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

描述（由申请人提供）： 虽然对脊髓损伤（SCI）及其潜在机制有了更好的了解，但仍然没有实现有效的治疗。炎症、细胞内Ca 2+内流和氧化损伤是导致SCI后细胞死亡的继发性损伤途径的启动。由于目前唯一可用的治疗，甲基强的松龙，具有有限的临床疗效，新的疗法，以阻断炎症，减少细胞和轴突髓鞘损伤，并恢复血液供应，必须发现。 在急性SCI中，使用低剂量的多活性剂雌激素可以实现神经保护。雌激素通过阻断L型钙通道抑制SCI和培养细胞内钙内流和炎症反应。初步数据表明，低剂量雌激素可减少炎症，抑制钙蛋白酶-半胱天冬酶活性，保护细胞，保护轴突和髓鞘，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。 由于多个通路导致SCI中的组织破坏，仅阻断一个通路可能不是最佳的。该提案的目标是通过利用雌激素治疗以及通过结合保护组织和促进更大功能恢复的药物来保护CNS细胞和轴突髓鞘单位免受继发性损伤。除了雌激素，血管生成促进因子，如血管内皮生长因子（VEGF）的治疗，将进一步增加对受损脐带的血液供应，并有助于功能恢复。我们假设雌激素将促进血管生长，阻止Ca 2+内流，并减弱细胞和轴突髓鞘损伤，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。三个具体目标将测试假设：（1）调查低剂量雌激素治疗是否会通过减少炎症和轴突损伤，保护神经元和神经胶质细胞免于凋亡事件来保护SCI后的运动功能;（2）确定低剂量雌激素的单一治疗或与血管生成因子VEGF的联合治疗是否会通过促进血管生成来进一步改善SCI后长期的运动功能;以及（3）在受到兴奋性毒性或炎性应激的神经元和胶质细胞中检查由雌激素+/- VEGF介导的神经保护机制。从拟议的研究中获得的结果将有很强的翻译应用SCI，表明雌激素的治疗意义。

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.