ESTROGEN EFFICACY IN SPINAL CORD INJURY

雌激素在脊髓损伤中的功效

• 批准号: 6805937
• 负责人: NAREN L BANIK
• 金额: $ 27.01万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6805937
• 关键词: behavioral /social science research tag; calcium flux; cellular pathology; electron microscopy; electrophysiology; enzyme activity; estrogens; functional ability; glutamates; hormone therapy; immunofluorescence technique; laboratory rat; mitochondrial disease /disorder; myeloperoxidase; neurons; neuroprotectants; nonhuman therapy evaluation; oxidative stress; progesterone; spinal cord injury; terminal nick end labeling

DESCRIPTION (provided by applicant): Although the understanding of spinal cord injury (SCI) and its mechanisms have increased over the years, effective therapy to minimize tissue damage and maximize functional recovery remains a primary goal. The only treatment, methylprednisolone, has limited clinical efficacy. Emphasis is needed on early pharmacological intervention of secondary damage involving Ca2+ overload, free radicals, glutamate toxicity, and enzyme activation. Investigations into cell and fiber damage, tissue destruction, neuron protection, and maintenance of structural integrity are essential to effective treatments. After SCI, intracellular Ca2+ influx initiates secondary pathological events (cell damage, tissue destruction). Our goal is to protect CNS cells from secondary damage by using agents that preserve and restore function. Since several pathways cause cell damage and tissue destruction, multiple action drugs or a combination therapy will likely be more effective. One group of potential agents, steroid hormones, estrogen, and progesterone, are neuroprotective in cultured neurons and in CNS disorders. We hypothesize that estrogen/progesterone will control inflammatory processes, suppress intracellular Ca2+ levels, and inhibit Ca2+-dependent events. Suppression of intracellular Ca2+ will inhibit activation of lipases and proteinases (e.g., calpain) and protect cells from secondary damage. Estrogen decreases infiltration of inflammatory cells (e.g., macrophages), reduces Ca2+ levels and Ca2+-dependent events, and restores mitochondrial function in SCI lesion and penumbra (compared to vehicle-treated animals). Our preliminary data reveals that the effects seen with estrogen treatment may be superior to those seen with methylprednisolone. Cells undergoing apoptosis due to H202 and glutamate toxicity have increased intracellular Ca2+. Estrogen treatment reduced Ca2+, protected these cells from damage, and led to functional recovery. Thus, the following Specific Aims are proposed: . Examine the effects of estrogen treatment on inflammation following acute SCI . Investigate estrogen effects on intracellular Ca2+ influx and Ca2+ -dependent events in cell and tissue damage in SCI . Investigate whether estrogen treatment will preserve motor function in chronic SCI . Examine whether estrogen treatment will protect and preserve the function of neurons (cortical and motor) and glial cells subjected to oxidative stress and glutamate toxicity in culture. Novel and relevant techniques, i.e., determining Ca levels in cultured cells and SCI slices (fura-2), cell damage (TUNEL), cell function (electrophysiology), and motor recovery ("BBB" scale), will be used. Understanding estrogen's mechanisms in cell protection and recovery as it relates to multidestructive pathways will establish it as a viable SCI treatment agent.

描述（由申请人提供）：尽管多年来对脊髓损伤（SCI）及其机制的了解有所增加，但最大限度地减少组织损伤和最大限度地功能恢复的有效治疗仍然是主要目标。唯一的治疗方法是甲基强的松龙，其临床疗效有限。需要强调对涉及 Ca2+ 超载、自由基、谷氨酸毒性和酶激活等继发性损伤的早期药物干预。对细胞和纤维损伤、组织破坏、神经元保护和结构完整性维持的研究对于有效的治疗至关重要。 SCI 后，细胞内 Ca2+ 流入引发继发性病理事件（细胞损伤、组织破坏）。我们的目标是通过使用保留和恢复功能的药物来保护中枢神经系统细胞免受二次损伤。由于多种途径会导致细胞损伤和组织破坏，因此多种作用药物或联合疗法可能会更有效。一组潜在的药物，类固醇激素、雌激素和黄体酮，对培养的神经元和中枢神经系统疾病具有神经保护作用。我们假设雌激素/孕激素将控制炎症过程、抑制细胞内 Ca2+ 水平并抑制 Ca2+ 依赖性事件。 抑制细胞内 Ca2+ 将抑制脂肪酶和蛋白酶（例如钙蛋白酶）的激活，并保护细胞免受二次损伤。雌激素减少炎症细胞（例如巨噬细胞）的浸润，降低 Ca2+ 水平和 Ca2+ 依赖性事件，并恢复 SCI 病变和半影中的线粒体功能（与媒介物治疗的动物相比）。我们的初步数据显示，雌激素治疗的效果可能优于甲基强的松龙。由于 H2O2 和谷氨酸毒性而发生凋亡的细胞细胞内 Ca2+ 增加。雌激素治疗可减少 Ca2+，保护这些细胞免受损伤，并导致功能恢复。因此，提出以下具体目标： 。检查雌激素治疗对急性 SCI 后炎症的影响 。研究雌激素对 SCI 中细胞内 Ca2+ 内流以及细胞和组织损伤中 Ca2+ 依赖性事件的影响 。研究雌激素治疗是否能保留慢性 SCI 患者的运动功能 。检查雌激素治疗是否会保护和保留在培养物中遭受氧化应激和谷氨酸毒性的神经元（皮质和运动）和神经胶质细胞的功能。 将使用新颖的相关技术，即确定培养细胞和 SCI 切片 (fura-2) 中的 Ca2+ 水平、细胞损伤 (TUNEL)、细胞功能（电生理学）和运动恢复（“BBB”量表）。了解雌激素在细胞保护和恢复方面的机制，因为它与多破坏性途径相关，将使其成为一种可行的 SCI 治疗剂。