Division of Neurotoxicology, National Center for Toxicological Research, United States Food and Drug Administration Jefferson, AR, USA.
Front Neurol. 2012 Oct 17;3:142. doi: 10.3389/fneur.2012.00142. eCollection 2012.
Advances in pediatric and obstetric surgery have resulted in an increase in the duration and complexity of anesthetic procedures. A great deal of concern has recently arisen regarding the safety of anesthesia in infants and children. Because of obvious limitations, it is not possible to thoroughly explore the effects of anesthetic agents on neurons in vivo in human infants or children. However, the availability of some advanced pre-clinical research approaches and models, such as imaging technology both in vitro and in vivo, stem cells, and non-human primate experimental models, have provided potentially invaluable tools for examining the developmental effects of anesthetic agents. This review discusses the potential application of some sophisticated research approaches, e.g., calcium imaging, in stem cell-derived in vitro models, especially human embryonic neural stem cells, along with their capacity for proliferation and their potential for differentiation, to dissect relevant mechanisms underlying the etiology of the neurotoxicity associated with developmental exposures to anesthetic agents. Also, this review attempts to discuss several advantages for using the developing rhesus monkey model (in vivo), when combined with dynamic molecular imaging approaches, in addressing critical issues related to the topic of pediatric sedation/anesthesia. These include the relationships between anesthetic-induced neurotoxicity, dose response, time-course, and developmental stage at time of exposure (in vivo studies), serving to provide the most expeditious platform toward decreasing the uncertainty in extrapolating pre-clinical data to the human condition.
儿科和产科手术的进步导致麻醉程序的持续时间和复杂性增加。最近，人们对婴儿和儿童麻醉的安全性产生了极大的关注。由于明显的局限性，不可能在体内对人类婴儿或儿童的神经元进行彻底探索麻醉剂的作用。然而，一些先进的临床前研究方法和模型的出现，如体外和体内的成像技术、干细胞和非人类灵长类动物实验模型，为研究麻醉剂的发育效应提供了潜在的宝贵工具。这篇综述讨论了一些复杂的研究方法的潜在应用，例如钙成像，在干细胞衍生的体外模型中，特别是人类胚胎神经干细胞中，以及它们的增殖能力及其分化潜力，以剖析与发育性暴露于麻醉剂相关的神经毒性的相关机制。此外，本综述还尝试讨论了使用发育中的恒河猴模型（体内）的几个优点，当与动态分子成像方法结合使用时，可以解决与儿科镇静/麻醉相关的关键问题。这些包括麻醉诱导的神经毒性、剂量反应、时间进程和暴露时的发育阶段（体内研究）之间的关系，为减少将临床前数据外推到人类状况的不确定性提供了最快捷的平台。
