Propofol inhibited autophagy through Ca(2+)/CaMKKβ/AMPK/mTOR pathway in OGD/R-induced neuron injury.
Propofol inhibited autophagy through Ca(2+)/CaMKKβ/AMPK/mTOR pathway in OGD/R-induced neuron injury.
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DOI：
10.1186/s10020-018-0054-1
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发表时间：
2018-11-23
期刊：
影响因子：
--
通讯作者：
Cai H
中科院分区：
文献类型：
--
作者：
Sun B;Ou H;Ren F;Huan Y;Zhong T;Gao M;Cai H
异丙酚（PPF）在脑缺血再灌注（I/R）中的神经保护作用最近受到重视。本研究旨在探讨PPF的神经保护机制是否与其调节Ca 2 +/CaMKKβ（钙调蛋白依赖性蛋白激酶激酶β）/AMPK（AMP活化蛋白激酶）/mTOR（雷帕霉素靶蛋白）/自噬通路有关。采用体外培养的原代大鼠大脑皮质神经元，进行氧糖剥夺再给氧（OGD/R）处理，模拟脑I/R损伤。与对照组相比，OGD/R暴露成功地诱导了神经元I/R损伤。此外，OGD/R暴露显著引起自噬诱导，反映为增加的LC 3-II/LC 3-I比率和Beclin 1表达，降低的p62表达和增加的LC 3斑点形成。此外，OGD/R暴露可引起细胞内Ca ~（2+）浓度（[Ca ~（2+）]i）升高。然而，PPF处理显著拮抗OGD/R触发的细胞损伤、自噬诱导和[Ca 2 +]i升高。进一步的研究表明，雷帕霉素诱导的自噬和离子载体离子霉素升高的[Ca 2 +]i显著逆转了PPF介导的OGD/R触发的细胞损伤的改善。重要的是，离子霉素还显著消除了OGD/R暴露神经元中PPF介导的自噬和CaMKKβ/AMPK/mTOR信号转导抑制。此外，CaMKKβ/AMPK/mTOR信号转导的激活消除了PPF介导的自噬抑制。我们的研究结果表明，PPF拮抗OGD/R引发的神经元损伤，这可能至少部分通过Ca 2 +/CaMKKβ/AMPK/mTOR通路抑制自噬介导。本文的在线版本（10.1186/s10020-018-0054-1）包含补充材料，可供授权用户使用。
The neuroprotective role of propofol (PPF) in cerebral ischemia-reperfusion (I/R) has recently been highlighted. This study aimed to explore whether the neuroprotective mechanisms of PPF were linked to its regulation of Ca2+/CaMKKβ (calmodulin-dependent protein kinase kinase β)/AMPK (AMP-activated protein kinase)/mTOR (mammalian target of rapamycin)/autophagy pathway. Cultured primary rat cerebral cortical neurons were treated with oxygen-glucose deprivation and re-oxygenation (OGD/R) to mimic cerebral I/R injury in vitro. Compared with the control neurons, OGD/R exposure successfully induced neuronal I/R injury. Furthermore, OGD/R exposure notably caused autophagy induction, reflected by augmented LC3-II/LC3-I ratio and Beclin 1 expression, decreased p62 expression, and increased LC3 puncta formation. Moreover, OGD/R exposure induced elevation of intracellular Ca2+ concentration ([Ca2+]i). However, PPF treatment significantly antagonized OGD/R-triggered cell injury, autophagy induction, and [Ca2+]i elevation. Further investigation revealed that both autophagy induction by rapamycin and [Ca2+]i elevation by the Ca2+ ionophore ionomycin significantly reversed the PPF-mediated amelioration of OGD/R-triggered cell injury. Importantly, ionomycin also significantly abrogated the PPF-mediated suppression of autophagy and CaMKKβ/AMPK/mTOR signaling in OGD/R-exposed neurons. Additionally, activation of CaMKKβ/AMPK/mTOR signaling abrogated the PPF-mediated autophagy suppression. Our findings demonstrate that PPF antagonized OGD/R-triggered neuronal injury, which might be mediated, at least in part, via inhibition of autophagy through Ca2+/CaMKKβ/AMPK/mTOR pathway. The online version of this article (10.1186/s10020-018-0054-1) contains supplementary material, which is available to authorized users.
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