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，这一描述适用于酒精和所有全身麻醉剂，可引发发育中的动物大脑中神经细胞的广泛死亡。为了最大限度地提高麻醉毒性研究的翻译意义，我们申请并获得了一笔拨款（开始日期为2007年1月），用于研究发育中的非人灵长类动物（NHP）大脑中的这种现象。目前的申请是为正在进行的有关麻醉药物在发育中的NHP脑中的凋亡特性的研究申请更新资金。这项工作是与华盛顿大学、俄勒冈健康与科学大学和俄勒冈国家灵长类动物研究中心的同事合作完成的。在资助期的前4年，我们建立了一个有价值的数据库，记录了发育中的胎儿和新生儿NHP脑对三种麻醉药物（异氟醚、氯胺酮、异丙酚）的临床相关暴露所诱导的脑细胞（神经元和少突胶质细胞）凋亡的易感性。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，以提高其对发育中的大脑的安全性。我们已经建立了一个有价值的数据库，现在希望在这个基础上实现在儿科和产科医学中麻醉药物临床应用中提高安全性的目标。本研究的目的是确定：1)麻醉暴露时间与发生凋亡细胞死亡的神经元和/或少突胶质细胞数量之间是否存在显著的正相关；2)不手术麻醉与手术麻醉毒性作用比较；3)在临床相关的麻醉暴露后，大脑在产后多长时间内仍易发生显著的神经元或胶质细胞损失；4)辅助给药神经保护药物能否预防或显著减轻麻醉后的凋亡反应。

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.