Hormonal Intervention Protects Axon-myelin to Promote Functional Recovery in SCI

激素干预保护轴突髓磷脂，促进 SCI 功能恢复

• 批准号: 8597921
• 负责人: NAREN L BANIK
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597921
• 关键词: Acute; Adverse effects; Angiogenic Factor; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Apoptotic; Attenuated; Axon; Blood Vessels; Blood flow; Body Weight; Calcium; Calpain; Caspase; Cell Death; Cells; Cessation of life; Chronic; Clinical Treatment; Combined Modality Therapy; Coupling; Cultured Cells; Cytoprotection; Data; Demyelinations; Dose; Drug Targeting; Estradiol; Estrogen Receptors; Estrogen Therapy; Estrogens; Event; Free Radicals; Functional disorder; Gliosis; Glutamates; Goals; Growth; Hormonal; Hormones; Human; In Vitro; Inflammation; Inflammatory; Injury; Intervention; Ischemia; Lesion; Lipid Peroxidation; Locomotor Recovery; Measures; Mediating; Methylprednisolone; Motor; Motor Neurons; Myelin; Nerve Degeneration; Neuroglia; Neurons; Oxidative Stress; Pathway interactions; Peptide Hydrolases; Perfusion; Phagocytosis; Pharmaceutical Preparations; Physiological; Production; Property; Rattus; Recovery; Recovery of Function; Regulation; Research; Role; Secondary to; Signaling Protein; Site; Spinal Cord; Spinal Ganglia; Spinal cord injury; Stress; Testing; Therapeutic Agents; Time; Tissues; Toxic effect; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Vascular blood supply; Work; angiogenesis; assault; astrogliosis; base; cell injury; clinical efficacy; design; effective therapy; ganglion cell; injured; monocyte; motor deficit; motor function improvement; neuroprotection; novel; oxidative damage; pre-clinical; prevent; receptor; receptor expression; restoration; translational study

DESCRIPTION (provided by applicant): Although better understanding of spinal cord injury (SCI) and its underlying mechanisms has been achieved, creating an effective therapy is still unrealized. Inflammation, intracellular Ca2+ influx, and oxidative damage are implicit in the initiation of secondary injury pathways leading to cell death following SCI. Since the only currently available treatment, methylprednisolone, has limited clinical efficacy, novel therapies to block inflammation, reduce cell and axon-myelin damage, and restore blood supply must be discovered. Neuroprotection has been achieved in acute SCI with a low dose of the multi-active agent estrogen. Estrogen suppresses Ca2+ influx and inflammation in SCI and cultured cells by blocking L-type Ca2+ channels. Preliminary data indicates that low dose estrogen reduces inflammation, inhibits calpain-caspase activity, protects cells, preserves axons and myelin, and restores locomotor function. These results indicate that estrogen may be used as a therapeutic agent for treatment of SCI. By understanding SCI pathophysiology, therapies with low dose estrogen (17¿-estradiol), alone or in combination, will be designed to prevent inflammation, axonal damage, and cell death in the spinal cord after injury. Because multiple pathways cause tissue destruction in SCI, blocking only one pathway may not be optimal. The goal of this proposal is to protect CNS cells and the axon-myelin unit from secondary damage by utilizing estrogen treatment and also by combining agents that preserve tissue and promote greater functional recovery. In addition to estrogen, treatment with angiogenesis-promoting factors, e.g. vascular endothelial growth factor (VEGF), will further increase the blood supply to the injured cord and aid in functional recovery. We hypothesize that estrogen will promote vascular growth, prevent Ca2+ influx, and attenuate cell and axon-myelin damage, lipid peroxidation, inflammation, and monocyte phagocytosis. Inhibition of these pathways will consequently block downstream calpain-mediated apoptotic events. Combination therapy with VEGF will further promote recovery by restoring tissue perfusion. Three specific aims will test the hypothesis: (1) investigate whether low dose estrogen therapy will preserve motor function following SCI by reducing inflammation and axonal damage, and protecting neuronal and glial cells from apoptotic events; (2) determine whether single therapy with low-dose estrogen or combination therapy with the angiogenic factor VEGF will further improve motor function long-term following SCI by promoting angiogenesis; and (3) examine the mechanisms of neuroprotection mediated by estrogen +/- VEGF in neurons and glia subjected to either excitotoxic or inflammatory stress. Results obtained from the proposed studies will have strong translational application to SCI, suggesting estrogen's therapeutic significance.

描述（由申请人提供）： 尽管人们已经对脊髓损伤（SCI）及其潜在机制有了更好的了解，但仍未实现有效的治疗方法。炎症、细胞内 Ca2+ 内流和氧化损伤隐含在导致 SCI 后细胞死亡的继发性损伤途径的启动中。由于目前唯一可用的治疗方法甲基泼尼松龙的临床疗效有限，因此必须发现阻止炎症、减少细胞和轴突髓磷脂损伤以及恢复血液供应的新疗法。 使用低剂量的多活性药物雌激素已在急性 SCI 中实现了神经保护。雌激素通过阻断 L 型 Ca2+ 通道来抑制 SCI 和培养细胞中的 Ca2+ 流入和炎症。初步数据表明，低剂量雌激素可减轻炎症，抑制钙蛋白酶-半胱天冬酶活性，保护细胞，保留轴突和髓磷脂，并恢复运动功能。这些结果表明雌激素可用作治疗SCI的治疗剂。通过了解 SCI 病理生理学，低剂量雌激素（17-雌二醇）单独或联合治疗将被设计用于预防损伤后脊髓中的炎症、轴突损伤和细胞死亡。 由于多种途径会导致 SCI 中的组织破坏，因此仅阻断一种途径可能不是最佳选择。该提案的目标是通过利用雌激素治疗以及结合保护组织和促进更大功能恢复的药物来保护中枢神经系统细胞和轴突髓磷脂单元免受继发性损伤。除了雌激素外，还可以使用血管生成促进因子进行治疗，例如：血管内皮生长因子（VEGF）将进一步增加受伤脊髓的血液供应，有助于功能恢复。我们假设雌激素会促进血管生长，防止 Ca2+ 内流，并减轻细胞和轴突髓磷脂损伤、脂质过氧化、炎症和单核细胞吞噬作用。这些途径的抑制将因此阻断下游钙蛋白酶介导的细胞凋亡事件。与 VEGF 联合治疗将通过恢复组织灌注进一步促进康复。三个具体目标将检验这一假设：（1）研究低剂量雌激素治疗是否可以通过减少炎症和轴突损伤以及保护神经元和神经胶质细胞免受凋亡事件来保护脊髓损伤后的运动功能； (2) 确定低剂量雌激素单一治疗或与血管生成因子VEGF联合治疗是否会通过促进血管生成进一步改善SCI后的长期运动功能； (3) 检查在受到兴奋性毒性或炎症应激的神经元和神经胶质细胞中由雌激素+/- VEGF 介导的神经保护机制。从拟议研究中获得的结果将对 SCI 具有强大的转化应用价值，表明雌激素的治疗​​意义。