Abstract：
Traumatic brain injury (TBI) is a common disease worldwide with high mortality and disability rates. Besides the primary mechanical injury, the secondary injury associated with TBI can also induce numerous pathological changes, such as brain edema, nerve apoptosis, and neuroinflammation, which further aggravates neurological dysfunction and even causes the death due to the primary injury. Among them, neuronal apoptosis is a key link in the injury. Melanocortin-1 receptor (MC1R) is a G protein coupled receptor, belonging to the melanocortin receptor family. Studies have shown that activation of MC1R inhibits oxidative stress and apoptosis, and confers neuroprotective effects against various neurological diseases. Merlin is a protein product of the NF2 gene, which is widely expressed in the central nervous system (CNS) of mice, rats, and humans. Studies have indicated that Merlin is associated with MC1R. In this study, we explored the anti-apoptotic effects and potential mechanisms of MC1R. A rat model of TBI was established through controlled cortical impact. The MC1R-specific agonist Nle4-D-Phe7-α-Melanocyte (NDP-MSH) and the inhibitor MSG-606 were employed to explore the effects of MC1R and Merlin following TBI and investigated the associated mechanisms. The results showed that the expression levels of MC1R and Merlin were upregulated after TBI, and activation of MC1R promoted Merlin expression. Further, we found that MC1R activation significantly improved neurological dysfunction and reduced brain edema and neuronal apoptosis induced by TBI in rats. Mechanistically, its neuroprotective function and anti-apoptotic were partly associated with MC1R activation. In conclusion, we demonstrated that MC1R activation after TBI may inhibit apoptosis and confer neuroprotection by upregulating the expression of Merlin.
摘要：
创伤性脑损伤(TBI)是世界范围内的常见疾病,具有很高的死亡率和致残率。除了主要的机械损伤,与TBI相关的继发性损伤也可以引起许多病理变化，比如脑水肿，神经细胞凋亡，和神经炎症，这进一步加剧了神经功能障碍，甚至导致因原发性损伤而死亡。其中,神经元凋亡是损伤的关键环节。黑皮质素-1受体(MC1R)是一种G蛋白偶联受体,属于黑皮质素受体家族。研究表明,MC1R的激活抑制氧化应激和细胞凋亡,并赋予对各种神经系统疾病的神经保护作用。Merlin是NF2基因的蛋白质产物,在小鼠的中枢神经系统（CNS）中广泛表达，老鼠,和人类。研究表明Merlin与MC1R有关。在这项研究中,我们探讨了MC1R的抗凋亡作用和潜在机制。通过控制皮质冲击建立TBI大鼠模型。使用MC1R特异性激动剂Nle4-D-Phe7-α-黑素细胞（NDP-MSH）和抑制剂MSG-606来探索TBI后MC1R和Merlin的作用，并研究相关机制。结果表明，TBI后MC1R和Merlin的表达水平上调，MC1R的激活促进了Merlin的表达。Further,我们发现MC1R激活能显著改善TBI诱导的大鼠神经功能障碍,减轻脑水肿和神经元凋亡。机械上,其神经保护功能和抗凋亡作用部分与MC1R激活有关。总之,我们证明，TBI后MC1R的激活可能通过上调Merlin的表达来抑制细胞凋亡并赋予神经保护作用。
