Necrostatin decreases oxidative damage, inflammation, and injury after neonatal HI
Necrostatin decreases oxidative damage, inflammation, and injury after neonatal HI
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DOI：
10.1038/jcbfm.2010.72
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发表时间：
2011-01-01
影响因子：
6.3
通讯作者：
Martin, Lee J.
中科院分区：
文献类型：
--
作者：
Northington, Frances J.;Chavez-Valdez, Raul;Martin, Lee J.
Necrostatin-1 抑制受体相互作用蛋白 (RIP)-1 激酶和程序性坏死，并且在成年啮齿动物模型中具有神经保护作用。由于新生儿缺氧缺血（HI）中坏死和连续细胞死亡的显着性，我们测试了坏死他汀是否对发育中的大脑具有神经保护作用。出生后第7天(P)小鼠暴露于HI并脑室内注射0.1μL 80μmol坏死他汀、Nec-1,5-(1H-吲哚-3-基甲基)-(2-硫代-3-甲基)乙内酰脲或媒介物。 Necrostatin 在 P11 和 P28 时显着减少了前脑和丘脑的损伤。接受坏死性抑制素治疗的雄性动物具有特定的神经保护作用。 Necrostatin 治疗减少了坏死细胞死亡并增加了凋亡细胞死亡。缺氧缺血促进 RIP1-RIP3 复合物形成并抑制 RIP3-FADD（具有死亡结构域的 Fas 相关蛋白）相互作用，而这些作用可被 necrostatin 阻断。 Necrostatin 还可以减少 HI 诱导的蛋白质氧化损伤，并减弱炎症标志物，同时减少核因子 kappa B 和 caspase 1 的激活，以及 FLIP（（Fas 相关死亡结构域样 IL-1 β 转换酶）抑制蛋白）基因和蛋白质表达。在这种严重的新生儿脑损伤模型中，我们发现可以通过HI后施用单剂量的坏死他汀来治疗细胞坏死，这可能是通过中断RIP1-RIP3驱动的氧化损伤和炎症来实现的。 HI后necrostatin治疗的效果反映了坏死在新生儿脑损伤迟发期的重要性，并代表了新生儿HI治疗的新方向。脑血流与代谢杂志 (2011) 31, 178-189; doi：10.1038/jcbfm.2010.72； 2010 年 6 月 23 日在线发布
Necrostatin-1 inhibits receptor-interacting protein (RIP)-1 kinase and programmed necrosis and is neuroprotective in adult rodent models. Owing to the prominence of necrosis and continuum cell death in neonatal hypoxia-ischemia (HI), we tested whether necrostatin was neuroprotective in the developing brain. Postnatal day (P) 7 mice were exposed to HI and injected intracerebroventricularly with 0.1 mu L of 80 mu mol necrostatin, Nec-1, 5-(1H-Indol-3-ylmethyl)-(2-thio-3-methyl) hydantoin, or vehicle. Necrostatin significantly decreased injury in the forebrain and thalamus at P11 and P28. There was specific neuroprotection in necrostatin-treated males. Necrostatin treatment decreased necrotic cell death and increased apoptotic cell death. Hypoxia-ischemia enforced RIP1-RIP3 complex formation and inhibited RIP3-FADD (Fas-associated protein with death domain) interaction, and these effects were blocked by necrostatin. Necrostatin also decreased HI-induced oxidative damage to proteins and attenuated markers of inflammation coincidental with decreased nuclear factor-kappa B and caspase 1 activation, and FLIP ((Fas-associated death-domain-like IL-1 beta-converting enzyme)-inhibitory protein) gene and protein expression. In this model of severe neonatal brain injury, we find that cellular necrosis can be managed therapeutically by a single dose of necrostatin, administered after HI, possibly by interrupting RIP1-RIP3-driven oxidative injury and inflammation. The effects of necrostatin treatment after HI reflect the importance of necrosis in the delayed phases of neonatal brain injury and represent a new direction for therapy of neonatal HI. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 178-189; doi:10.1038/jcbfm.2010.72; published online 23 June 2010