...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >FLIP(L) protects neurons against in vivo ischemia and in vitro glucose deprivation-induced cell death.
【24h】

FLIP(L) protects neurons against in vivo ischemia and in vitro glucose deprivation-induced cell death.

机译：FLIP（L）保护神经元免受体内缺血和体外葡萄糖剥夺诱导的细胞死亡。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Knowledge of the molecular mechanisms that underlie neuron death after stroke is important to allow the development of effective neuroprotective strategies. In this study, we investigated the contribution of death receptor signaling pathways to neuronal death after ischemia using in vitro and in vivo models of ischemic injury and transgenic mice that are deficient in tumor necrosis factor receptor I (TNFRI KO) or show neuron-specific overexpression of the long isoform of cellular Fas-associated death domain-like interleukin-1-beta-converting enzyme-inhibitory protein (FLIP(L)). Caspase 8 was activated in brain lesions after permanent middle cerebral artery occlusion (pMCAO) and in cortical neurons subjected to glucose deprivation (GD) and was necessary for GD-induced neuron death. Thus, neurons treated with zIETD-FMK peptide or overexpressing a dominant-negative caspase 8 mutant were fully protected against GD-induced death. The presence of the neuroprotective TNFRI was necessary for selectively sustaining p50/p65NF-kappaB activity and the expression of the p43 cleavage form of FLIP(L), FLIP(p43), an endogenous inhibitor of caspase 8, in pMCAO lesions and GD-treated neurons. Moreover, TNF pretreatment further upregulated p50/p65NF-kappaB activity and FLIP(p43) expression in neurons after GD. The knock-down of FLIP in wild-type (WT) neurons using a short hairpin RNA revealed that FLIP(L) is essential for TNF/TNFRI-mediated neuroprotection after GD. Furthermore, the overexpression of FLIP(L) was sufficient to rescue TNFRI KO neurons from GD-induced death and to enhance TNF neuroprotection in WT neurons, and neuron-specific expression of FLIP(L) in transgenic mice significantly reduced lesion volume after pMCAO. Our results identify a novel role for the TNFRI-NF-kappaB-FLIP(L) pathway in neuroprotection after ischemia and identify potential new targets for stroke therapy.
机译：对中风后神经元死亡的分子机制的了解对于开发有效的神经保护策略很重要。在这项研究中，我们使用缺血性损伤的体外和体内模型以及缺乏肿瘤坏死因子受体I（TNFRI KO）或显示神经元特异性过表达的转基因小鼠，研究了缺血后死亡受体信号通路对神经元死亡的贡献。 Fas相关死亡域样白介素1-β转换酶抑制蛋白（FLIP（L））的长同工型。 Caspase 8在永久性大脑中动脉闭塞（pMCAO）后的脑损伤中以及在葡萄糖剥夺（GD）的皮质神经元中被激活，这对于GD诱导的神经元死亡是必需的。因此，用zIETD-FMK肽治疗或过表达显性负性半胱天冬酶8突变体的神经元得到了完全保护，以防止GD诱导的死亡。神经保护性TNFRI的存在对于在pMCAO病变和GD治疗中选择性维持p50 /p65NF-κB活性以及FLIP（L），FLIP（p43）（一种半胱天冬酶8的内源性抑制剂）的p43裂解形式的表达是必需的神经元。此外，TNF预处理进一步上调GD后神经元中的p50 / p65NF-kappaB活性和FLIP（p43）表达。使用短发夹RNA敲低野生型（WT）神经元中FLIP的结果表明，FLIP（L）对于GD后TNF / TNFRI介导的神经保护至关重要。此外，FLIP（L）的过表达足以从GD诱导的死亡中拯救TNFRI KO神经元并增强WT神经元中的TNF神经保护，并且转基因小鼠中FLIP（L）的神经元特异性表达显着降低了pMCAO后的病变体积。我们的结果确定了TNFRI-NF-kappaB-FLIP（L）通路在缺血后神经保护中的新作用，并确定了中风治疗的潜在新靶标。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号