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首页> 外文期刊>American Journal of Physiology >Perinatal nicotine exposure alters Akt/GSK-3beta/ mTOR/autophagy signaling, leading to development of hypoxic-ischemic-sensitive phenotype in rat neonatal brain.
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Perinatal nicotine exposure alters Akt/GSK-3beta/ mTOR/autophagy signaling, leading to development of hypoxic-ischemic-sensitive phenotype in rat neonatal brain.

机译：围产尼古丁暴露会改变AKT / GSK-3β/ mTOR /自噬信号，导致大鼠新生大脑缺氧缺血敏感表型的开发。

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Maternal cigarette smoking is a major perinatal insult that contributes to an increased risk of cardiovascular and neurodevelopmental diseases in offspring. Our previous studies revealed that perinatal nicotine exposure reprograms a sensitive phenotype in neonatal hypoxic-ischemic encephalopathy (HIE), yet the underlying molecular mechanisms remain largely elusive. The present study tested the hypothesis that perinatal nicotine exposure impacts autophagy signaling in the developing brain, resulting in enhanced susceptibility to neonatal HIE. Nicotine was administered to pregnant rats via subcutaneous osmotic minipumps. Neonatal HIE was conducted in 9-day-old male rat pups. Protein kinase B/glycogen synthase kinase-3beta/mammalian target of rapamycin (Akt/GSK-3beta/mTOR) signaling and key autophagy markers were determined by Western blotting analysis. Rapamycin and MK2206 were administered via intracerebroventricular injection. Nicotine exposure significantly inhibited autophagy activities in neonatal brain tissues, characterized by an increased ratio of phosphoylated (p-) to total mTOR protein expression but reduced levels of autophagy-related 5, Beclin 1, and LC3betaI/II. Treatment with mTOR inhibitor rapamycin effectively blocked nicotine-mediated autophagy deficiency and, more importantly, reversed the nicotine-induced increase in HI brain infarction. In addition, nicotine exposure significantly upregulated p-Akt and p-GSK-3beta. Treatment with the Akt selective inhibitor MK2206 reversed the enhanced p-Akt and p-GSK-3beta, restored basal autophagic flux, and abolished nicotine-mediated HI brain injury. These findings suggest that perinatal nicotine-mediated alteration of Akt/GSK-3beta/mTOR signaling plays a key role in down-regulation of autophagic flux, which contributes to the development of hypoxia/ischemia-sensitive phenotype in the neonatal brain.
机译：母婴吸烟是一个主要的围产期侮辱，有助于后代心血管和神经发育疾病的风险增加。我们以前的研究表明，围产尼古丁暴露重新编程新生儿缺氧缺血性脑病（HIE）的敏感表型，但下面的分子机制仍然很难以难以捉摸。本研究检测了围产量尼古丁暴露在发育大脑中产生自噬信号的假设，导致对新生儿HIE的易感性提高。尼古丁通过皮下渗透微型泵给予孕鼠。新生儿HIE是在9日龄雄性鼠幼仔中进行的。通过蛋白质印迹分析测定蛋白质激素（AKT / GSK-3β/ mTOR）信号传导和关键自噬标志物的蛋白激酶B /糖原合酶激酶-3β/哺乳动物靶标。雷帕霉素和MK2206通过颅内注射施用。尼古丁暴露在新生儿脑组织中显着抑制了自噬活性，其特征在于磷酸盐（P-）与总MTOR蛋白表达的比例增加，但含有的自噬相关5，BECLIN 1和LC3βII水平降低。 MTOR抑制剂雷帕霉素的治疗有效地阻断了尼古丁介导的自噬缺乏，更重要的是，逆转尼古丁诱导的脑梗塞血液梗死增加。此外，尼古丁暴露显着上调P-AKT和P-GSK-3Beta。用AKT选择性抑制剂MK2206处理逆转增强的P-AKT和P-GSK-3Beta，恢复的基础自噬助剂，并废除了尼古丁介导的HI脑损伤。这些发现表明，围产尼古特尼曲线介导的AKT / GSK-3Beta / mTOR信号传导的改变在自噬助线的下调中起关键作用，这有助于新生儿脑中的缺氧/缺血敏感表型的发育。

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