Inter-alpha-inhibitors in Hypoxic-Ischemic Brain Injury

描述(申请人提供)：新生儿缺氧缺血(HI)仍然是围产期急性脑损伤的主要原因，最终导致神经功能障碍，表现为脑瘫、智力低下和癫痫。脐带闭塞、长时间分娩和/或颅内出血引起的脑缺氧和/或血流量减少会引起炎症反应，导致神经细胞死亡。不幸的是，目前新生儿的治疗和预防策略是缺乏和不充分的。目前还没有可用的疗法来预防/治疗和/或减轻早产儿的脑损伤，而对足月儿唯一可用的治疗干预措施是低体温，这是唯一 部分是保护性的。间α抑制蛋白(IAIP)是天然衍生的分子，在多种新生儿和成人全身炎症实验模型以及炎症诱导的早产模型中，已被证明通过下调促炎症细胞因子而在调节炎症反应中发挥重要作用。此外，IAIP的降低已被证明可以准确地预测早产儿脓毒症的发展，并在绵羊胎儿脑缺血诱导后检测到IAIP的降低。因此，外源性IAIP治疗可能减轻新生儿脑缺血发生率中炎症诱导的脑损伤。我们最近的数据有力地证明了在建立的绵羊胎儿、新生大鼠和成年小鼠的HI损伤模型中早期给予IAIP的有益效果。IAIP治疗不仅减少了实验动物大脑的神经解剖损伤，而且实现了学习和记忆任务的长期改善。这个第一阶段SBIR项目的目标是确认和获得IAIP在新生儿脑损伤中的神经保护作用的概念证明。我们假设IAIP治疗将减少神经元死亡和延缓脑缺血再灌注损伤的发展。本研究的具体目的是观察延迟IAIP治疗新生大鼠缺氧缺血性脑损伤的疗效和长期行为结局。建议的研究具有很大的翻译潜力，可以开发IAIP作为一种新的药物来预防/减轻有精神发育迟滞风险的婴儿的脑损伤。

DESCRIPTION (provided by applicant): Neonatal hypoxia-ischemia (HI) remains a major cause of acute perinatal brain injury, leading ultimately to neurologic dysfunction manifesting as cerebral palsy, mental retardation, and epilepsy. Cerebral oxygen deprivation and/or reduced blood flow due to umbilical cord occlusion, prolonged labor, and/or intracranial hemorrhage produce an inflammatory response contributing to neuronal cell death. Unfortunately, current treatment and prevention strategies in newborns are lacking and inadequate. There are no currently available therapies to prevent/treat and/or attenuate brain damage in premature infants and the only available therapeutic intervention for full term infants is hypothermia, which is only partially protective. Inter-alpha Inhibitor Proteins (IAIP) are naturally derived molecules that have been shown to play an important role in modulating inflammatory response by down-regulating pro-inflammatory cytokines in several experimental models of newborn and adult systemic inflammation and in models of inflammation- induced premature labor. Moreover, decreased IAIP has been shown to accurately predict the development of sepsis in premature infants and decreases in IAIP have been detected following induced ischemia in the ovine fetus brains. Thus, exogenous treatment with IAIP is likely to attenuate inflammation-induced brain injury in neonatal incidences of cerebral ischemia. Our recent data strongly demonstrate the beneficial effects of early administration of IAIP in established models of HI injury in the ovine fetus, neonatal rats and adult mice. Not only does IAIP treatment reduce neuroanatomical injury in the brain of experimental animals, but long-term improvement on learning and memory tasks was achieved. The goal of this Phase I SBIR project is to confirm and obtain proof-of-concept of the neuroprotective effects of IAIP in newborn brain injuries. We hypothesize that IAIP treatment will reduce neuronal death and attenuate the development of ischemic-reperfusion injury in the brain. The Specific Aims of the study are to examine the therapeutic effects and long-term behavioral outcome of delayed IAIP treatment in neonatal rat hypoxic-ischemic brain injury model. The proposed studies have significant translational potential to develop IAIP as a novel agent to prevent/attenuate brain damage in infants at risk for mental retardation.