Mechanisms of secondary injury after SCI

描述（由申请人提供）：先天免疫应答显然是CNS创伤中继发性损伤级联的组成部分，但胶质细胞和单核细胞衍生的促炎细胞因子的作用因多种浓度依赖性受体介导的多种下游效应以及快速变化和演变的微环境而复杂化。我们有新的发现，强烈支持的假设，TNF和AMPAR的变化是至关重要的继发性损伤和恢复后中枢神经系统损伤。使用可溶性TNF受体蛋白（sTNFR 1）隔离TNF可减少颈椎SCI后的损伤，并以高度剂量依赖性的方式改善神经功能结局。我们建议扩展我们的研究TNF和AMPAR贩运作为SCI的治疗靶点，使用多变量方法来测试临床前疗效。依那西普（ETAN）是一种临床上用于类风湿性关节炎的TNF螯合蛋白生物制剂;托吡酯（TPM）是一种具有AMPAR拮抗作用的神经保护性抗癫痫药物。我们将使用这些药物分别或联合打击AMPAR贩运和AMPAR活动。我们将系统地评估这些药物的生物反应，使用早期损伤后的生物标志物，在我们以前的工作中预测神经系统的结果。我们将使用生物标志物数据来计划临床前剂量和时间方案，以评估颈部和胸部大鼠SCI的有效性，并评估其对自主神经，感觉和运动结果的影响。这些努力旨在将抗TNF疗法用于SCI的临床应用，并且可能也适用于其他CNS退行性疾病。我们提出了三个具体的目标：目标1：我们将评估ETAN和TPM对颈脊髓损伤后AMPAR表面表达，细胞死亡和促炎细胞因子产生的生物标志物的时间过程和程度的影响。我们预测这些治疗将减少细胞死亡的前馈级联。目标二。在这些数据的指导下，我们将优化单药和联合治疗的剂量和时间，以最大限度地利用各种前肢功能测试（梳理、爪放置、猫道和伊布）在单侧颈脊髓损伤后6周恢复。目标3：我们将使用一系列包括自主神经、感觉和运动结果的测试来测试优化的药物治疗方案对胸部挫伤病变恢复的影响。这将确定疗效是否扩展到SCI的多种模型。TNF和AMPAR也参与神经损伤后慢性超敏反应的产生（Choi et al，2010），我们将测试SCI后是否也会发生这种情况。TPM已经用于治疗慢性SCI疼痛。我们预测，使用ETAN和TPM进行急性治疗可获得更好的运动结局，也可减少长期异常性疼痛和强直性、厌恶性中枢性疼痛（King et al，2009），后者通过位置偏好测试进行测量。

DESCRIPTION (provided by applicant): The innate immune response is clearly an integral part of the secondary injury cascade in CNS trauma, but the role of glial and monocyte derived pro-inflammatory cytokines is complicated by multiple downstream effects mediated by multiple concentration-dependent receptors, and a rapidly changing and evolving microenvironment. We have new findings that strongly support the hypothesis that TNF and AMPAR changes are critical in both secondary injury and recovery after CNS injury. Sequestering TNF using soluble TNF receptor protein (sTNFR1) reduces damage after cervical SCI, and, in a highly dose-dependent manner, improves neurological outcomes. We propose to extend our studies of TNF and AMPAR trafficking as a therapeutic target for SCI using a multivariate approach to test preclinical efficacy. Etanercept (ETAN) is a TNF-sequestering protein biologic used clinically in rheumatoid arthritis; topiramate (TPM) is a neuroprotective, anti-epileptic drug that has AMPAR antagonism. We will use these drugs to target AMPAR-trafficking and AMPAR activity, separately and in combination. We will systematically evaluate the biological responses to these drugs using early post-injury biomarkers that have predicted neurological outcomes in our prior work. We will use the biomarker data to plan preclinical dose and timing regimens to evaluate effectiveness in both cervical and thoracic rat SCI, and evaluate their effects on autonomic, sensory and motor outcomes. These efforts are aimed at moving towards clinical application of anti-TNF therapies for SCI, and may be applicable to other CNS degenerative disorders as well. We propose three specific aims: Aim 1: We will evaluate the effects of ETAN and TPM on the time course and extent of biomarkers of AMPAR surface expression, cell death and the production of pro-inflammatory cytokines after cervical SCI. We predict that these treatments will reduce the feed-forward cascade of cell death. Aim 2. Guided by these data, we will optimize dose and timing of single and combination therapies to maximize six week recovery after unilateral cervical SCI using a variety of forelimb functional tests (grooming, paw placement, Catwalk and IBB). Aim 3: We will test the effects of optimized drug regimens on recovery from thoracic contusion lesions using a battery of tests that includes autonomic, sensory, and motor outcomes. This will establish whether efficacy extends to multiple models of SCI. TNF and AMPARs are also involved in the production of chronic hypersensitivity after nerve injury (Choi et al, 2010), and we will test whether this occurs after SCI as well. TPM is already used to treat chronic SCI pain. We predict that acute treatments with ETAN and TPM that result in better motor outcomes will also result in reductions in long term allodynia and in tonic, aversive central pain (King et al, 2009), the latter measured by place preference tests.