Zhong Yu, Chen Jing, Li Li, Qin Yi, Wei Yi, Pan Shining, Jiang Yage, Chen Jialin, Xie Yubo
Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, PR China.
Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, PR China.
Brain Res. 2018 Jul 15;1691:64-74. doi: 10.1016/j.brainres.2018.04.022. Epub 2018 Apr 21.
Studies have found that propofol can induce widespread neuroapoptosis in developing brains, which leads to cause long-term learning and memory abnormalities. However, the specific cellular and molecular mechanisms underlying propofol-induced neuroapoptosis remain elusive. The aim of the present study was to explore the role of PKA-CREB-BDNF signaling pathway in propofol-induced long-term learning and memory impairment during brain development. Seven-day-old rats were randomly assigned to control, intralipid and three treatment groups (n = 5). Rats in control group received no treatment. Intralipid (10%, 10 mL/kg) for vehicle control and different dosage of propofol for three treatment groups (50, 100 and 200 mg/kg) were administered intraperitoneally. FJB staining, immunohistochemistry analysis for neuronal nuclei antigen and transmission electron microscopy were used to detect neuronal apoptosis and structure changes. MWM test examines the long-term spatial learning and memory impairment. The expression of PKA, pCREB and BDNF was quantified using western blots. Propofol induced significant increase of FJB-positive cells and decrease of PKA, pCREB and BDNF protein levels in the immature brain of P7 rats. Using the MWM test, propofol-treated rats demonstrated long-term spatial learning and memory impairment. Moreover, hippocampal NeuN-positive cell loss, long-lasting ultrastructural abnormalities of the neurons and synapses, and long-term down-regulation of PKA, pCREB and BDNF protein expression in adult hippocampus were also found. Our results indicated that neonatal propofol exposure can significantly result in long-term learning and memory impairment in adulthood. The possible mechanism involved in the propofol-induced neuroapoptosis was related to down-regulation of PKA-CREB-BDNF signaling pathway.
研究发现，丙泊酚可诱导发育中的大脑广泛发生神经细胞凋亡，进而导致长期的学习和记忆异常。然而，丙泊酚诱导神经细胞凋亡的具体细胞和分子机制仍不清楚。本研究的目的是探讨蛋白激酶A（PKA）-环磷腺苷反应元件结合蛋白（CREB）-脑源性神经营养因子（BDNF）信号通路在丙泊酚诱导的脑发育过程中长期学习和记忆损伤中的作用。将7日龄大鼠随机分为对照组、脂肪乳组和三个处理组（n = 5）。对照组大鼠不接受任何处理。脂肪乳组（10%，10 mL/kg）作为溶剂对照，三个处理组分别腹腔注射不同剂量的丙泊酚（50、100和200 mg/kg）。采用FJB染色、神经元细胞核抗原免疫组化分析和透射电子显微镜检测神经细胞凋亡和结构变化。采用 Morris 水迷宫（MWM）试验检测长期空间学习和记忆损伤。采用蛋白质免疫印迹法对PKA、磷酸化CREB（pCREB）和BDNF的表达进行定量分析。丙泊酚可使P7大鼠未成熟脑中FJB阳性细胞显著增加，PKA、pCREB和BDNF蛋白水平降低。采用MWM试验，发现丙泊酚处理的大鼠存在长期空间学习和记忆损伤。此外，还发现成年海马中NeuN阳性细胞丢失、神经元和突触长期存在超微结构异常，以及PKA、pCREB和BDNF蛋白表达长期下调。我们的结果表明，新生期暴露于丙泊酚可显著导致成年期长期学习和记忆损伤。丙泊酚诱导神经细胞凋亡的可能机制与PKA-CREB-BDNF信号通路下调有关。
