Neuroprotective effects of autophagy inhibition on hippocampal glutamate receptor subunits after hypoxia-ischemia-induced brain damage in newborn rats.
Neuroprotective effects of autophagy inhibition on hippocampal glutamate receptor subunits after hypoxia-ischemia-induced brain damage in newborn rats.
复制标题
自噬抑制对新生大鼠缺氧缺血脑损伤后海马谷氨酸受体亚基的神经保护作用
DOI：
10.4103/1673-5374.202945
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发表时间：
2017-03
影响因子：
6.1
通讯作者：
Feng X
中科院分区：
文献类型：
--
作者：
Xu LX;Tang XJ;Yang YY;Li M;Jin MF;Miao P;Ding X;Wang Y;Li YH;Sun B;Feng X
自噬被认为参与了缺氧缺血性脑损伤（HIBD）的病理过程。然而，其在HIBD中的调节作用尚不清楚，因此本文使用大鼠模型进行了研究。为诱导HIBD，结扎新生大鼠左颈总动脉，缺氧2小时。部分大鼠在结扎前1小时腹腔注射自噬抑制剂3-甲基腺嘌呤（10 μL, 10 mM）或自噬刺激剂雷帕霉素（1 g/kg）。我们的研究结果表明，缺氧缺血诱导的新生大鼠海马损伤伴随着自噬相关蛋白轻链3和Beclin-1以及AMPA受体亚基GluR1的表达水平升高，但GluR2的表达降低。自噬抑制剂3-甲基腺嘌呤预处理可阻断缺氧缺血诱导的海马损伤，而自噬刺激剂雷帕霉素预处理可显著增强海马损伤。此外，3-甲基腺苷预处理可阻断缺氧缺血诱导的海马GluR1上调和GluR2下调。相比之下，雷帕霉素进一步升高了HIBD新生儿海马GluR1水平，并加剧了GluR2表达水平的下降。我们的研究结果表明，自噬抑制有助于预防新生大鼠的HIBD，至少部分是通过使GluR1和GluR2的表达正常化。
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.