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Inhibition of caspase-3-mediated cell death via peroxynitrite formation following traumatic brain injury.

机译：颅脑损伤后通过过亚硝酸盐的形成来抑制caspase-3介导的细胞死亡。

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摘要

Psychological and neurological deficits experienced by TBI victims are caused by neurodegeneration which can be classified under two headings: primary or secondary. Although primary injury is considered unsalvageable, secondary injury includes neurons slowly degenerating from a complex combination of pathological events following the initial impact and is potentially treatable by pharmacology. Currently, however, no pharmacological interventions for attenuating secondary injury are available. Studies have demonstrated many cell death pathways activated following TBI, including oxidative and proteolytic mechanisms. Oxidants can decrease proteolysis in vitro, thus it was postulated that oxidants might inhibit proteolytic death following TBI.;We examined a cortical culture model of secondary injury for possible interactions between death pathways mediated by caspase-3 and peroxynitrite representing archetypical proteolytic and oxidative mechanisms respectively. Peroxynitrite formation was readily evident after injury but, while cytoplasmic cytochrome c release indicated initiation of Type II apoptosis, no caspase-3 cleavage or activity was observed. We further demonstrated that peroxynitrite interacted directly with caspase-3.;To isolate the effect of peroxynitrite on caspases, we next developed recombinant cell-free caspase systems. Treatment with pure peroxynitrite or peroxynitrite donors decreased caspase-mediated proteolysis. Furthermore, this inhibition could be alleviated using a sulphydryl reducing agent, suggesting cysteinyl oxidation as a mechanism of inhibition.;To study the effects of the simultaneous activation of cell death pathways, we induced artificial caspase-3 activation and peroxynitrite formation in cortical cultures. Application of staurosporine alone induced caspase-3 activation and cell death, but subsequent application of the peroxynitrite donor SIN-1 prevented caspase-3-mediated effects. Ultimately, no neuroprotection was observed.;To test relevance in vivo, we assayed a whole animal model of TBI for similar hallmarks. We determined that peroxynitrite was associated with neuronal death and an oxidative inhibition of caspase-3 activity, but not caspase-9 activity. These findings support the notion that oxidative inhibition of caspase-3 occurs following TBI.;Overall, we observed an inhibition of caspase-3 by peroxynitrite in multiple models of TBI of increasing complexity. This interaction may not only explain the failure of caspase inhibitors and anti-oxidant treatments in the treatment of TBI, but might also suggest novel neuroprotective pharmacological approaches.
机译：TBI受害者经历的心理和神经功能缺陷是由神经退行性病变引起的，神经退行性病变可分为两个类别：初级或次级。尽管原发性损伤被认为是无法挽救的，但继发性损伤包括神经元，其在最初的影响后会因病理事件的复杂组合而缓慢退化，并且有可能通过药理学治疗。但是，目前尚无用于减轻继发性损伤的药理干预措施。研究表明TBI后激活了许多细胞死亡途径，包括氧化和蛋白水解机制。氧化剂可以降低体外蛋白水解，因此推测氧化剂可能抑制了TBI后的蛋白水解性死亡。 。损伤后容易形成过氧亚硝酸盐，但是，虽然细胞质中的细胞色素c释放表明II型细胞凋亡开始，但未观察到caspase-3裂解或活性。我们进一步证明了过氧亚硝酸盐直接与caspase-3相互作用。为了分离过氧亚硝酸盐对caspase的作用，我们接下来开发了重组的无细胞caspase系统。纯过氧亚硝酸盐或过氧亚硝酸盐供体的治疗减少了胱天蛋白酶介导的蛋白水解。此外，可以使用巯基还原剂减轻这种抑制作用，表明半胱氨酰氧化是一种抑制机制。为了研究细胞死亡途径同时激活的作用，我们在皮质培养物中诱导了人工胱天蛋白酶-3激活和过氧亚硝酸盐形成。单独应用星形孢菌素可诱导caspase-3活化和细胞死亡，但随后应用过氧亚硝酸盐供体SIN-1可阻止caspase-3介导的作用。最终，未观察到神经保护作用。为了测试体内相关性，我们对TBI的整个动物模型进行了分析，以寻找相似的特征。我们确定过亚硝酸盐与神经元死亡和caspase-3活性的氧化抑制有关，但与caspase-9活性无关。这些发现支持了在TBI之后发生caspase-3氧化抑制的观点。总体而言，我们观察到在复杂性不断提高的多个TBI模型中过氧亚硝酸盐对caspase-3的抑制作用。这种相互作用不仅可以解释半胱天冬酶抑制剂和抗氧化剂在TBI治疗中的失败，而且还可能暗示了新型的神经保护药理方法。

著录项

  • 作者

    Lau, Anthony Chi-Wing.;

  • 作者单位

    University of Toronto (Canada).;

  • 授予单位 University of Toronto (Canada).;
  • 学科 Neurosciences.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 206 p.
  • 总页数 206
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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