Excitotoxicity in Circulatory Arrest-Brain Injury

描述(申请人提供)：低温停循环(HCA)技术是一种公认的神经保护策略，可以对胸主动脉和先天性心脏畸形进行复杂的修复。尽管HCA在临床医学上有用，但它并不是没有显著的神经后遗症，包括智力和神经精神运动障碍、癫痫、舞蹈动作障碍、发育迟缓和中风。这一应用建立在我们的开创性工作基础上，在HCA脑损伤的翻译模型中描绘了兴奋性毒性和神经炎症的关键神经化学机制，该模型与目前在接受复杂心脏和主动脉手术的患者中每天使用的支持技术直接相关。我们先前已经证明丙戊酸(VPA)可以减轻兴奋性毒性损伤，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的临床应用受到血脑屏障(BBB)穿透能力的限制。我们最近证明了树枝状大分子-药物结合物可以穿透这个HCA翻译模型中的血脑屏障，然后在大脑受损区域的神经元和小胶质细胞上“回家”。因此，我们处于一个独特的位置来评估这个靶向药物输送到受伤的大脑的平台。我们假设树枝状大分子-药物结合物可以选择性地通过血脑屏障向受损的神经元和小胶质细胞递送，与全身注射未结合化合物相比，在较低剂量下可以提高疗效并减少副作用。我们的具体目标是：1)确定全身应用VPA或NAC单一疗法以及树枝状大分子偶联VPA或NAC(D-VPA或D-NAC)单一疗法的剂量-反应关系；2)评估联合应用VPA和NAC治疗HCA后神经损伤的疗效；以及3)评估靶向联合治疗D-VPA和D-NAC对HCA后神经损伤的疗效。在临床相关的大动物模型中对基于树枝状大分子的治疗进行评估将为翻译给患者提供重要的信息。

DESCRIPTION (provided by applicant): 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.