hemorrhage (ICH)-induced secondary brain injury. Activation of melanocortin receptor 4 (MC4R) has been shown to elicit anti-inflammatory effects in many diseases. The objective of this study was to explore the role of MC4R activation on neuroinflammation in a mouse ICH model and to investigate the contribution of adenosine monophosphate-activated protein kinase (AMPK)/c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (p38 MAPK) pathway in MC4R-mediated protection. METHODS: Adult male CD1 mice (n = 189) were subjected to intrastriatal injection of bacterial collagenase or sham surgery. The selective MC4R agonist RO27-3225 was administered by intraperitoneal injection at 1 h after collagenase injection. The specific MC4R antagonist HS024 and selective AMPK inhibitor dorsomorphin were administered prior to RO27-3225 treatment to elucidate potential mechanism. Short- and long-term neurobehavioral assessments, brain water content, immunofluorescence staining, and western blot were performed. RESULTS: The expression of MC4R and p-AMPK increased after ICH with a peak at 24 h. MC4R was expressed by microglia, neurons, and astrocytes. Activation of MC4R with RO27-3225 improved the neurobehavioral functions, decreased brain edema, and suppressed microglia/macrophage activation and neutrophil infiltration after ICH. RO27-3225 administration increased the expression of MC4R and p-AMPK while decreasing p-JNK, p-p38 MAPK, TNF-α, and IL-1β expression, which was reversed with inhibition of MC4R and AMPK. CONCLUSIONS: Our study demonstrated that activation of MC4R with RO27-3225 attenuated neuroinflammation through AMPK-dependent inhibition of JNK and p38 MAPK signaling pathway, thereby reducing brain edema and improving neurobehavioral functions after experimental ICH in mice. Therefore, the activation of MC4R with RO27-3225 may be a potential therapeutic approach for ICH management.

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  • CREB activation and JNK inhibition are involved in the anti-inflammatory and neuroprotective action of melanocortins in models of ischemic and inflammatory processes in the brain.

    “It should be noted that CREB activation and JNK inhibition are involved in the anti-inflammatory and neuroprotective action of melanocortins in models of ischemic and inflammatory processes in the brain [4,60].”

    From Brain Protein Expression Profile Confirms the Protective Effect of the ACTH(4–7)PGP Peptide (Semax) in a Rat Model of Cerebral Ischemia–Reperfusion (2021) · cites this paper as [60]

    The Discussion (page unavailable) reports that RO27-3225 reduced phosphorylated JNK and inflammatory cytokines and improved neurobehavioral outcomes after intracerebral hemorrhage in mice. The Background also discusses protective effects in cerebral ischemia, but the paper does not identify CREB activation as a mechanism; its proposed pathway involves AMPK, JNK, and p38 MAPK. (LLM, conf=0.88)

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Cited by

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Authors
Chen, S., Zhao, L., Sherchan, P., Ding, Y., Yu, J., Nowrangi, D., Tang, J., Xia, Y., & Zhang, J. H.
Affiliations
  • Central South University (CN)
  • Loma Linda University (US)
  • Loma Linda University Medical Center (US)
Corresponding author
  • Xia, Ying
  • Zhang, John H.
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2018-04-11
Volume
15
Issue
1
Pages
106-106
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-018-1140-6
PMC
PMC5896146
OpenAlex
W2800963290
Cited by
122
References
2
Citations by year
2026: 5 · 2025: 10 · 2024: 21 · 2023: 9 · 2022: 18 · 2021: 17 · 2020: 24 · 2019: 14 · 2018: 3
FWCI
9.85
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute of Neurological Disorders and Stroke (NS091042, NS082184)
Topics
  • Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
Keywords
intracerebral hemorrhage, neuroinflammation, AMPK, JNK, p38 MAPK, secondary brain injury, microglial activation, cerebral edema, neurobehavioral recovery, TNF-α, IL-1β, collagenase-induced hemorrhage
MeSH terms
Animals, Anti-Inflammatory Agents, Brain Edema, Calcium-Binding Proteins, Cerebral Hemorrhage, Disease Models, Animal, Encephalitis, Enzyme Inhibitors, Gene Expression Regulation, Macrophages, Male, Microfilament Proteins, Peptides, Time Factors, Signal Transduction, Microglia, Neutrophil Infiltration, Receptor, Melanocortin, Type 4, p38 Mitogen-Activated Protein Kinases, MAP Kinase Kinase 4, Mice, AMP-Activated Protein Kinases

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