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

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

  • J Neuroinflammation. 2018 Apr 11;15(1):106. doi: 10.1186/s12974-018-1140-6.
Shengpan Chen 1 2,  Lianhua Zhao 2 3,  Prativa Sherchan 2,  Yan Ding 2,  Jing Yu 2,  Derek Nowrangi 2,  Jiping Tang 2,  Ying Xia 4,  John H Zhang 5 6
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Affiliated Haikou Hospital, Xiangya School of Medicine, Central South University, Haikou, 570208, China.
  • 2 Department of Physiology and Pharmacology, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA.
  • 3 Department of Neurology, Tianjin TEDA Hospital, Tianjin, 300457, China.
  • 4 Department of Neurosurgery, Affiliated Haikou Hospital, Xiangya School of Medicine, Central South University, Haikou, 570208, China. [email protected].
  • 5 Department of Physiology and Pharmacology, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA. [email protected].
  • 6 Department of Neurosurgery and Anesthesiology, Loma Linda University Medical Center, Loma Linda, CA, 92354, USA. [email protected].
PMID: 29642894 DOI: 10.1186/s12974-018-1140-6
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.

Keywords

Brain edema; Intracerebral hemorrhage; Melanocortin receptor 4; Neuroinflammation; RO27-3225.

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