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Abstract
BackgroundNeuroinflammation 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.MethodsAdult 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.ResultsThe 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.ConclusionsOur 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.
Highlights
Neuroinflammation plays an important role in the pathogenesis of intracerebral hemorrhage (ICH)-induced secondary brain injury
Blood products, and thrombin can initiate inflammatory cell activation which contributes to neuroinflammation, a major contributor to secondary brain injury after ICH that results in brain edema, disruption of the blood-brain barrier, and cell death [2, 3]
The results showed that the expression of Melanocortin receptor 4 (MC4R) and phosphorylated Adenosine monophosphateactivated protein kinase (AMPK) increased as early as 3 h, reached the peak at 24 h, and decreased at 72 h after ICH (p < 0.05, Fig. 1a, b)
Summary
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. Blood products, and thrombin can initiate inflammatory cell activation which contributes to neuroinflammation, a major contributor to secondary brain injury after ICH that results in brain edema, disruption of the blood-brain barrier, and cell death [2, 3]. Numerous studies have demonstrated the critical role of inflammation in ICH-induced secondary brain injury, including microglia/macrophage activation and neutrophil infiltration [4,5,6]. The potential role of MC4R activation against neuroinflammation after ICHinduced brain injury still has not been studied
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