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）： 尽管已经实现了对脊髓损伤（SCI）及其潜在机制的更好了解，但仍未实现有效的疗法。炎症，细胞内Ca2+影响和氧化损伤在导致SCI后导致细胞死亡的继发性损伤途径中隐含。由于目前唯一可用的治疗方法，甲基强酮的临床有效性有限，可阻止感染的新疗法，减少细胞和轴突 - 膜蛋白损伤，并且必须发现恢复血液供应。在急性SCI中，具有低剂量的多动剂雌激素的神经保护作用。雌激素通过阻断L型Ca2+通道来抑制SCI和培养细胞中的Ca2+影响和感染。初步数据表明，低剂量雌激素会降低感染，抑制钙蛋白酶蛋白酶的活性，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，单独或组合的低剂量雌激素（17？ - 雌二醇）的疗法将被设计为防止受伤后的脊髓感染，轴突损伤和细胞死亡。由于多种途径会导致SCI组织破坏，因此仅阻止一个途径可能不是最佳的。该提案的目的是通过利用雌激素处理以及结合保留组织并促进更大功能恢复的剂来保护CNS细胞和轴突膜蛋白单位免受次要损伤。除雌激素外，用血管生成因子处理，例如血管内皮生长因子（VEGF）将进一步增加受伤的绳索的血液供应并有助于功能恢复。我们假设雌激素将促进血管生长，预防Ca2+影响，并减弱细胞和轴突膜蛋白损伤，脂质过氧化，感染和单核细胞吞噬作用。因此，抑制这些途径将阻止下游钙蛋白酶介导的凋亡事件。与VEGF结合疗法将通过恢复组织灌注进一步促进恢复。三个具体目的将检验假设：（1）研究低剂量的雌激素治疗是否会通过减少注射和轴突损伤并保护SCI后的运动功能，并保护神经元和神经胶质细胞免受凋亡事件的影响； （2）确定低剂量雌激素或与血管生成因子VEGF的单次治疗是否会通过促进血管生成后长期长期改善运动功能； （3）检查由雌激素+/- VEGF介导的神经保护的机制，在神经元和神经元中受到兴奋性或炎症胁迫的作用。从拟议的研究中获得的结果将对SCI具有很强的翻译应用，这表明雌激素的治疗​​意义。