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.
- 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].
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.