Excitotoxicity in Circulatory Arrest-Brain Injury

项目摘要/摘要 低温停循环(Hca)技术是一种公认的神经保护策略， 复杂的胸主动脉修复术和先天性心脏畸形。尽管它在临床上很有用 医学上，HCA并不是没有显著的神经后遗症，包括智力和神经精神运动 损伤、癫痫、舞蹈运动障碍、发育迟缓和中风。此应用程序构建在我们的 开创性工作描绘了兴奋性毒性和神经炎症的关键神经化学机制 与当前使用的支持技术直接相关的HCA脑损伤的翻译模型 每天在接受复杂心脏和主动脉手术的患者中使用。我们之前已经证明丙戊酸(VPA) 可以减轻兴奋性损伤，N-乙酰半胱氨酸(NAC)可以减轻神经炎症。然而， VPA的临床应用受到严重代谢性酸中毒的限制，而NAC的临床应用也因质量差而受到限制。 血脑屏障(BBB)穿透。我们最近证明了树枝状大分子-药物结合物可以 在这个HCA的翻译模型中穿透血脑屏障，然后在下丘脑区的神经元和小胶质细胞上“回家” 受损的大脑。因此，我们处于一个独特的位置来评估这个靶向药物的平台 运送到受伤的大脑。我们假设树枝状大分子-药物结合物可以靶向通过 血脑屏障选择性地作用于受损的神经元和小胶质细胞，从而在较低剂量下提高疗效 副作用，与全身注射未结合化合物相比。我们的具体目标是：1) 确定全身给药VPA或NAC单一疗法的剂量-反应关系 树枝状大分子偶联VPA或NAC(D-VPA或D-NAC)单一治疗；2)评估联合VPA的疗效 和NAC治疗HCA后神经损伤；以及3)评估靶向联合D-VPA的疗效 D-NAC治疗HCA后神经损伤。树枝状大分子治疗的临床评价 相关的大动物模型将为患者提供重要的翻译信息。

PROJECT SUMMARY/ABSTRACT The technique of hypothermic circulatory arrest (HCA) is an established neuroprotective strategy allowing complex repairs of the thoracic aorta and congenital cardiac malformations. Despite its utility in clinical medicine, HCA is not without significant neurological sequelae, including intellectual and neuropsychomotor impairment, seizures, choreoathetosis, delayed development, and stroke. This application builds on our pioneering work delineating critical neurochemical mechanisms of excitotoxicity and neuroinflammation in a translational model of brain injury from HCA that is directly relevant to the support techniques currently used daily in patients undergoing complex heart and aortic surgery. We previously showed that valproic acid (VPA) can mitigate excitotoxic injury and that N-acetylcysteine (NAC) can attenuate neuroinflammation. However, the clinical use of VPA is limited by a severe metabolic acidosis, while the clinical use of NAC is limited by poor blood-brain barrier (BBB) penetration. We recently demonstrated that that dendrimer-drug conjugates can penetrate the BBB in this translational model of HCA and then "home-in" on neurons and microglia in areas of the brain that are damaged. We are thus in a unique position to evaluate this platform for targeted drug delivery to the injured brain. We hypothesize that dendrimer-drug conjugates can target delivery across the BBB selectively to injured neurons and microglia, resulting in improved efficacy at lower doses with reduced side effects, compared to systemic injections of unconjugated compounds. Our specific aims are: 1) To determine dose-response relationships for systemic administration of VPA or NAC monotherapy and for dendrimer-coupled VPA or NAC (D-VPA or D-NAC) monotherapy; 2) To assess the efficacy of combined VPA and NAC therapy on neurological injury after HCA; and 3) To assess the efficacy of targeted, combined D-VPA and D-NAC therapy on neurological injury after HCA. Evaluation of dendrimer-based therapies in a clinically relevant large-animal model will provide important information for translation to patients.