Department of Anaesthesiology and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Cell Death Dis. 2012 Jan 12;3(1):e250. doi: 10.1038/cddis.2011.133.
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.
在过去的十年中，很明显，氧气会导致新生儿脑损伤的发病机制，并导致早产儿在以后的生活中出现神经认知障碍。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大脑中的关键作用。然而，在新生鼠大脑中，伴随着激活 caspase-2 的内在凋亡途径在高氧条件下的作用仍不清楚。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，我们应用了一种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-甲氧基羰基-2（S）-（3-甲基-2（S）-（（喹啉-2-羰基）-氨基）-丁酰基氨基）丙酰基氨基）3-甲基丁酰基氨基）丙酰基氨基）-4-氧代戊酸甲酯；TRP601）。在这里，我们报告说，升高的氧气（高氧）会触发活性 caspase-2 表达的显著增加，从而启动内在凋亡途径，上调关键蛋白，即细胞色素 c、凋亡蛋白酶激活因子-1 和 caspase 非依赖性蛋白凋亡诱导因子，而 BH3 相互作用结构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 活性的上调和明显的神经退行性变一致。然而，在高氧开始时单独用 TRP601 处理可逆转该模型中的有害影响。高氧介导的神经退行性变得到内在凋亡的支持，这表明开发高度选择性的半胱天冬酶抑制剂将代表早产儿的潜在有用治疗策略。
