Immunomodulatory effects of Inter-alpha Inhibitors in attenuating Ischemic Stroke

 描述（由申请人提供）：目前批准用于人类的卒中治疗是有限的。临床上可用的一种药物，即溶栓剂组织纤溶酶原激活剂（t-PA），仅适用于症状发作后4.5小时内给药，并伴有颅内出血的显著风险。因此，只有一小部分患者接受这种治疗。新出现的数据表明，缺血后氧化应激和炎症介质会导致脑损伤和缺血性病变的扩大。由于炎症反应延迟（数小时至数天），因此它是治疗干预的有吸引力的目标。α间抑制蛋白（IAIP）是一种复杂的蛋白质（250和125 kDa），在血液中循环，它由多个亚基组成。在日本和中国，已经从尿液中分离出一种亚基（轻链，也称为bikunin），并在临床上用于治疗急性胰腺炎和其他炎性疾病。然而，这种亚基的半衰期非常短（3-10分钟），需要大量的蛋白质和持续的静脉输注。我们建议评估IAIP的血液衍生复合物形式（半衰期为8-12小时）。作为潜在的神经保护剂，因为这种形式对于临床使用更可行。由于复合物中存在其他亚基（重链），该制剂也可能具有累加保护作用。我们实验室的初步工作使用外源性给予的血液来源的人IAIP，剂量为30 mg/kg（在败血症中显示出保护作用的剂量），发现IAIP在年轻成年小鼠实验性中风后具有显著的神经保护作用。即使在缺血发作后6小时给予IAIP，脑体积也会减少，功能结局也会改善。我们现在已经证明，这种保护作用可以持续30天，而且这种药物对老年动物也有保护作用。基于这些非常有希望的初步结果，我们建议系统地确定最佳剂量，检查药代动力学，并直接评估脑和血清中IAIP（Aim 1）的水平。我们将确定两种性别的老年小鼠在慢性（1个月和3个月）终点时神经保护和行为改善是否持续（目标2），并确定在栓塞性卒中模型中是否也观察到保护（目标3）。这些研究是根据NINDS“转化研究中的探索/开发项目”（PAR 13 -023）计划设计的。

 DESCRIPTION (provided by applicant): Current stroke therapies approved for human use are limited. The one drug clinically available, the thrombolytic agent tissue plasminogen activator (t-PA), is indicated only if administered within 4.5 hours of symptom onset and carries with it a significant risk of intracranial hemorrhage. Consequently, only a small percentage of patients receive this therapy. Emerging data suggest that post-ischemic oxidative stress and inflammatory mediators contribute to brain injury and expansion of the ischemic lesion. As the inflammatory response is delayed (hours to days), it is an attractive target for therapeutic intervention. Inter-alpha inhibitor proteins (IAIP) are complex proteins (250 and 125 kDa) circulating in blood, which consist of multiple subunits. In Japan and China, one subunit (the light chain, also known as bikunin) has been isolated from urine and is used clinically to treat acute pancreatitis and other inflammatory diseases. However, the half-life of this subunit is very short (3-10 min), requiring large amounts of protein and constant intravenous infusion. We propose to evaluate the blood-derived complexes form of IAIP (half-life of 8-12 hrs.) as a potential neuroprotective agent, as this form is more feasible for clinical use. This formulation may also have additive protective effects due to the presence of other subunits (the heavy chain) in the complex. Preliminary work in our lab using exogenously administered blood-derived human IAIP at a dose of 30mg/kg (a dose that has shown protection in sepsis) found that IAIP is strikingly neuroprotective after experimental stroke in young adult mice. Infarct volumes are reduced and functional outcomes improved even when IAIP was given six hours after ischemic onset. We have now shown that the protection is sustained at 30 days, and that this agent is also protective in aged animals. Based on these very promising initial results we propose to systematically determine the optimal dose, examine the pharmacokinetics, and directly evaluate brain and serum levels of IAIP (Aim1). We will determine if neuroprotection and behavioral improvements are sustained at chronic (1 and 3 month) endpoints in aged mice of both sexes (Aim 2) and determine if protection is also seen in an embolic model of stroke (Aim 3). These studies were designed in response to the NINDS "Exploratory/Developmental Projects in Translational Research" (PAR13-023) program.