Neuroprotective Strategy: Novel Purine Derivatives for Neonatal Hypoxia-ischemia

项目摘要/摘要 缺氧缺血(HI)是早产儿神经发育障碍的主要原因之一。 足月婴儿。治疗足月新生儿缺氧缺血性脑病(HIE)的唯一治疗策略是 体温过低，只能起到部分保护作用。早产儿HI的唯一治疗方法是支持性 关心。Hi脑损伤的特征是明显的炎症反应以及早期 血脑屏障(BBB)/神经血管单位(NVU)结构改变。两者都是炎症 血脑屏障异常易致神经元损伤。在目前的提案中，我们调查了一部小说 一类分子，它们是嘌呤衍生物，通过葛兰素史克-3β和抑制素(Phb)起作用。 小路。PHB保护脑线粒体中OPA1的完整性，这是一个特别重要的 未成熟大脑中的保护性蛋白质。先前的研究表明，OPA1可以预防 神经元和血管床线粒体通透性、呼吸恶化和细胞凋亡。 我们发表的数据表明，PDD i)挽救与衰老相关的小鼠认知缺陷，ii)防止 神经发生障碍，III)增强突触功能，IV)减少神经炎性脑 成年小鼠的损伤。葛兰素史克-3β和PHB信号通路，包括核因子-kβ，参与了 PDD的神经保护机制。我们在具有良好特性的水稻-万努奇中的初步结果 新生儿缺氧缺血模型显示，缺氧后给予PDD可使HI相关的脑梗塞体积减少 40%。我们的初步数据表明，PDDS在脑内发挥着重要和一致的神经保护作用 新生儿和成人脑损伤模型，II)OPA-1表达增加，III)增加 新生大鼠缺氧缺血后经处理的雌性而非雄性新生大鼠神经营养因子的转录表达。 这些结果表明，在该模型中诱导神经元可塑性和OPA-1表达可能是 有益于新生儿缺氧缺血性脑病。我们建议的总体假设是PDD针对葛兰素史克-3β和 PHB可减轻新生儿缺氧缺血后血脑屏障的异常和炎症反应。我们将对此进行测试 两个特定目标的主要假设：目的1：PDD303减轻新生大鼠脑损伤 暴露于中、重度HI。目的2：服用PDD303可改善行为结果 并证明了新生儿缺氧缺血性脑病后持久的长期神经保护效果。我们 预计这一针对血脑屏障和神经炎症的创新治疗策略通过 GSK3β和PHB最终可能为目前的标准提供一种额外的治疗策略 照顾足月和早产儿。

PROJECT SUMMARY/ABSTRACT Hypoxia-ischemia (HI) is the one of leading causes of neurodevelopmental morbidities in preterm and full-term infants. The only therapeutic strategy to treat HI encephalopathy (HIE) in full term infants is hypothermia, which is only partially protective. The only therapy for HI in preterm infants is supportive care. HI brain injury is characterized by a pronounced inflammatory response along with early structural alterations in the blood-brain barrier (BBB)/neurovasculature unit (NVU). Both inflammation and BBB abnormalities predispose to neuronal damage. In the current proposal, we investigate a novel family of molecules, which are purine derivatives (PDD), acting through GSK-3β and prohibitin (PHB) pathways. PHB protects the integrity of OPA1 in brain mitochondria, which is a particularly important protective protein in the immature brain. Previous studies have shown that OPA1 prevents mitochondrial permeabilization, respiratory deterioration and apoptosis in neurons and vascular beds. Our published data show that PDD i) rescue cognitive deficits associated with aging in mice, ii) prevent impairment of neurogenesis, iii) enhance synaptic function and iv) reduce neuroinflammatory brain injury in adult mice. GSK-3β and PHB signaling pathways, including NF-kβ, are involved in the neuroprotective mechanisms of PDD. Our preliminary results in the well-characterized Rice-Vannucci model of neonatal HI showed that PDD given after HI i) decreased in the HI related infarct volumes by 40%. Our preliminary data suggests PDDs exert i) important and consistent neuroprotective effects in neonatal and adult models of brain injury, ii) increased OPA-1 expression and iii) increased the transcriptional expression of neurotrophic factors in treated female, but not male, neonatal rats after HI. These results suggest induction of neuronal plasticity and OPA-1 expression in this model that could be beneficial after neonatal HI. The overall hypothesis of our proposal is that PDD targets GSK-3β and PHB to attenuate both the BBB abnormalities and inflammation after neonatal HI. We will test this major hypothesis in two specific aims: Aim 1: PDD303 attenuates brain injury in neonatal rats after exposure to moderate and severe HI. Aim 2: Treatment with PDD303 improves behavioral outcomes and demonstrates durable long-term neuroprotective efficacy after HI in neonatal subjects. We anticipate that this innovative therapeutic strategy targeting the BBB and neuroinflammation through GSK3β and PHB could eventually provide an additional treatment strategy to the current standard of care for both full term and premature infants.