氯氨酮（K粉）干扰早期胚胎神经嵴发育的分子机制研究

Ketamine also termed super K is an N-methyl D-aspartete (NMDA) receptor antagonist and is commonly applied as anesthetic in clinical surgery.It has become one of the most popular recreational drugs abused by teenagers and young.adults.Data according to Chinese anti-drugs administration indicates that, 46.19% addict abuse new pttern drugs such as ketamine, among them, 30% are female that will be or being in childbearing age.although extensive studies have been done in ketamine phamacology and toxical effect, its roles in early embryonic development especially the first month of pregnancy are poorly understood. To address this problem , we analyze the effect of ketamine exposure in Xenopus animal model. Our preliminary data shows that ketamine disturbs neural crest induction and migration and thereby results in the developmental deficiency of neural crest derivatives. In this programme, we plan to explore the molecular mechanism of ketamine roles in neural crest developmental disturbance. Such study owns strong practical and scientific value for assessing application risk in clinical surgery as well as for future prevention and intervention of ketamine exposure induced birthdefects.

氯胺酮俗称K粉，属非特异性N-甲基-D-天门冬氨酸(NMDA)受体拮抗剂，临床常用于手术麻醉，是目前国际上流行的新型毒品。据中国禁毒报告显示吸食氯胺酮等新型毒品人数占现有吸毒人数46.19%，女性占30%，且多为或将要进入育龄期的妇女。针对氯胺酮的药理毒理作用开展了大量研究，但是氯氨酮滥用对怀孕早期尤其是怀孕第一个月许多妇女不知道怀孕的情况下对胚胎发育的影响知之甚少。我们运用模式动物非洲爪蛙研究了氯氨酮暴露对胚胎早期（相当于人类怀孕第一个月）的发育影响，前期工作发现氯氨酮抑制胚胎神经嵴的诱导和迁移，导致发育后期神经嵴来源组织器官发育缺陷，但是详细分子机制不明。本课题在前期研究的基础上希望能够阐明氯氨酮干扰神经嵴发育的分子机制，这一研究对于我们了解该类药物的药理毒理作用、评估该类药物在手术麻醉中的风险，预防和干预该类药物滥用导致的出生缺陷具有很强的现实意义和科学价值。

本项目着眼于研究早期胚胎发育过程中氯胺酮暴露对胚胎发育的影响及机制，经过三年的研究工作，基本完成了预定目标。我们的工作发现早期胚胎氯胺酮暴露阻碍胚胎神经嵴的诱导，这一过程不干扰早期胚胎中胚层发育，是通过特异抑制Zic5的表达实现的。我们的工作首次揭示在神经嵴诱导过程中Zic5在Notch信号下游，并且我们在Zic5的调控区鉴定出15bp的受到Notch信号调节的关键结合位点，氯胺酮通过抑制NOTCH信号进而阻碍下游Zic5的表达。. 该研究以模式动物非洲爪蛙为模型在分子水平上说明了早期胚胎氯胺酮暴露对胚胎神经嵴发育的影响以及相关的分子机制，为后续的干预治疗提供了理论基础。项目资助下目前已经在Molecular Brain, Molecular Medicine Reports杂志发表两篇文章，该项目的关键成果文章目前正在投稿。