METHYLPREDNISOLONE TREATMENT IN ACUTE SPINAL CORD INJURY

描述：(逐字摘自申请人摘要)甲基强的松龙(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)。甲基强的松龙对脊髓损伤的治疗作用 此前归因于其抗氧化作用。Tirilazad，一种GC类似物， 比MP有更强的抗氧化作用，但GC活性很低 在最近的临床脊髓损伤试验中，其疗效优于甲氧西林。这一发现表明， MP治疗脊髓损伤的疗效可能更多地与其GC活性有关，而不是 抗氧化作用。炎症反应已被广泛记录在案。 在SCI之后。包括MP在内的GCS是最有效的抗炎药之一 从未开发过的。GC的抗炎作用是由一种受体介导的 涉及核受体、糖皮质激素受体(GR)的机制。气相色谱 (配体)与GR(受体)结合，形成活化的GR(AGR)。AGR是一种 转录因子具有双重和互补的作用，赋予广泛的 抗炎作用的范围：(1)与核结合 糖皮质激素反应元件(GRE)反式激活抗炎基因； 和(2)抑制两个关键的促炎转录因子，核因子-B和AP-1， 来反式抑制促炎基因。与抗炎药形成对比 ，MP或替拉扎德的抗氧化作用不涉及 受体机制。这个项目的目的是探索分子 MP在脊髓损伤中的作用机制主要集中在受体介导的事件上。我们会 验证甲基强的松龙对脊髓损伤的治疗作用是中介的中心假设 至少部分是通过涉及AGR的受体机制。首先，我们将研究 甲基强的松龙在脊髓损伤中的抗炎作用。第二, 我们将研究MP在脊髓损伤中的抗炎作用是否可以被阻断 一种强有力的GR拮抗剂RU486。第三，具有可变效价的GR激动剂 将测试它们对创伤后炎症反应的影响。 第四，通过比较来评价GR在脊髓损伤中的治疗意义。 某些GR激动剂和拮抗剂在功能性和非功能性的MP效应 形态结果研究。这个项目的总体目标是 确定涉及AGR的受体机制有助于 甲基强的松龙对脊髓损伤的治疗作用最终目标是发展更多 基于对脊髓损伤的更好认识的有效治疗策略 MP的作用机制。

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.