Excitotoxicity and Mitochondrial Dysfunction in Circulatory Arrest- Brain Injury

循环骤停脑损伤中的兴奋性毒性和线粒体功能障碍

• 批准号: 10622536
• 负责人: JENNIFER S LAWTON
• 金额: $ 70.18万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622536
• 关键词: Adenosine Triphosphate; Animal Model; Aorta; Apoptosis; Attenuated; Biochemistry; Biological Markers; Brain; Brain Injuries; Brain imaging; Calcium; Cardiac; Cardiac Myocytes; Cardiac Surgery procedures; Cardiovascular Diseases; Cell Death; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrum; Clinical; Complex; Dendrimers; Diazoxide; Dose Limiting; Drug Delivery Systems; Effectiveness; Funding; Glutamates; Goals; Grant; Heart; Hippocampus; Histopathology; Human; Injury; Ischemia; Ischemic Brain Injury; Ischemic Preconditioning; Ketamine; Knowledge; Laboratories; MK801; Magnetic Resonance Imaging; Mediator; Microglia; Mitochondria; Modality; Modeling; Molecular; Myocardial Ischemia; Myocardium; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Necrosis; Nervous System Trauma; Neurologist; Neuronal Injury; Neurons; Neuroprotective Agents; Neurosurgeon; Operative Surgical Procedures; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Pharmacotherapy; Potassium Channel; Potassium Phosphate; Receptor Activation; Serum; Stress; Surgeon; Techniques; Testing; Therapeutic; Therapeutic Uses; Time; Tissues; Transesophageal Echocardiography; Translating; United States; Woman; Work; antagonist; arterial spin labeling; blood-brain barrier crossing; canine model; clinical practice; effectiveness evaluation; excitotoxicity; experience; experimental study; glial activation; improved; improved outcome; ischemic injury; men; mitochondrial dysfunction; multidisciplinary; nanodevice; nanomedicine; nanoparticle; natural hypothermia; neurobehavioral; neurochemistry; neuroinflammation; neuron loss; neuroprotection; neurotransmitter release; novel; novel therapeutics; pharmacologic; pre-clinical; prevent; protective effect; randomized trial; side effect; targeted delivery; targeted treatment; translational model

Project Summary / Abstract This application builds on our laboratory's pioneering work delineating critical neurochemical mechanisms of excitotoxicity and neuroinflammation in a translational model of brain injury from hypothermic circulatory arrest (HCA) that is directly relevant to the techniques currently used in patients undergoing complex heart and aortic surgery. We propose to test these mechanisms, specifically N-methyl-D-aspartate (NMDA) antagonism with ketamine and mitochondrial adenosine triphosphate potassium (KATP) activation with diazoxide, using targeted delivery with dendrimer conjugation in our translational HCA model with the addition of antegrade cerebral perfusion. Prolongation of the safe HCA time during complex aortic surgery with such agents will dramatically reduce neurological injury and improve outcomes in these patients. By identifying the underlying mechanisms of injury and testing them in a pre-clinical large animal model, the work proposed in this application will advance the field because there are no currently available pharmacologic agents that have been proven in randomized trials to provide significant improvement to the current use of hypothermia. We propose the following aims: 1) To determine if the NMDA receptor antagonist ketamine is a neuroprotectant during hypothermic circulatory arrest in a canine model, 2) To determine the mechanisms of mitochondrial injury during hypothermic circulatory arrest and the effectiveness of mitochondrial KATP channel openers as neuroprotective agents in a canine model, and 3) To evaluate targeted neuroprotective strategies in a hypothermic circulatory arrest model with antegrade cerebral perfusion (ACP) Our multidisciplinary team includes a practicing cardiac surgeon who experiences the current challenges when performing complex aortic surgery, a practicing neurologist specializing in brain injury and mitochondrial stress, a practicing neurosurgeon who specializes in brain injury, a neuroscientist with expertise in brain injury and mechanisms of neurorepair and microglial activation, the co-director of the Center for Nanomedicine with expertise in dendrimer-drug nanodevices for targeted therapy to attenuate neuroinflammation, and a neuropathologist that specializes in neural cell death and mitochondrial pathobiology. Together we possess the unique ability to translate our findings to clinical practice. The proposed experiments provide a comprehensive approach to understanding the mechanisms of neurological injury due to hypothermic circulatory arrest. The knowledge gained could potentially provide benefit for any patient with cardiovascular disease who requires cardiac surgery, which remains the #1 killer of men and women in the United States.

项目概要/摘要 该应用程序建立在我们实验室的开创性工作之上，该工作描述了关键的神经化学机制 低温停循环脑损伤转化模型中的兴奋性毒性和神经炎症 （HCA）与目前用于接受复杂心脏和主动脉手术的患者的技术直接相关 外科手术。我们建议测试这些机制，特别是 N-甲基-D-天冬氨酸 (NMDA) 拮抗作用 使用二氮嗪激活氯胺酮和线粒体三磷酸腺苷钾 (KATP) 在我们的转化 HCA 模型中通过树状聚合物缀合进行递送，并添加顺行大脑 灌注。使用此类药物可显着延长复杂主动脉手术期间的安全 HCA 时间 减少神经损伤并改善这些患者的预后。 通过确定损伤的潜在机制并在临床前大型动物模型中进行测试， 本申请中提出的工作将推动该领域的发展，因为目前还没有可用的药理学药物 经随机试验证明可显着改善目前使用的药物 低温。我们提出以下目标：1) 确定 NMDA 受体拮抗剂氯胺酮是否是一种 犬模型低温停循环期间的神经保护剂，2) 确定机制 低温停循环过程中线粒体损伤及线粒体 KATP 通道的有效性 开启剂作为犬模型中的神经保护剂，3) 评估有针对性的神经保护策略 顺行脑灌注（ACP）低温停循环模型 我们的多学科团队包括一位经历过当前挑战的执业心脏外科医生 在进行复杂的主动脉手术时，专门研究脑损伤和线粒体的执业神经科医生 压力，一位专门研究脑损伤的执业神经外科医生，一位专门研究脑损伤的神经科学家 以及神经修复和小胶质细胞激活的机制，纳米医学中心的联合主任 用于减轻神经炎症靶向治疗的树枝状药物纳米装置的专业知识，以及 神经病理学家，专门研究神经细胞死亡和线粒体病理学。我们共同拥有 将我们的发现转化为临床实践的独特能力。 所提出的实验提供了一种全面的方法来理解其机制 低温停循环引起的神经损伤。获得的知识可能会带来好处 对于任何需要进行心脏手术的心血管疾病患者来说，心脏手术仍然是男性和女性的第一杀手 美国的女性。

项目成果

Nanotechnology Approaches to Targeting Inflammation and Excitotoxicity in a Canine Model of Hypothermic Circulatory Arrest-Induced Brain Injury.

• DOI: 10.1016/j.athoracsur.2016.02.077
• 发表时间: 2016-09
• 期刊: The Annals of thoracic surgery
• 作者: Grimm JC;Magruder JT;Wilson MA;Blue ME;Crawford TC;Troncoso JC;Zhang F;Kannan S;Sciortino CM;Johnston MV;Kannan RM;Baumgartner WA
• 通讯作者: Baumgartner WA

Brain injury in canine models of cardiac surgery.

• DOI: 10.1097/nen.0000000000000134
• 发表时间: 2014-12
• 期刊: Journal of neuropathology and experimental neurology
• 影响因子: 3.2
• 作者: Blue ME;Wilson MA;Beaty CA;George TJ;Arnaoutakis GJ;Haggerty KA;Jones M;Brawn J;Manmohan S;Lange MS;Johnston MV;Baumgartner WA;Troncoso JC
• 通讯作者: Troncoso JC

Dendrimer brain uptake and targeted therapy for brain injury in a large animal model of hypothermic circulatory arrest.

• DOI: 10.1021/nn404872e
• 发表时间: 2014-03-25
• 期刊: ACS NANO
• 影响因子: 17.1
• 作者: Mishra, Manoj K.;Beaty, Claude A.;Lesniak, Wojciech G.;Kambhampati, Siva R.;Zhang, Fan;Wilson, Mary A.;Blue, Mary E.;Troncoso, Juan C.;Kannan, Sujatha;Johnston, Michael V.;Baumgartner, William A.;Kannan, Rangaramanujam M.
• 通讯作者: Kannan, Rangaramanujam M.

Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model.

• DOI: 10.1016/j.jconrel.2017.01.032
• 发表时间: 2017-03-10
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Zhang F;Trent Magruder J;Lin YA;Crawford TC;Grimm JC;Sciortino CM;Wilson MA;Blue ME;Kannan S;Johnston MV;Baumgartner WA;Kannan RM
• 通讯作者: Kannan RM

Inflammatory profile in a canine model of hypothermic circulatory arrest.

• DOI: 10.1016/j.jss.2021.02.014
• 发表时间: 2021-08
• 期刊: The Journal of surgical research
• 作者: Giuliano K;Torres-Odio S;Etchill E;Carr P;Conover Talbot C Jr;Blue ME;Johnston MV;Baumgartner WA;Lawton JS;Wilson MA
• 通讯作者: Wilson MA