中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2017, Vol. 12 ›› Issue (3): 417-424.doi: 10.4103/1673-5374.202945

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

抑制自噬影响缺氧缺血性脑损伤海马组织中谷氨酸受体亚基表达：发挥神经保护作用

  

  • 收稿日期:2017-02-08 出版日期:2017-03-15 发布日期:2017-03-15
  • 基金资助:

    中国国家自然科学基金项目（81471488, 81271378, 81502157, 81501291）；江苏省医学重点学科（XK201120）；江苏省省级重点研发专项基金（BE2015644）；苏州市科技发展计划项目（SYSD2013105, SYS201446, SYS201441）；苏州市公共卫生技术项目（SS201536）；苏州市临床医学中心（Szzx201504）

Neuroprotective effects of autophagy inhibition on hippocampal glutamate receptor subunits after hypoxiaischemia-induced brain damage in newborn rats

Li-xiao Xu1, Xiao-juan Tang2, Yuan-yuan Yang2, Mei Li1, Mei-fang Jin1, Po Miao2, Xin Ding2, Ying Wang2, Yan-hong Li2, Bin Sun2, Xing Feng2   

  1. 1 Institute of Pediatric Research, Affiliated Children’s Hospital of Soochow University, Suzhou, Jiangsu Province, China; 2 Department of Neonatology, Affiliated Children’s Hospital of Soochow University, Suzhou, Jiangsu Province, Chin
  • Received:2017-02-08 Online:2017-03-15 Published:2017-03-15
  • Contact: Bin Sun, Ph.D. or Xing Feng, Ph.D., sunyu0628@126.com or xing_feng66@suda.edu.cn.
  • Supported by:

    This work was supported by the National Natural Science Foundation of China, No. 81471488, 81271378, 81502157, and 81501291; the Key Medical Subjects of Jiangsu Province of China, No. XK201120; the Jiangsu Province Key Research and Development of Special Funds in China, No. BE2015644; the Science and Technology Project of Suzhou City of China, No. SYSD2013105, SYS201446, SYS201441; the Public Health Technology Project of Suzhou City of China, No. SS201536; the Department of Pediatrics Clinical Center of Suzhou City of China, No. Szzx201504.

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摘要：

自噬可参与缺氧缺血性脑损伤，然而其具体机制仍不清楚。实验将7d龄大鼠左侧颈总动脉结扎2h建立缺氧缺血性脑损伤模型，造模前1h腹腔注射10 mM(10 μL)自噬抑制剂3-甲基腺嘌呤或1g/kg自噬刺激剂雷帕霉素进行干预。结果表明，缺氧缺血性脑损伤新生大鼠海马损伤伴随着自噬标志物LC3和Beclin 1以及α-氨基-3-羟基-5-甲基-4-异恶唑丙酸型谷氨酸受体亚基谷氨酸受体1的表达而增加，α-氨基-3-羟基-5-甲基-4-异恶唑丙酸型谷氨酸受体亚基谷氨酸受体2表达而降低；3-甲基腺嘌呤预处理可使海马损伤明显减轻，而雷帕霉素预处理则能明显加剧海马损伤；同时3-甲基腺嘌呤预处理还能逆转海马组织中缺氧缺血性脑损伤上调的谷氨酸受体1和下调的谷氨酸受体2的表达，而雷帕霉素预处理则加剧缺氧缺血性脑损伤对谷氨酸受体1和谷氨酸受体2的影响。数据表明抑制自噬可能通过影响α-氨基-3-羟基-5-甲基-4-异恶唑丙酸型谷氨酸受体亚基表达，对新生大鼠缺氧缺血性脑损伤发挥神经保护作用。

ORCID:0000-0002-9756-9468(Bin Sun)

关键词: 神经再生, 缺氧缺血性脑损伤, 缺氧, 缺血, 缺氧, α-氨基-3-羟基-5-甲基-4-异恶唑丙酸型谷氨酸受体亚基, 谷氨酸, 海马, 雷帕霉素, 3-甲基腺嘌呤

Abstract:

Autophagy has been suggested to participate in the pathology of hypoxic-ischemic brain damage (HIBD). However, its regulatory role in HIBD remains unclear and was thus examined here using a rat model. To induce HIBD, the left common carotid artery was ligated in neonatal rats, and the rats were subjected to hypoxia for 2 hours. Some of these rats were intraperitoneally pretreated with the autophagy inhibitor 3-methyladenine (10 mM in 10 μL) or the autophagy stimulator rapamycin (1 g/kg) 1 hour before artery ligation. Our findings demonstrated that hypoxia-ischemia-induced hippocampal injury in neonatal rats was accompanied by increased expression levels of the autophagy-related proteins light chain 3 and Beclin-1 as well as of the AMPA receptor subunit GluR1, but by reduced expression of GluR2. Pretreatment with the autophagy inhibitor 3-methyladenine blocked hypoxia-ischemia-induced hippocampal injury, whereas pretreatment with the autophagy stimulator rapamycin significantly augmented hippocampal injury. Additionally, 3-methyladenine pretreatment blocked the hypoxia-ischemia-induced upregulation of GluR1 and downregulation of GluR2 in the hippocampus. By contrast, rapamycin further elevated hippocampal GluR1 levels and exacerbated decreased GluR2 expression levels in neonates with HIBD. Our results indicate that autophagy inhibition favors the prevention of HIBD in neonatal rats, at least in part, through normalizing GluR1 and GluR2 expression.

Key words: nerve regeneration, hypoxic-ischemic brain damage, hypoxia, ischemi, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor subunit, GluR, hippocampus, rapamycin, 3-methyladenine, neural regeneration