Anesthesia Toxicity in Neonatal Primate Brain

新生儿灵长类动物大脑的麻醉毒性

基本信息

批准号：
8607199
负责人：
JOHN W OLNEY
金额：
$ 39.94万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-05 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8607199
关键词：
Address Age Agonist Alcohols Anesthesia procedures Anesthetics Animals Apoptotic Attenuated Award Birth Brain Cell Count Cell Death Cessation of life Childhood Collaborations Databases Development Dexmedetomidine Discipline of obstetrics Dose Elderly Ethers Exposure to Fetus Funding General anesthetic drugs Gestational Age Goals Grant Growth Health Sciences Hour Human Infant Isoflurane Ketamine Light Link Lithium Macaca mulatta Medicine Methods N-Methylaspartate Neonatal Neuroglia Neurons Neuroprotective Agents Oligodendroglia Operative Surgical Procedures Oregon Pharmaceutical Preparations Predisposition Pregnancy Primates Property Propofol Protocols documentation Research Research Personnel Risk Rodent Safety Testing Toxic effect Treatment Protocols Unconscious State Universities Washington Work alcohol response base brain cell clinical application clinically relevant fetal immature animal improved neonate neurobehavioral neurotoxic neurotoxicity nonhuman primate postnatal prevent research study response

项目摘要

DESCRIPTION (provided by applicant): A decade ago, the applicant and colleagues discovered that drugs that have either NMDA antagonist or GABAA agonist properties, a description that fits alcohol and all general anesthetics, trigger widespread death of nerve cells in the developing animal brain. In order to maximize the translational significance of our anesthesia toxicity studies, we applied for and were awarded a grant (start date Jan 2007) to study this phenomenon in the developing non-human primate (NHP) brain. The present application is a request for renewal of funding for ongoing studies pertaining to the apoptogenic properties of anesthetic drugs in the developing NHP brain. This work is being performed in collaboration with colleagues at Washington University and Oregon Health & Science University and Oregon National Primate Research Center. In the first 4 years of the grant period we have developed a valuable data base documenting susceptibility of the developing fetal and neonatal NHP brain to apoptotic death of brain cells (both neurons and oligodendrocytes) induced by clinically relevant exposure to each of three anesthetic drugs (isoflurane, ketamine, propofol). In this renewal application we are proposing to conduct additional NHP studies to further clarify the potential neurotoxicity of anesthetic drugs for the developing NHP brain and explore ways of modifying anesthesia protocols to enhance their safety for the developing brain. We have already developed a valuable data base, and now want to build upon that base toward the goal of achieving improved safety in the clinical application of anesthetic drugs in pediatric and obstetric medicine. The aims of the proposed research are to determine: 1) If there is a significant positive correlation between duration of anesthesia exposure and the number of neurons and/or oligodendrocytes that undergo apoptotic cell death; 2) How anesthesia without surgery compares in toxic impact with anesthesia with surgery; 3) How long into the post natal period does the brain remain vulnerable to significant neuronal or glial loss following clinically relevant exposure to anesthesia; and 4) Can the apoptotic response to anesthesia be prevented or significantly mitigated by adjunctive administration of neuroprotective drugs.

描述（由申请人提供）：十年前，申请人及其同事发现具有NMDA拮抗剂或GABAA激动剂特性的药物，该描述适合酒精和所有一般麻醉，触发了发育中动物大脑中神经细胞的广泛死亡。为了最大程度地提高我们麻醉毒性研究的转化意义，我们申请并获得了赠款（开始日期，2007年1月开始），以研究这种非人类灵长类动物（NHP）大脑中的这种现象。本申请是要求续签与发育中NHP大脑中麻醉药物的凋亡特性有关的正在进行的研究的资金。这项工作正在与华盛顿大学，俄勒冈州健康与科学大学以及俄勒冈州国家灵长类动物研究中心合作进行。在赠款期的前4年中，我们开发了一个有价值的数据库，记录了胎儿和新生儿NHP大脑对脑细胞（神经元和少突胶质细胞）凋亡死亡的敏感性，这是由于临床相关的三种麻醉药物（异氟烷，酮，酮，酮，丙胺，propofol，propofol，propofol）引起的临床相关暴露而引起的。在此续签应用中，我们建议进行其他NHP研究，以进一步阐明发育中NHP大脑的麻醉药物的潜在神经毒性，并探索修改麻醉方案的方法，以增强其对发育中大脑的安全性。我们已经建立了一个宝贵的数据库，现在希望以这一基础为基础，以在小儿和产科医学中临床应用麻醉药物的临床应用中提高安全性。拟议研究的目的是确定：1）如果麻醉持续时间与经历凋亡细胞死亡的神经元数量和/或少突胶质细胞之间存在显着正相关； 2）没有手术的麻醉与手术与麻醉的毒性影响相比如何； 3）在临床上与麻醉相关后，大脑在出生后期的时间仍然容易受到明显的神经元或神经胶质损失的影响； 4）可以通过辅助施用神经保护药物来预防对麻醉的凋亡反应。