Role of Acrolein in Spinal Cord Injury

丙烯醛在脊髓损伤中的作用

• 批准号: 8295852
• 负责人: RIYI SHI
• 金额: $ 35.04万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8295852
• 关键词: Acrolein; Address; Aldehydes; Animal Model; Animals; Belief; Binding; Biochemical; Biochemical Reaction; Clinical; Data; Disease; Dose; Effectiveness; Free Radical Scavengers; Free Radicals; Goals; Half-Life; High Pressure Liquid Chromatography; Hydralazine; Immunoblotting; In Vitro; Injury; Intervention; Laboratories; Lesion; Life; Lipid Peroxidation; Mechanics; Mediating; Methods; Modeling; Nerve Degeneration; Nervous System Trauma; Neurons; Outcome; Oxidative Stress; Oxygen; Pathogenesis; Pathology; Patients; Pharmacologic Substance; Pharmacy (field); Phenelzine; Play; Primary Lesion; Production; Rattus; Reactive Oxygen Species; Recovery; Recovery of Function; Research; Role; Severities; Site; Spinal Cord; Spinal Cord Contusions; Spinal cord injury; Structure; Testing; Therapeutic; Therapeutic Intervention; Tissues; Toxin; Translating; Trauma; Work; clinical efficacy; functional loss; in vivo; injured; innovation; neuroprotection; novel; relating to nervous system; research study; response; success; therapeutic target; treatment planning

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. PUBLIC HEALTH RELEVANCE: This project is seeking to determine if acrolein plays a key role in spinal cord injury (SCI) in vivo. Following quantification in SCI, acrolein will be examine for its role in secondary injury and anti-acrolein therapy will be tested for enhancing recovery in SCI. Success in this study will establish acrolein as a novel target for therapeutic intervention i SCI.

描述（由申请人提供）：身体创伤只是脊髓损伤 (SCI) 问题的一部分：在损伤后的几天和几周内，氧化应激在 SCI 病理学中起着至关重要的作用。尽管经过多年的研究，旨在清除短暂自由基的传统策略尚未证明在减少氧化应激方面有任何临床功效。 有证据表明，脂质过氧化的醛类副产物——丙烯醛——在 SCI 后升高，并且该物质对神经组织具有直接毒性，其半衰期比更广为人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，因此构成更有效的靶点 用于治疗。我们进一步假设抑制丙烯醛可以显着减少神经元损伤并增强 SCI 后的功能恢复。在体外和离体证明了充分的支持后，我们现在准备通过 SCI 动物模型在体内测试这一假设，这是表明丙烯醛是 SCI 关键因素的不可或缺的下一步。本申请的目的是确定丙烯醛在活体 SCI 动物模型创伤后发病机制中的作用。我们将使用已建立的大鼠脊髓挫伤模型，具有三个具体目标。首先，我们寻求使用高效液相色谱和免疫印迹方法量化多种损伤严重程度的丙烯醛水平，并将这些水平与体内 SCI 的病理变化相关联。其次，我们将通过直接向未受伤大鼠的脊髓注射不同浓度的丙烯醛来评估丙烯醛在独立于身体创伤引起的 SCI 中的作用。该实验将为丙烯醛参与 SCI 继发性损伤机制提供重要证据。最后，我们将使用两种已知的丙烯醛清除剂肼屈嗪和苯乙嗪，评估丙烯醛结合作为治疗策略在大鼠 SCI 体内的有效性。这项工作的预期结果是，我们将确定丙烯醛是脊髓损伤后的一种内源性毒素，也是 SCI 病变继发性扩张的关键因素。通过证明丙烯醛是一种新颖、有效的治疗干预靶标，我们期望现有的药物能够迅速转化为 SCI 患者的临床治疗，并且将研究新的和现有的化合物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受益，还可以使患有其他疾病的患者受益。 与氧化应激有关的疾病。 公共健康相关性：该项目旨在确定丙烯醛是否在体内脊髓损伤 (SCI) 中发挥关键作用。在 SCI 中进行量化后，将检查丙烯醛在继发性损伤中的作用，并将测试抗丙烯醛治疗是否能促进损伤的恢复。 SCI。这项研究的成功将确立丙烯醛作为 SCI 治疗干预的新靶点。