Neural Regeneration Research ›› 2017, Vol. 12 ›› Issue (3): 417-424.doi: 10.4103/1673-5374.202945

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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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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