Role of Acrolein in Spinal Cord Injury

描述（由申请人提供）：物理创伤只是脊髓损伤（SCI）问题的一部分：在损伤后的几天和几周内，氧化应激在SCI病理学中起着关键作用。尽管经过多年的研究，旨在抑制瞬时自由基的常规策略在减少氧化应激方面没有表现出任何临床疗效。 有证据表明，SCI后脂质过氧化的醛副产物--丙烯醛--含量升高，并且该物质对神经组织直接有毒，其半衰期比已知的活性氧物质长得多。因此，我们假设丙烯醛是SCI后持续氧化应激的关键因素，因此构成了更有效的靶点 用于治疗。我们进一步假设，抑制丙烯醛可能会显着减少神经元损伤和增强功能恢复后SCI。在体外和离体实验中已经证明了充分的支持，我们现在准备通过SCI动物模型在体内测试这一假设，这是将丙烯醛作为SCI关键因素的不可或缺的下一步。本申请的目的是在SCI的活体动物模型中确定丙烯醛在创伤后发病机制中的作用。我们将使用一个建立的大鼠脊髓挫伤模型，有三个具体的目标。首先，我们试图用高效液相色谱法和免疫印迹法定量丙烯醛在多种损伤程度下的水平，并将这些水平与体内SCI的病理变化相关联。其次，我们将评估丙烯醛的作用，导致SCI独立的物理创伤，直接注射不同浓度的丙烯醛的未受伤大鼠的脊髓。本实验为丙烯醛参与脊髓损伤继发性损伤机制提供了重要证据。最后，我们将评估丙烯醛结合的有效性作为治疗策略，使用两个已知的丙烯醛清除剂，肼苯哒嗪和苯乙肼在大鼠SCI在体内。这项工作的预期结果是，我们将建立丙烯醛作为脊髓创伤后的内源性毒素和脊髓损伤继发性扩大的关键因素。通过证明丙烯醛是一种新的，有效的治疗干预目标，我们希望现有的药物可以迅速转化为SCI患者的临床治疗，新的和现有的化合物将被研究其作为丙烯醛清除治疗的潜力。这种治疗策略不仅可以使脊髓损伤患者受益，而且可以使其他患者受益。 与氧化应激有关的疾病。

DESCRIPTION (provided by applicant): Physical trauma is only part of the problem in spinal cord injury (SCI): in the days and weeks following damage, oxidative stress plays a critical role in SCI pathology. Despite years of research, conventional strategies aiming to scavenge transient free radicals have not demonstrated any clinical efficacy at curtailing oxidative stress. Evidence indicates that an aldehyde byproduct of lipid peroxidation-acrolein-is elevated following SCI, and that this species is directly toxic to neural tissues, with a much longer half-lfe than the better known reactive oxygen species. Therefore, we hypothesize that acrolein is a key factor in perpetuating oxidative stress following SCI, and thus constitutes a more effective target for therapeutic treatments. We further hypothesize that suppression of acrolein may significantly reduce neuronal damage and enhance functional recovery following SCI. Having demonstrated ample support in vitro and ex vivo, we are now poised to test this hypothesis in vivo through animal models of SCI, an indispensible next step to implicate acrolein as a key factor in SCI. The objective of this application is to ascertain the role of acrolein in post-traumatic pathogenesis in a live animal model of SCI. We will use an established rat spinal cord contusion injury model with three specific aims. First, we seek to quantify the levels of acrolein for multipe severities of injury using high performance liquid chromatography and immunoblotting methods, and correlate those levels with pathological changes in SCI in vivo. Secondly, we will assess the role of acrolein in causing SCI independent of physical trauma by directly injecting varying concentrations of acrolein to the spinal cord of uninjured rats. This experiment will provide crucial evidence to implicate acrolein in secondary injury mechanisms of SCI. Finally, we will evaluate the effectiveness of acrolein binding as therapeutic strategy using two known acrolein scavengers, hydralazine and phenelezine in rat SCI in vivo. The expected outcomes of the proposed work are that we will establish acrolein as an endogenous toxin following spinal cord trauma and a critical factor in secondary expansion of lesions in SCI. By demonstrating that acrolein is a novel, effective target for therapeutic intervention, we expect that existing pharmaceutics can be rapidly translated to clinical therapy for SCI victims, and that new and existing compounds will be investigated for their potential as acrolein scavenging treatments. Such therapeutic strategies could benefit not only spinal cord injury, but also patients with other diseases associated with oxidative stress.