Anesthesia Toxicity in Neonatal Primate Brain

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（适用于酒精和所有全身麻醉剂的描述）会引发发育中动物大脑中神经细胞的广泛死亡。为了最大限度地提高我们的麻醉毒性研究的转化意义，我们申请并获得了资助（开始日期2007年1月），以研究发育中的非人灵长类动物（NHP）大脑中的这种现象。本申请是对正在进行的关于麻醉药物在发育中的NHP脑中的致癫痫性质的研究的资金更新的请求。这项工作是与华盛顿大学、俄勒冈州健康与科学大学和俄勒冈州国家灵长类动物研究中心的同事合作进行的。在授权期的前4年，我们开发了一个有价值的数据库，记录了发育中的胎儿和新生儿NHP大脑对脑细胞（神经元和少突胶质细胞）凋亡的敏感性，这些脑细胞凋亡是由临床相关暴露于三种麻醉药物（异氟烷、氯胺酮、丙泊酚）中的每一种诱导的。在本次更新申请中，我们建议进行额外的NHP研究，以进一步阐明麻醉药物对发育中的NHP大脑的潜在神经毒性，并探索修改麻醉方案的方法，以提高其对发育中大脑的安全性。我们已经开发了一个有价值的数据库，现在希望在此基础上实现提高麻醉药物在儿科和产科临床应用中的安全性的目标。拟进行的研究的目的是确定：1）麻醉暴露的持续时间与经历凋亡细胞死亡的神经元和/或少突胶质细胞的数量之间是否存在显著的正相关性; 2）无手术麻醉与手术麻醉的毒性影响如何比较; 3）在临床相关的麻醉暴露后，大脑在纳塔尔后多久仍然容易受到显著的神经元或神经胶质损失的影响;和4）神经保护药物的连续给药能否预防或显著减轻麻醉引起的凋亡反应。

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.