Zhao Lei, Liu Haixiao, Yue Liang, Zhang Jingbo, Li Xia, Wang Bodong, Lin Yan, Qu Yan
Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
Department of Scientific Research, The Fourth Military Medical University, Xi'an, China.
Mol Neurobiol. 2017 Apr;54(3):1612-1621. doi: 10.1007/s12035-016-9776-7. Epub 2016 Feb 11.
Melatonin (Mel) has been reported to alleviate early brain injury (EBI) following subarachnoid hemorrhage (SAH). The activation of silent information regulator 1 (Sirt1), a histone deacetylase, has been suggested to be beneficial in SAH. However, the precise role of Sirt1 in Mel-mediated protection against EBI following SAH has not been elucidated. The present study aims to evaluate the role of melatonin receptor/Sirt1/nuclear factor-kappa B (NF-κB) in this process. The endovascular perforation SAH model was used in male C57BL/6J mice, and melatonin was administrated intraperitoneally (150 mg/kg). The mortality, SAH grade, neurological score, brain water content, and neuronal apoptosis were evaluated. The expression of Sirt1, acetylated-NF-κB (Ac-NF-κB), Bcl-2, and Bax were detected by western blot. To study the underlying mechanisms, melatonin receptor (MR) antagonist luzindole and Sirt1 small interfering RNA (siRNA) were administrated to different groups. The results suggest that Mel improved the neurological deficits and reduced the brain water content and neuronal apoptosis. In addition, Mel enhanced the expression of Sirt1 and Bcl-2 and decreased the expression of Ac-NF-κB and Bax. However, the protective effects of Mel were abolished by luzindole or Sirt1 siRNA. In conclusion, our results demonstrate that Mel attenuates EBI following SAH via the MR/Sirt1/NF-κB signaling pathway.
据报道，褪黑素（Mel）可减轻蛛网膜下腔出血（SAH）后的早期脑损伤（EBI）。沉默信息调节因子1（Sirt1）作为一种组蛋白去乙酰化酶，其激活已被认为对SAH有益。然而，Sirt1在Mel介导的SAH后EBI保护中的具体作用尚未阐明。本研究旨在评估褪黑素受体/Sirt1/核因子-κB（NF-κB）在这一过程中的作用。采用血管内穿刺SAH模型，对雄性C57BL/6J小鼠进行实验，腹腔注射褪黑素（150 mg/kg）。评估小鼠的死亡率、SAH分级、神经功能评分、脑含水量和神经元凋亡情况。通过蛋白质免疫印迹法检测Sirt1、乙酰化NF-κB（Ac-NF-κB）、Bcl-2和Bax的表达。为了研究潜在机制，对不同组小鼠分别给予褪黑素受体（MR）拮抗剂鲁辛朵和Sirt1小干扰RNA（siRNA）。结果表明，Mel改善了神经功能缺损，降低了脑含水量和神经元凋亡。此外，Mel增强了Sirt1和Bcl-2的表达，降低了Ac-NF-κB和Bax的表达。然而，鲁辛朵或Sirt1 siRNA消除了Mel的保护作用。总之，我们的结果表明，Mel通过MR/Sirt1/NF-κB信号通路减轻SAH后的EBI。
