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

描述(由申请人提供)： 尽管对脊髓损伤(SCI)及其潜在机制已有了更好的了解，但创造有效的治疗方法仍未实现。炎症、细胞内钙内流和氧化损伤在脊髓损伤后导致细胞死亡的继发性损伤通路的启动中是隐含的。由于目前唯一可用的治疗方法是甲基强的松龙，临床疗效有限，因此必须找到新的治疗方法来阻断炎症，减少细胞和轴突-髓鞘损伤，并恢复血液供应。在急性脊髓损伤中，使用低剂量的多活性雌激素可以实现神经保护。雌激素通过阻断L钙通道抑制脊髓损伤和培养细胞的钙内流和炎症反应。初步数据表明，低剂量的雌激素可以减轻炎症，抑制钙蛋白酶-半胱氨酸酶活性，保护细胞，保护轴突和髓鞘，恢复运动功能。这些结果表明，雌激素可作为治疗脊髓损伤的药物。通过了解脊髓损伤的病理生理学，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脊髓损伤后的炎症、轴突损伤和细胞死亡。由于多条途径会导致脊髓损伤的组织破坏，因此仅阻断一条途径可能并不是最优的。这项建议的目标是通过利用雌激素治疗以及通过结合保存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-髓鞘单位免受二次损伤。除雌激素外，血管生成促进因子(如血管内皮生长因子)的治疗将进一步增加损伤脊髓的血液供应，并有助于功能恢复。我们假设雌激素将促进血管生长，防止钙离子内流，并减轻细胞和轴突髓鞘损伤、脂质过氧化、炎症和单核细胞吞噬。因此，抑制这些通路将阻断下游的钙蛋白酶介导的细胞凋亡事件。与血管内皮生长因子联合治疗将通过恢复组织灌注量进一步促进康复。将有三个具体目标验证这一假说：(1)研究低剂量雌激素治疗是否可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的影响来保护脊髓损伤后的运动功能；(2)确定低剂量雌激素单独治疗或联合血管生成因子VEGF是否可通过促进血管生成来进一步改善脊髓损伤后长期的运动功能；以及(3)研究雌激素+/-血管内皮生长因子介导的神经保护作用在兴奋性应激或炎性应激下神经元和胶质细胞中的作用机制。建议的研究结果将对脊髓损伤有很强的翻译应用，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.