Drug Repurposing to Accelerate Progress in Neonatal Neuroprotection

摘要 在儿童时期，急性脑损伤的风险在新生儿期达到顶峰。围产期脑的主要机制 损伤包括缺氧缺血(HI)和宫内炎症(例如绒毛膜羊膜炎)或 新生儿感染(例如坏死性小肠结肠炎)。在足月儿中，先天的缺氧缺血事件可能 在早产儿中，多因素的作用机制往往更难被识别。 辨认身份。鉴于与围产期脑损伤相关的显著神经学发病率 对于早产儿来说，非常需要有效的神经保护干预措施。许多药物可以减少脑损伤 并改善新生大鼠缺氧缺血(HI)脑损伤模型的功能结局。一位少校 翻译的挑战是选择那些优先发展到补充较大动物围产期的动物 损伤模型，并最终进行早期的人类新生儿试验。鉴于新药上市的时间滞后 从开发到临床试验，我们的战略是优先评估符合以下条件的潜在神经保护药物 已获批准用于其他适应症，即“重新调整用途”，并利用“适应性平台设计模式” 比较功效研究。这项建议建立在我们最近的发现基础上，即临床上用一种 可用的抗生素阿奇霉素(AZ)可减少脑损伤并改善多发性硬化症患者的功能预后 新生大鼠缺氧缺血性脑损伤模型的建立。我们的目标是比较神经保护的效果 在临床上可用的药物中，包括AZ，在类似的新生啮齿动物模型中具有神经保护作用，以 帮助确定进入人体试验的最佳候选人(S)的优先顺序。疗效将在特征良好的患者中进行比较 大鼠缺氧缺血和炎症放大缺氧缺血性脑损伤模型。我们将把 在两个年龄组的研究中，出生后第7天(P7)模拟足月脑发育，P3模拟 早产儿。为诱导单侧前脑损伤，动物行单侧颈动脉结扎和双侧颈总动脉结扎。 随后定时(45-90分钟)暴露在8%的氧气中；这会导致可量化的感觉运动障碍和 单侧脑组织损伤。促炎刺激，例如注射TLR-4(脂多糖) 或在损伤前使用TLR-2(Pam3CSK4)激动剂，可放大HI损伤。我们的初步研究表明 与HI和炎症相比，AZ治疗在两个年龄段都提供了剂量和时间依赖的神经保护。 放大的HI损伤。我们目前的目标是比较多个临床病例的神经保护效果。 P7(Aim 1)和P3(Aim 2)大鼠的有效药物(AZ、促红细胞生成素、褪黑素、西地那非、咖啡因、托吡酯) 缺氧缺血和炎症放大的缺氧缺血性脑损伤模型。我们量化了保护性 综合了感觉运动功能、记忆和神经病理学的综合评分的疗效 措施，并将死亡作为可能的伤害后果考虑在内。我们假设这些比较 疗效研究将确定在每个年龄段具有最高优势概率的一到两种药物，因此 加快推动安全有效的药物进入足月儿和早产儿临床试验的进展。

Abstract In childhood, the risks of acute brain injury peak in the neonatal period. Major mechanisms of perinatal brain injury include hypoxia-ischemia (HI) and inflammation in response to intrauterine (e.g. chorioamnionitis) or neonatal (e.g. necrotizing enterocolitis) infections. In term infants, antecedent hypoxic-ischemic events can often be discerned; in premature neonates, multifactorial contributing mechanisms are often more difficult to identify. In view of the significant neurologic morbidity associated with perinatal brain injury in both term and preterm infants, effective neuroprotective interventions are greatly needed. Many drugs decrease brain injury and improve functional outcome in neonatal rodent hypoxic-ischemic (HI) brain injury models. A major translational challenge is to select those to prioritize for advancement to complementary larger animal perinatal injury models, and ultimately to early stage human neonatal trials. In view of the time lag from new drug development to clinical trials, our strategy is to prioritize evaluation of potentially neuroprotective drugs that are already approved for other indications i.e. “repurposing”, and utilize an “adaptive platform design model” for comparative efficacy studies. This proposal builds upon our recent findings that treatment with a clinically available antibiotic, azithromycin (AZ), reduces brain damage and improves functional outcomes in multiple neonatal rodent hypoxic-ischemic (HI) brain injury models. Our aims are to compare neuroprotective efficacy among clinically available drugs, including AZ, that are neuroprotective in similar neonatal rodent models, to help prioritize the best candidate(s) to advance to human trials. Efficacy will be compared in well-characterized rat models of hypoxic-ischemic and inflammation-amplified hypoxic-ischemic brain injury. We will incorporate studies in two age groups, post-natal day 7 (P7), to model term brain development, and P3, to model premature neonates. To elicit unilateral forebrain injury, animals undergo unilateral carotid artery ligation and subsequent timed (45-90 min) exposure to 8% oxygen; this results in quantifiable sensorimotor deficits and unilateral brain tissue damage. Pro-inflammatory stimuli, e.g. injections of a TLR-4 (lipopolysaccharide, LPS) or a TLR-2 (Pam3CSK4) agonist prior to lesioning, amplify HI injury. Our preliminary studies showed that treatment with AZ confers dose and time-dependent neuroprotection, at both ages, vs. HI and inflammation- amplified HI injury. Our current goals are to compare the neuroprotective efficacy among multiple clinically available drugs (AZ, erythropoietin, melatonin, sildenafil, caffeine, topiramate) in P7 (Aim 1) and P3 (Aim 2) rat hypoxic-ischemic and inflammation-amplified hypoxic-ischemic brain injury models. We quantify protective efficacy with composite scores that incorporate lateralizing sensorimotor function, memory and neuropathology measures, and also account for death as a possible injury outcome. We hypothesize that these comparative efficacy studies will identify one or two drugs with the highest probability of superiority at each age, and thus accelerate progress towards advancing safe and effective drugs to clinical trials in term and preterm neonates.