中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (10): 2232-2237.doi: 10.4103/1673-5374.337049

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

缓激肽可保护心脏骤停恢复自主循环后的海马神经元

  

  • 出版日期:2022-10-15 发布日期:2022-03-16
  • 基金资助:
    福建省卫生技术项目(2018-CX-16);福建省立医院火石基金项目(2020HSJJ17)

Bradykinin postconditioning protects rat hippocampal neurons after restoration of spontaneous circulation following cardiac arrest via activation of the AMPK/mTOR signaling pathway

Shi-Rong Lin1, 2, 3, 4, 5, Qing-Ming Lin1, 3, 4, 5, Yu-Jia Lin1, Xin Qian1, 3, 4, 5, Xiao-Ping Wang1, 3, 4, 5, Zheng Gong1, 3, 4, 5, Feng Chen1, 3, 4, 5, Bin Song6, 7, 8   

  1. 1Provincial College of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian Province, China; 2Department of Emergency, Fujian Provincial Hospital South Branch, Fuzhou, Fujian Province, China; 3Department of Emergency, Fujian Provincial Hospital, Fuzhou, Fujian Province, China; 4Fujian Emergency Medical Center, Fuzhou, Fujian Province, China; 5Fujian Provincial Key Laboratory of Emergency Medicine, Fuzhou, Fujian Province, China; 6Department of Human Anatomy, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, China; 7Key Laboratory of Brain Aging and Neurodegenerative Diseases of Fujian Province, Fuzhou, Fujian Province, China; 8Laboratory of Clinical Applied Anatomy, Fujian Medical University, Fuzhou, Fujian Province, China
  • Online:2022-10-15 Published:2022-03-16
  • Contact: Feng Chen, MD, Cf9066@126.com; Bin Song, PhD, songbin@fjmu.edu.cn.
  • Supported by:
    This study was supported by the Fujian Provincial Health Technology Project of China, No. 2018-CX-16 and Fujian Provincial Hospital Flint Fund Project, No. 2020HSJJ17 (both to SRL)

摘要:

缓激肽是激肽释放酶-激肽系统中的活性物质成分,已被证实具有心脏和神经方面的保护作用;同时作者前期研究也显示缓激肽对心脏骤停后恢复自主循环大鼠海马神经元具有显著的保护作用,但其作用机制尚不明确。为此,实验采用窒息法建立心脏骤停大鼠模型,而后立即进行心肺复苏以恢复自主循环,48h后腹腔注射150 μg/kg缓激肽进行治疗。结果发现,缓激肽可有效促进心脏骤停恢复自主循环大鼠神经功能的恢复,增加海马组织中自噬小体数量,抑制海马神经细胞的凋亡及自噬相关蛋白LC3以及NBR1和凋亡相关蛋白caspase-3的表达,影响AMPK/mTOR信号通路相关蛋白表达。腺苷酸激活蛋白激酶抑制剂复合物C可明显抑制缓激肽对恢复自主循环大鼠自噬的激活作用,加重恢复自主循环的损伤,而哺乳动物雷帕霉素靶蛋白抑制剂雷帕霉素则可通过刺激自噬促进缓激肽对恢复自主循环损伤的保护作用。实验结果显示,缓激肽可通过激活腺苷酸激活蛋白激酶/哺乳动物雷帕霉素靶蛋白信号通路实现对心脏骤停后心肺复苏引起脑损伤的神经保护。

https://orcid.org/0000-0001-9959-482X (Shi-Rong Lin)

关键词: 缓激肽, 自噬, 心脏骤停, 心肺复苏, 恢复自主循环, 雷帕霉素, 复合物C, 海马, 神经元

Abstract: Bradykinin (BK) is an active component of the kallikrein-kinin system that has been shown to have cardioprotective and neuroprotective effects. We previously showed that BK postconditioning strongly protects rat hippocampal neurons upon restoration of spontaneous circulation (ROSC) after cardiac arrest. However, the precise mechanism underlying this process remains poorly understood. In this study, we treated a rat model of ROSC after cardiac arrest (induced by asphyxiation) with 150 μg/kg BK via intraperitoneal injection 48 hours after ROSC following cardiac arrest. We found that BK postconditioning effectively promoted the recovery of rat neurological function after ROSC following cardiac arrest, increased the amount of autophagosomes in the hippocampal tissue, inhibited neuronal cell apoptosis, up-regulated the expression of autophagy-related proteins LC3 and NBR1 and down-regulated p62, inhibited the expression of the brain injury marker S100β and apoptosis-related protein caspase-3, and affected the expression of adenosine monophosphate-activated protein kinase/mechanistic target of rapamycin pathway-related proteins. Adenosine monophosphate-activated protein kinase inhibitor compound C clearly inhibited BK-mediated activation of autophagy in rats after ROSC following cardiac arrest, which aggravated the injury caused by ROSC. The mechanistic target of rapamycin inhibitor rapamycin enhanced the protective effects of BK by stimulating autophagy. Our findings suggest that BK postconditioning protects against injury caused by ROSC through activating the adenosine monophosphate-activated protein kinase/mechanistic target of the rapamycin pathway.

Key words: autophagy, bradykinin, cardiac arrest, cardiopulmonary resuscitation, compound C, hippocampus, neuron, rapamycin, restoration of spontaneous circulation