Role of Acrolein in Spinal Cord Injury

丙烯醛在脊髓损伤中的作用

• 批准号: 8890974
• 负责人: RIYI SHI
• 金额: $ 2.67万
• 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/8890974
• 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.

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，氧化应激在脊髓损伤病理中起着关键作用。尽管多年的研究，旨在清除瞬态自由基的传统策略在减少氧化应激方面尚未显示出任何临床疗效。