氯胺酮诱导发育神经毒性的细胞内分子机制研究

项目名称： 氯胺酮诱导发育神经毒性的细胞内分子机制研究

项目编号： No.81503167

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 董朝轩

作者单位： 温州医科大学

项目金额： 17.9万元

中文摘要： 氯胺酮作为麻醉、镇静、镇痛药物广泛应用于儿科临床治疗和诊断过程。最新研究显示氯胺酮可通过改变大鼠胚胎皮质神经干、祖细胞的神经发生引起潜在的发育神经毒性。为进一步确定氯胺酮的发育神经毒性、指导临床安全用药、有针对性地探索降低氯胺酮所致的发育神经毒性改变的干预方法，探究氯胺酮引起的发育神经毒性的细胞内分子机制是非常必要和紧迫的。我们之前的研究发现氯胺酮可在大鼠胚胎皮质神经干、祖细胞中抑制PI3K/Akt的磷酸化，并上调增殖抑制蛋白p27。本研究将系统地检测PI3K/Akt-p27信号通路以及与神经干细胞增殖相关的FoxO3a转录因子、细胞周期蛋白、细胞周期蛋白激酶、p27在氯胺酮诱导大鼠胚胎皮质神经干、祖细胞增殖抑制中的作用；并通过分析之间的相互关系最终构建一条完整的氯胺酮-PI3K/Akt-FoxO3a-p27-细胞周期蛋白及其激酶-增殖抑制的信号通路。

中文关键词： 氯胺酮；发育神经毒性；分子机制；神经干；祖细胞；细胞周期

英文摘要： Ketamine has been widely used as an anesthetic, sedative or analgesic in pediatric clinical practice and diagnostic procedures. Recent studies indicate that ketamine can induce potential developmental neurotoxicity by altering neurogenesis (proliferation and differentiation) of rat fetal cortical neural stem progenitor cells (NSPCs). Investigating intracellular molecular mechanisms of ketamine induced developmental neurotoxicity is very necessary and urgent to further identify ketamine as a developmental neurotoxin for ketamine clinical safe use, and to explore effective specific therapeutics to ketamine-relevant developmental neurotoxic damage in children’s brain. Our previous studies show that ketamine can inhibit phosphorylation of PI3K/Akt and up-regulate expression of p27 in rat fetal cortical NSPCs. This study will systemically detect effects of PI3K/Akt signaling, and other factors relating to proliferation regulation: FoxO3a transcription factor, cyclins, cyclin dependent kinase (CDKs), and p27 on ketamine-induced proliferation inhibition in rat fetal cortical NSPCs. Also, a series of analysis on interactions among the above tested factors will result in identify an entire ketamine-PI3K/Akt-FoxO3a-p27-cyclin/CDKs-proliferation inhibition signaling pathway to explain potential intracellular molecular mechanisms of ketamine-induced developmental neurotoxicity in rat fetal cortical NSPCs.

英文关键词： Ketamine;Developmental neurotoxicity;Molecular mechanism;Neural stem progenitor cells;Cell cycle