Prevention of neonatal oxygen-induced brain damage by reduction of intrinsic apoptosis.
Prevention of neonatal oxygen-induced brain damage by reduction of intrinsic apoptosis.
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通过减少内在凋亡来预防新生儿氧诱导的脑损伤。
DOI：
10.1038/cddis.2011.133
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发表时间：
2012-01-12
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
在过去的十年中，很明显，氧气有助于新生儿脑损伤的发病机制，导致早产儿在以后的生活中神经认知障碍。最近，我们已经确定了受体介导的神经元凋亡在未成熟的啮齿动物脑中的关键作用。然而，在新生儿脑中，在高氧条件下伴随caspase-2活化的内在凋亡途径的贡献仍然是难以捉摸的。抑制半胱天冬酶似乎是一种有前途的神经保护策略。为了评估特定半胱天冬酶对发育中大脑的影响，我们应用了最近开发的基于五肽的II组半胱天冬酶抑制剂（5-（2，6-二氟-苯氧基）-3（R，S）-（2（S）-（2（S）-（3-甲氧羰基-2（S）-（3-甲基-2（S）-（（喹啉-2-羰基）-氨基）-丁酰氨基）丙酰氨基）3-甲基丁酰氨基）丙酰氨基）-4-氧代-戊酸甲酯; TRP 601）。在这里，我们报告说，高氧（hyperoxia）触发活性caspase-2的表达显着增加，导致内在的凋亡途径的启动与上调的关键蛋白，即细胞色素c，凋亡蛋白酶激活因子-1，caspase-独立的蛋白凋亡诱导因子，而BH 3相互作用域死亡激动剂和抗凋亡蛋白B细胞淋巴瘤-2下调。这些结果与caspase-3活性的上调和显著的神经变性相一致。然而，在高氧开始时用TRP 601单次治疗逆转了该模型中的有害作用。高氧介导的神经退行性变是由内在细胞凋亡的支持，这表明高选择性半胱天冬酶抑制剂的发展将代表一个潜在的有用的治疗策略，在早产儿。
Within the last decade, it became clear that oxygen contributes to the pathogenesis of neonatal brain damage, leading to neurocognitive impairment of prematurely born infants in later life. Recently, we have identified a critical role for receptor-mediated neuronal apoptosis in the immature rodent brain. However, the contribution of the intrinsic apoptotic pathway accompanied by activation of caspase-2 under hyperoxic conditions in the neonatal brain still remains elusive. Inhibition of caspases appears a promising strategy for neuroprotection. In order to assess the influence of specific caspases on the developing brain, we applied a recently developed pentapeptide-based group II caspase inhibitor (5-(2,6-difluoro-phenoxy)-3(R,S)-(2(S)-(2(S)-(3-methoxycarbonyl-2(S)-(3-methyl-2(S)-((quinoline-2-carbonyl)-amino)-butyrylamino)propionylamino)3-methylbutyrylamino)propionylamino)-4-oxo-pentanoic acid methyl ester; TRP601). Here, we report that elevated oxygen (hyperoxia) triggers a marked increase in active caspase-2 expression, resulting in an initiation of the intrinsic apoptotic pathway with upregulation of key proteins, namely, cytochrome c, apoptosis protease-activating factor-1, and the caspase-independent protein apoptosis-inducing factor, whereas BH3-interacting domain death agonist and the anti-apoptotic protein B-cell lymphoma-2 are downregulated. These results coincide with an upregulation of caspase-3 activity and marked neurodegeneration. However, single treatment with TRP601 at the beginning of hyperoxia reversed the detrimental effects in this model. Hyperoxia-mediated neurodegeneration is supported by intrinsic apoptosis, suggesting that the development of highly selective caspase inhibitors will represent a potential useful therapeutic strategy in prematurely born infants.
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影响因子：
1.9
作者：
Hagberg H;Mallard C;Rousset CI;Xiaoyang Wang
通讯作者：
Xiaoyang Wang
影响因子：
4.8
作者：
Guo, Y;Srinivasula, SM;Alnemri, ES
通讯作者：
Alnemri, ES
影响因子：
6.1
作者：
Felderhoff-Mueser, U;Bittigau, P;Ikonomidou, C
通讯作者：
Ikonomidou, C
影响因子：
11.2
作者：
Dzietko, Mark;Boos, Vinzenz;Felderhoff-Mueser, Ursula
通讯作者：
Felderhoff-Mueser, Ursula
影响因子：
7.2
作者：
Chauvier, D;Lecoeur, H;Jacotot, E
通讯作者：
Jacotot, E