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: 8330422
• 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/8330422
• 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。 SCI 后导致细胞死亡的继发性损伤途径的启动隐含着炎症、细胞内 Ca2+ 内流和氧化损伤。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，因此必须找到阻止炎症、减少细胞和轴突髓磷脂损伤以及恢复神经保护的新疗法。在急性 SCI 中，使用低剂量的多活性雌激素可通过阻断 L 型 Ca2+ 通道来抑制 SCI 和培养细胞中的 Ca2+ 内流和炎症。通过了解 SCI，雌激素可用作治疗 SCI 的药物。病理生理学，低剂量雌激素治疗（17¿ -雌二醇），单独或组合，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，因为多种途径会导致 SCI 中的组织破坏，因此仅阻断一种途径可能不是最佳目标。该提议是通过利用雌激素治疗以及除雌激素外结合保护组织和促进更大功能恢复的药物以及血管生成促进因子（例如血管生成素）的治疗来保护中枢神经系统细胞和轴突髓鞘单元免受继发性损伤。内皮生长因子（VEGF），将进一步增加受伤脊髓的血液供应并帮助功能恢复，我们认为雌激素会促进血管生长，防止Ca2+流入，并减轻细胞和轴突髓磷脂损伤，脂质过氧化，炎症，抑制这些途径将阻止下游钙蛋白酶介导的细胞凋亡事件，与 VEGF 的联合治疗将通过恢复组织灌注进一步促进恢复。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；剂量雌激素或与血管生成因子 VEGF 的联合治疗将通过促进血管生成进一步改善 SCI 后的长期运动功能；(3) 检查雌激素 +/- VEGF 介导的神经元和神经胶质细胞的神经保护机制；从所提出的研究中获得的结果将对 SCI 具有很强的转化应用，表明雌激素的治疗​​意义。