Department of Neurosurgery, Affiliated Haikou Hospital, Xiangya School of Medicine, Central South University, Haikou, 570208, China.
Department of Physiology and Pharmacology, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA.
J Neuroinflammation. 2018 Apr 11;15(1):106. doi: 10.1186/s12974-018-1140-6.
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.
神经炎症在脑出血（ICH）继发性脑损伤的发病机制中起重要作用。激活黑皮质素受体 4（MC4R）已被证明在许多疾病中具有抗炎作用。本研究旨在探讨 MC4R 激活在小鼠 ICH 模型中的神经炎症中的作用，并研究腺苷酸活化蛋白激酶（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）接受纹状体注射细菌胶原酶或假手术。胶原酶注射后 1 小时，通过腹腔内注射选择性 MC4R 激动剂 RO27-3225。在 RO27-3225 治疗前给予特异性 MC4R 拮抗剂 HS024 和选择性 AMPK 抑制剂 dorsomorphin，以阐明潜在机制。进行短期和长期神经行为评估、脑水含量、免疫荧光染色和 Western blot。
ICH 后 MC4R 和 p-AMPK 的表达增加，24 小时达到峰值。MC4R 由小胶质细胞、神经元和星形胶质细胞表达。用 RO27-3225 激活 MC4R 可改善 ICH 后的神经功能，减少脑水肿，并抑制小胶质细胞/巨噬细胞活化和中性粒细胞浸润。RO27-3225 给药增加 MC4R 和 p-AMPK 的表达，同时降低 p-JNK、p-p38 MAPK、TNF-α和 IL-1β 的表达，而 MC4R 和 AMPK 的抑制则逆转了这一作用。
本研究表明，用 RO27-3225 激活 MC4R 通过 AMPK 依赖性抑制 JNK 和 p38 MAPK 信号通路减轻神经炎症，从而减少实验性 ICH 后小鼠的脑水肿和改善神经功能。因此，用 RO27-3225 激活 MC4R 可能是 ICH 治疗的一种潜在治疗方法。
