Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury
Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury
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DOI：
10.1016/j.nbd.2008.07.022
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发表时间：
2008-12-01
影响因子：
6.1
通讯作者：
Balduini, Walter
中科院分区：
文献类型：
--
作者：
Carloni, Silvia;Buonocore, Giuseppe;Balduini, Walter
自噬是一种细胞成分的细胞内大量降解过程，在细胞内稳态中起关键作用，并且可由诸如营养缺乏、闭合性头部损伤或局灶性脑缺血等应激诱导。本研究聚焦于自噬在新生儿缺氧缺血（HI）中的作用。自噬所需的一种与Bcl - 2相互作用的蛋白——Beclin 1表达增强，已被用作自噬的标志物。在HI后的短时间内，海马体和大脑皮层中的Beclin 1均显著增加。Beclin 1阳性细胞在损伤侧被发现，而在对侧未发现，并且与MAP2共定位，但不与GFAP或ED1共定位，这表明该蛋白在神经元中过度表达。Beclin 1阳性细胞也是TUNEL阳性。抑制自噬的3 - 甲基腺嘌呤和渥曼青霉素显著降低了Beclin 1的表达，并使细胞死亡模式从凋亡转变为坏死。相反，增加自噬的雷帕霉素增强了Beclin 1的表达，减少了坏死细胞死亡，并减轻了脑损伤。用辛伐他汀或缺氧预处理进行预防性治疗也增加了Beclin 1的表达。综上所述，这些数据表明新生儿缺氧缺血后神经元细胞中的自噬增加，并提示自噬途径的过度激活在脑损伤的早期阶段是一种潜在的保护机制。（C）2008爱思唯尔公司。保留所有权利。
Autophagy, an intracellular bulk degradation process of cellular constituents, plays a key role in cell homeostasis and can be induced by stresses, such as nutrient depletion, closed head injury or focal cerebral ischemia. This study focuses on the role of autophagy in neonatal hypoxia-ischemia (HI). Enhanced beclin 1 expression, a Bcl-2-interacting protein required for autophagy, has been used as a marker of autophagy. Beclin I was significantly increased at short times after HI, both in the hippocampus and in the cerebral cortex. Beclin 1-positive cells were found in the injured but not in the contralateral side and co-localized with MAP2 but not with GFAP or ED1, indicating that the protein is over-expressed in neurons. Beclin 1-positive cells were also TUNEL-positive. 3-Methyladenine and wortmannin, that inhibit autophagy, significantly reduced beclin I expression and switched the mechanism of the cell death mode from apoptosis to necrosis. Conversely, rapamycin, that increases autophagy, augmented beclin I expression, reduced necrotic cell death, and decreased brain injury. A prophylactic treatment with simvastatin or hypoxic preconditioning also increased beclin I expression. Taken together. these data indicate that autophagy is increased in neuronal cells after neonatal hypoxia-ischemia and suggest that over-activation of autophagic pathways represents a potential protective mechanism in the early stage of the brain injury. (C) 2008 Elsevier Inc. All rights reserved.