Multi-Mechanism Inhibition of Lipid Peroxidation in TBI

TBI 中脂质过氧化的多机制抑制

基本信息

  • 批准号:
    8870460
  • 负责人:
  • 金额:
    $ 32.48万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-07-01 至 2016-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): We have previously documented that generation of the potent reactive nitrogen species (RNS) peroxynitrite (PN) is responsible for oxidative damage by lipid peroxidation (LP) and protein modification (carbonylation and tyrosine nitration) to mitochondrial and other cellular elements during the first 72 hrs after traumatic brain injury (TBI). The PN-mediated oxidative damage leads to brain mitochondrial dysfunction and ultimately failure. As a consequence of oxidative compromise of mitochondrial function including calcium (Ca++) buffering), posttraumatic intracellular Ca++ overload is exacerbated leading to calpain-mediated cytoskeletal degradation, neurodegeneration and neurological impairment. We have preliminarily shown that treatment with the potent LP inhibitor U-83836E, with the LP-derived lipid aldehyde 4-hydroxynonenal (4-HNE) scavenger phenelzine or with the mitochondrial permeability transition inhibitor cyclosporine (CsA) can partially attenuate posttraumatic brain LP damage, mitochondrial dysfunction and calpain-mediated cytoskeletal damage in a mouse TBI model. Most importantly, the window for this effect is at least 12 hrs post-injury. However, our preliminary results show only a partial attenuation of post-injury LP-related neural damage' even when any of these antioxidant compounds is individually administered after injury. This partial neuroprotective effect strongly points to the logic of an antioxidant neuroprotective strategy that combines either two or all three of these mechanistically complimentary antioxidant compounds to achieve a greater degree of neuroprotection. Therefore, the overall goal of the proposed experiments is to explore the hypothesis that interrupting post-traumatic secondary LP oxidative damage at multiple points will produce a quantitatively greater neuroprotective effect with less variability that will have a greater chance of translational success in future TBI clinical trials. The combination approach should not only increase the maximal neuroprotective effect, but may also prolong the therapeutic window for inhibition of secondary brain injury after TBI.
描述(由申请人提供):我们之前已经证明,在创伤性脑损伤(TBI)后的前 72 小时内,强效活性氮(RNS)过氧亚硝酸盐(PN)的产生是导致脂质过氧化(LP)和蛋白质修饰(羰基化和酪氨酸硝化)对线粒体和其他细胞元件造成氧化损伤的原因。 PN 介导的氧化损伤导致脑线粒体功能障碍并最终衰竭。由于线粒体功能(包括钙 (Ca++) 缓冲)氧化受损,创伤后细胞内 Ca++ 超载加剧,导致钙蛋白酶介导的细胞骨架降解、神经变性和神经损伤。我们初步表明,用强效 LP 抑制剂 U-83836E、LP 衍生脂质醛 4-羟基壬烯醛 (4-HNE) 清除剂苯乙肼或线粒体通透性转变抑制剂环孢菌素 (CsA) 治疗可以部分减轻创伤后脑 LP 损伤、线粒体 小鼠 TBI 模型中的功能障碍和钙蛋白酶介导的细胞骨架损伤。最重要的是,这种效果的窗口期至少是受伤后 12 小时。然而,我们的初步结果显示,即使在损伤后单独施用这些抗氧化剂化合物中的任何一种,也只能部分减弱损伤后腰椎间盘突出相关的神经损伤。这种部分神经保护作用强烈指出了抗氧化神经保护策略的逻辑,该策略将这些机械上互补的抗氧化化合物中的两种或全部三种结合起来,以实现更大程度的神经保护。因此,所提出的实验的总体目标是探索这样的假设:在多个点中断创伤后继发性 LP 氧化损伤将产生数量上更大的神经保护作用,且变异性更小,从而产生更小的变异性。 未来 TBI 临床试验转化成功的机会更大。联合治疗不仅可以增加最大的神经保护作用,还可以延长抑制 TBI 后继发性脑损伤的治疗窗。

项目成果

期刊论文数量(0)
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EDWARD D. HALL其他文献

EDWARD D. HALL的其他文献

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{{ truncateString('EDWARD D. HALL', 18)}}的其他基金

Nrf2-Antioxidant Response Element Neuroprotection in TBI
Nrf2-抗氧化反应元件在 TBI 中的神经保护作用
  • 批准号:
    9241702
  • 财政年份:
    2016
  • 资助金额:
    $ 32.48万
  • 项目类别:
Carbonyl Scavenging for Traumatic Brain Injury
羰基清除治疗创伤性脑损伤
  • 批准号:
    8993650
  • 财政年份:
    2014
  • 资助金额:
    $ 32.48万
  • 项目类别:
Carbonyl Scavenging for Traumatic Brain Injury
羰基清除治疗创伤性脑损伤
  • 批准号:
    8795231
  • 财政年份:
    2014
  • 资助金额:
    $ 32.48万
  • 项目类别:
Multi-Mechanism Inhibition of Lipid Peroxidation in TBI
TBI 中脂质过氧化的多机制抑制
  • 批准号:
    9093852
  • 财政年份:
    2013
  • 资助金额:
    $ 32.48万
  • 项目类别:
Multi-Mechanism Inhibition of Lipid Peroxidation in TBI
TBI 中脂质过氧化的多机制抑制
  • 批准号:
    9303474
  • 财政年份:
    2013
  • 资助金额:
    $ 32.48万
  • 项目类别:
Multi-Mechanism Inhibition of Lipid Peroxidation in TBI
TBI 中脂质过氧化的多机制抑制
  • 批准号:
    8658871
  • 财政年份:
    2013
  • 资助金额:
    $ 32.48万
  • 项目类别:
Multi-Mechanism Inhibition of Lipid Peroxidation in TBI
TBI 中脂质过氧化的多机制抑制
  • 批准号:
    8602633
  • 财政年份:
    2013
  • 资助金额:
    $ 32.48万
  • 项目类别:
Inhibition of Lipid Peroxidation in SCI
SCI 中脂质过氧化的抑制
  • 批准号:
    8239698
  • 财政年份:
    2011
  • 资助金额:
    $ 32.48万
  • 项目类别:
Inhibition of Lipid Peroxidation in SCI
SCI 中脂质过氧化的抑制
  • 批准号:
    8333969
  • 财政年份:
    2011
  • 资助金额:
    $ 32.48万
  • 项目类别:
26th National Neurotrauma Symposium, 2008
第26届全国神经创伤研讨会,2008年
  • 批准号:
    7541566
  • 财政年份:
    2008
  • 资助金额:
    $ 32.48万
  • 项目类别:

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