Anesthesia Toxicity in Neonatal Primate Brain

描述(申请人提供)：十年前，申请人和同事发现，具有NMDA拮抗剂或GABAA激动剂特性的药物，符合酒精和所有全身麻醉药的描述，会导致发育中的动物大脑中的神经细胞广泛死亡。为了最大限度地发挥麻醉毒性研究的翻译意义，我们申请并获得了在发育中的非人类灵长类(NHP)脑中研究这一现象的拨款(开始日期为2007年1月)。本申请是为正在进行的有关麻醉药物在发育中的NHP脑中的致细胞凋亡特性的研究提供更新资金的申请。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州国家灵长类研究中心的同事合作进行的。在资助期的前4年，我们已经建立了一个有价值的数据库，记录了发育中的NHP脑对临床上相关的三种麻醉药(异氟醚、氯胺酮、异丙酚)诱导的脑细胞(神经元和少突胶质细胞)凋亡的敏感性。在这一更新申请中，我们建议进行更多的NHP研究，以进一步阐明麻醉药对发育中的NHP脑的潜在神经毒性，并探索修改麻醉方案的方法，以增强其对发育中的脑的安全性。我们已经开发了一个有价值的数据库，现在希望以此为基础，朝着提高儿科和产科药物临床应用的安全性的目标前进。拟议研究的目的是确定：1)麻醉暴露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；2)非手术麻醉与手术麻醉在毒性影响方面的比较；3)出生后多久，大脑在临床相关的麻醉暴露后仍容易受到显著的神经元或神经胶质细胞丢失的影响；以及4)辅助应用神经保护药物能否预防或显著缓解麻醉的细胞凋亡反应。

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.