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.
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RO27-3225 激活黑皮质素受体 4 通过 AMPK/JNK/p3 8 MAPK 通路减轻小鼠脑出血后的神经炎症
DOI：
10.1186/s12974-018-1140-6
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发表时间：
2018-04-11
影响因子：
9.3
通讯作者：
Zhang JH
中科院分区：
文献类型：
--
作者：
Chen S;Zhao L;Sherchan P;Ding Y;Yu J;Nowrangi D;Tang J;Xia Y;Zhang JH
神经炎症在脑出血（ICH）致继发性脑损伤的发病机制中起重要作用。黑素皮质素受体4 （MC4R）的激活已被证明在许多疾病中引起抗炎作用。本研究旨在探讨MC4R激活在小鼠ICH模型神经炎症中的作用，并探讨单磷酸腺苷活化蛋白激酶(AMPK)/c-Jun n末端激酶(JNK)/p38丝裂原活化蛋白激酶（p38 MAPK）通路在MC4R介导的保护中的作用。成年雄性CD1小鼠（n = 189）分别接受骨腔内注射细菌胶原酶或假手术。选择性MC4R激动剂RO27-3225于胶原酶注射后1 h腹腔注射。在RO27-3225治疗之前使用特异性MC4R拮抗剂HS024和选择性AMPK抑制剂dorsomorphin来阐明潜在的机制。进行短期和长期神经行为评估、脑含水量、免疫荧光染色和western blot。MC4R和p-AMPK的表达在ICH后增加，并在24 h达到峰值。MC4R在小胶质细胞、神经元和星形胶质细胞中表达。RO27-3225激活MC4R可改善脑出血后神经行为功能，减少脑水肿，抑制小胶质细胞/巨噬细胞活化和中性粒细胞浸润。RO27-3225增加了MC4R和p-AMPK的表达，降低了p-JNK、p-p38 MAPK、TNF-α和IL-1β的表达，与MC4R和AMPK的抑制相反。我们的研究表明，RO27-3225激活MC4R通过ampk依赖性抑制JNK和p38 MAPK信号通路来减轻神经炎症，从而减轻实验性脑出血小鼠脑水肿，改善神经行为功能。因此，用RO27-3225激活MC4R可能是脑出血治疗的一种潜在治疗方法。本文的在线版本（10.1186/s12974-018-1140-6）包含补充材料，可供授权用户使用。
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. 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. 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. 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. The online version of this article (10.1186/s12974-018-1140-6) contains supplementary material, which is available to authorized users.
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影响因子：
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作者：
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