Huang He, Liu Cun-Ming, Sun Jie, Hao Ting, Xu Chun-Mei, Wang Dan, Wu Yu-Qing
Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China.
Neurotox Res. 2016 Aug;30(2):185-98. doi: 10.1007/s12640-016-9615-7. Epub 2016 Mar 10.
Ketamine has been reported to cause neonatal neurotoxicity via a neuronal apoptosis mechanism; however, no in vivo research has reported whether ketamine could affect postnatal neurogenesis in the hippocampal dentate gyrus (DG). A growing number of experiments suggest that postnatal hippocampal neurogenesis is the foundation of maintaining normal hippocampus function into adulthood. Therefore, this study investigated the effect of ketamine on hippocampal neurogenesis. Male Sprague-Dawley rats were divided into two groups: the control group (equal volume of normal saline), and the ketamine-anesthesia group (40 mg/kg ketamine in four injections at 1 h intervals). The S-phase marker 5-bromodeoxyuridine (BrdU) was administered after ketamine exposure to postnatal day 7 (PND-7) rats, and the neurogenesis in the hippocampal DG was assessed using single- or double-immunofluorescence staining. The expression of GFAP in the hippocampal DG was measured by western blot analysis. Spatial reference memory was tested by Morris water maze at 2 months after PND-7 rats exposed to ketamine treatment. The present results showed that neonatal ketamine exposure significantly inhibited neural stem cell (NSC) proliferation, decreased astrocytic differentiation, and markedly enhanced neuronal differentiation. The disruptive effect of ketamine on the proliferation and differentiation of NSCs lasted at least 1 week and disappeared by 2 weeks after ketamine exposure. Moreover, the migration of newborn neurons in the granule cell layer and the growth of astrocytes in the hippocampal DG were inhibited by ketamine on PND-37 and PND-44. Finally, ketamine caused a deficit in hippocampal-dependent spatial reference memory tasks at 2 months old. Our results suggested that ketamine may interfere with hippocampal neurogenesis and long-term neurocognitive function in PND-7 rats. These findings may provide a new perspective to explain the adult neurocognitive dysfunction induced by neonatal ketamine exposure.
据报道，氯胺酮可通过神经元凋亡机制导致新生儿神经毒性；然而，尚无体内研究报道氯胺酮是否会影响海马齿状回（DG）的产后神经发生。越来越多的实验表明，产后海马神经发生是维持成年后正常海马功能的基础。因此，本研究调查了氯胺酮对海马神经发生的影响。将雄性Sprague-Dawley大鼠分为两组：对照组（等体积生理盐水）和氯胺酮麻醉组（40mg/kg氯胺酮，分四次注射，间隔1小时）。在氯胺酮暴露于出生后第7天（PND-7）的大鼠后给予S期标记物5-溴脱氧尿苷（BrdU），并使用单免疫荧光或双免疫荧光染色评估海马DG中的神经发生。通过蛋白质免疫印迹分析测量海马DG中GFAP的表达。在PND-7大鼠接受氯胺酮治疗2个月后，通过莫里斯水迷宫测试空间参考记忆。目前的结果表明，新生儿氯胺酮暴露显著抑制神经干细胞（NSC）增殖，减少星形胶质细胞分化，并显著增强神经元分化。氯胺酮对NSC增殖和分化的破坏作用至少持续1周，并在氯胺酮暴露后2周消失。此外，氯胺酮在PND-37和PND-44时抑制了颗粒细胞层中新生神经元的迁移以及海马DG中星形胶质细胞的生长。最后，氯胺酮在2个月大时导致海马依赖性空间参考记忆任务出现缺陷。我们的结果表明，氯胺酮可能会干扰PND-7大鼠的海马神经发生和长期神经认知功能。这些发现可能为解释新生儿氯胺酮暴露引起的成人神经认知功能障碍提供新的视角。
