Excitotoxicity in Circulatory Arrest-Brain Injury

循环骤停脑损伤中的兴奋性毒性

• 批准号: 8696132
• 负责人: WILLIAM Anthony BAUMGARTNER
• 金额: $ 125.11万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-12-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696132
• 关键词: Acetylcysteine; Adverse effects; Animal Model; Animals; Area; Attenuated; Biodistribution; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Brain; Brain Injuries; Canis familiaris; Clinical; Clinical Medicine; Combined Modality Therapy; Complex; Congenital Heart Defects; Coupled; Data; Dendrimers; Development; Dose; Drug Delivery Systems; Drug Kinetics; Evaluation; Fluorescence; Funding; Genes; Goals; Heart; Home environment; Hour; Impairment; Individual; Inflammatory; Injection of therapeutic agent; Injury; Measures; Mediator of activation protein; Metabolic acidosis; Methods; Microglia; Modeling; Molecular; Monitor; Nervous System Trauma; Neurologic; Neurons; Operative Surgical Procedures; Organ; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Pharmacotherapy; Positioning Attribute; Repair Complex; Research; Research Project Grants; Seizures; Serum; Stroke; Techniques; Testing; Therapeutic; Thoracic aorta; Time; Translations; Up-Regulation; Valproic Acid; Work; attenuation; base; choreoathetosis; clinically relevant; dosage; excitotoxicity; fluorescence imaging; hemodynamics; improved; injured; nanoparticle; neurobehavioral; neurochemistry; neuroinflammation; neuroprotection; novel; prevent; public health relevance; response; targeted delivery; uptake

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.

项目概要/摘要 低温停循环（HCA）技术是一种既定的神经保护策略，允许 胸主动脉和先天性心脏畸形的复杂修复。尽管它在临床上具有实用性 医学上，HCA并非没有明显的神经系统后遗症，包括智力和神经精神运动 损伤、癫痫、舞蹈手足徐动症、发育迟缓和中风。该应用程序建立在我们的 描述兴奋性毒性和神经炎症的关键神经化学机制的开创性工作 HCA 脑损伤的转化模型与当前使用的支持技术直接相关 每天对接受复杂心脏和主动脉手术的患者进行治疗。我们之前表明丙戊酸 (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 的临床使用受到严重代谢性酸中毒的限制，而 NAC 的临床使用则受到不良代谢性酸中毒的限制。 血脑屏障（BBB）穿透。我们最近证明，树枝状聚合物-药物缀合物可以 在 HCA 的翻译模型中穿透 BBB，然后“归巢”到以下区域的神经元和小胶质细胞： 受损的大脑。因此，我们处于独特的地位来评估该平台的靶向药物 运送到受伤的大脑。我们假设树枝状大分子-药物缀合物可以靶向递送 BBB 选择性地针对受损的神经元和小胶质细胞，从而在较低剂量下提高疗效，并减少 与全身注射未结合化合物相比，副作用较小。我们的具体目标是： 1) 确定 VPA 或 NAC 单一疗法全身给药的剂量-反应关系 树枝状大分子偶联的 VPA 或 NAC（D-VPA 或 D-NAC）单一疗法； 2) 评估联合VPA的疗效 和 NAC 治疗对 HCA 后神经损伤的影响； 3) 评估靶向联合 D-VPA 的疗效 和 D-NAC 治疗 HCA 后神经损伤。基于树枝状大分子的疗法的临床评价 相关的大型动物模型将为患者提供重要的翻译信息。