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）及其机制的理解及其机制有所提高，但有效的治疗方法可以最大程度地减少组织损伤和最大化功能恢复仍然是主要目标。唯一的治疗方法是甲基强酮，其临床功效有限。需要强调涉及Ca2+过载，自由基，谷氨酸毒性和酶激活的次要损伤的早期药理干预措施。研究细胞和纤维损伤，组织破坏，神经元保护和结构完整性的维持对于有效治疗至关重要。 SCI之后，细胞内CA2+流入启动次要病理事件（细胞损伤，组织破坏）。我们的目标是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继发损伤。由于几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，雌激素和孕酮是培养的神经元和中枢神经系统疾病中的神经保护作用。我们假设雌激素/孕酮将控制炎症过程，抑制细胞内Ca2+水平并抑制CA2+依赖性事件。 细胞内Ca2+的抑制作用将抑制脂肪酶和蛋白酶（例如钙蛋白酶）的激活，并保护细胞免受继发性损伤。雌激素可降低炎性细胞（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病变和半阴茎中的线粒体功能（与媒介物处理的动物相比）。我们的初步数据表明，雌激素治疗所见的作用可能优于甲基泼尼松龙看到的作用。由于H202和谷氨酸毒性引起的细胞凋亡的细胞增加了细胞内Ca2+。雌激素治疗降低了Ca2+，保护了这些细胞免受损伤，并导致功能恢复。因此，提出了以下具体目标： 。检查急性SCI后雌激素治疗对炎症的影响 。研究雌激素对细胞内Ca2+流入和Ca2+依赖性事件的影响在SCI中的细胞和组织损伤中 。研究雌激素治疗是否会保留慢性科学的运动功能 。检查雌激素治疗是否会保护和保留神经元（皮质和运动）的功能以及受氧化应激和谷氨酸毒性的神经胶质细胞的功能。 新型技术和相关技术，即确定培养细胞和SCI切片（Fura-2），细胞损伤（TUNEL），细胞功能（电生理学）和运动恢复（“ BBB”量表）的CA水平。了解雌激素在细胞保护和恢复方面的机制与多造影途径有关，将其确定为可行的SCI治疗剂。