METHYLPREDNISOLONE TREATMENT IN ACUTE SPINAL CORD INJURY

甲基泼尼松龙治疗急性脊髓损伤

• 批准号: 6287485
• 负责人: Chung Y. Hsu
• 金额: $ 33.16万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6287485
• 关键词: corticosteroid receptors; disease /disorder model; hormone therapy; laboratory rat; methylprednisolone; nonhuman therapy evaluation; spinal cord injury; transcription factor

DESCRIPTION: (Verbatim from the Applicant's Abstract) Methylprednisolone (MP), a synthetic glucocorticoid (GC), is the only proven therapeutic agent for acute spinal cord injury (SCI). The therapeutic action of MP in SCI has been previously attributed to its antioxidant action. Tirilazad, a GC analog with more potent antioxidant action than MP but little GC activity, is less effective than MP in recent clinical SCI trials. This finding suggests that the therapeutic efficacy of MP in SCI may be more related to its GC activity than antioxidant action. An inflammatory reaction has been extensively documented after SCI. GCs including MP are among the most potent anti-inflammatory agents ever developed. The anti-inflammatory action of GC is mediated by a receptor mechanism involving a nuclear receptor, glucocorticoid receptor (GR). GC (ligand) binds to GR (receptor) forming an activated GR (aGR). aGR is a transcription factor serving dual and complimentary roles to confer a broad spectrum of anti-inflammatory actions: (1) binding to the nuclear glucocorticoid response element (GRE) to transactivate anti-inflammatory genes; and (2) inhibiting 2 key pro-inflammatory transcription factors, NF-B and AP-1, to transrepress pro-inflammatory genes. In contrast to the anti-inflammatory effects of GCs, the antioxidant action of MP or tirilazad does NOT involve a receptor mechanisms. This project is designed to explore the molecular mechanisms of MP action in SCI focusing on receptor-mediated events. We will test a central hypothesis that the therapeutic effect of MP in SCI is mediated at least in part by a receptor mechanism involving aGR. First, we will study anti-inflammatory effects of MP in SCI involving aGR mediated events. Second, we will examine whether anti-inflammatory actions of MP in SCI can be blocked by a potent GR antagonist, RU486. Third, GR agonists with variable potencies will be tested for their effects on the post-traumatic inflammatory reaction. Fourth, the therapeutic significance of GR in SCI will be assessed by comparing MP effects with selected GR agonists and antagonists in functional and morphological outcome studies. The overall objective of this project is to establish that a receptor mechanism involving aGR contributes to the therapeutic effects of MP in SCI. The ultimate goal is to develop more effective therapeutic strategies for SCI based on a better understanding of the mechanism of MP action.

描述：（逐字摘自申请人摘要）甲基强的松龙（MP）， 一种合成糖皮质激素 (GC)，是唯一经过验证的急性急性发作治疗剂 脊髓损伤（SCI）。 MP 对 SCI 的治疗作用 先前归因于其抗氧化作用。 Tirilazad，一种 GC 类似物 比 MP 更有效的抗氧化作用，但 GC 活性较低， 在最近的临床 SCI 试验中比 MP 更有效。这一发现表明 MP 在 SCI 中的治疗效果可能与其 GC 活性更相关 抗氧化作用。炎症反应已被广泛记录 SCI之后。包括 MP 在内的 GC 是最有效的抗炎剂之一 曾经发展过。 GC 的抗炎作用是由受体介导的 机制涉及核受体，糖皮质激素受体（GR）。气相色谱 （配体）与 GR（受体）结合形成激活的 GR (aGR)。 aGR 是一个 转录因子具有双重和互补的作用，赋予广泛的 抗炎作用谱：(1) 与核结合 糖皮质激素反应元件（GRE）反式激活抗炎基因； (2) 抑制 2 种关键促炎转录因子 NF-B 和 AP-1， 反式抑制促炎基因。与抗炎药相比 GC 的影响，MP 或替拉扎德的抗氧化作用不涉及 受体机制。该项目旨在探索分子 MP 在 SCI 中的作用机制侧重于受体介导的事件。我们将 检验 MP 在 SCI 中的治疗作用是介导的中心假设 至少部分是通过涉及 aGR 的受体机制实现的。首先我们要学习的是 MP 在涉及 aGR 介导事件的 SCI 中的抗炎作用。第二， 我们将研究 SCI 中 MP 的抗炎作用是否可以被阻断 一种有效的 GR 拮抗剂 RU486。第三，GR激动剂具有不同的效力 将测试它们对创伤后炎症反应的影响。 第四，将通过比较来评估 GR 在 SCI 中的治疗意义 所选 GR 激动剂和拮抗剂在功能和功能方面的 MP 效应 形态学结果研究。该项目的总体目标是 确定涉及 aGR 的受体机制有助于 MP在SCI中的治疗作用。最终目标是发展更多 基于对 SCI 更好理解的有效治疗策略 MP作用机制。