METHYLPREDNISOLONE TREATMENT IN ACUTE SPINAL CORD INJURY

甲基泼尼松龙治疗急性脊髓损伤

• 批准号: 6529564
• 负责人: Chung Y. Hsu
• 金额: $ 31.75万
• 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/6529564
• 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）甲泼尼龙（MP）， 一种合成的糖皮质激素（GC），是唯一被证实的急性 脊髓损伤（SCI）。MP在SCI中的治疗作用已被证实。 以前归因于其抗氧化作用。Tirilazad，GC类似物， 比MP更有效的抗氧化作用，但GC活性较小， 在最近的临床SCI试验中，MP的疗效更好。这一发现表明， MP在SCI中的治疗效果可能与其GC活性比与其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。GC的抗炎作用是由受体介导的 其机制涉及核受体，糖皮质激素受体（GR）。GC （配体）与GR（受体）结合，形成活化的GR（aGR）。aGR是一个 具有双重和互补作用的转录因子， 抗炎作用谱：（1）与核 糖皮质激素反应元件（GRE）反式激活抗炎基因; 和（2）抑制2种关键的促炎性转录因子NF-B和AP-1， 来反式抑制促炎基因。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中的作用机制集中于受体介导的事件。我们将 检验一个中心假设，即MP在SCI中的治疗作用是介导的 至少部分通过涉及aGR的受体机制。首先，我们将研究 MP在涉及aGR介导事件的SCI中的抗炎作用。第二、 我们将研究MP在SCI中的抗炎作用是否可以被阻断， 一种有效的GR拮抗剂RU 486第三，具有可变效力的GR激动剂 将测试它们对创伤后炎症反应的影响。 第四，通过比较GR在SCI中的治疗意义， 选择的GR激动剂和拮抗剂在功能性和 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对SCI的治疗作用。最终目标是发展更多 有效的治疗策略，SCI的基础上更好地了解 MP作用机制。