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PKA-CREB-BDNF signaling pathway mediates propofol-induced long-term learning and memory impairment in hippocampus of rats
背景与目的：研究发现，丙泊酚可以引起发育中大脑广泛的神经细胞凋亡，从而导致长期的学习和记忆障碍。然而，由丙泊酚诱导的的神经细胞凋亡的具体细胞和分子机制仍然不清楚。
本研究的目的是探讨PKA-CREB-BDNF信号通路在脑发育过程丙泊酚引起的长期学习和记忆损伤中所起的作用。
方法：七日龄大鼠随机分为对照组、脂肪乳剂组和三个处理组（n=5）。对照组的大鼠没有接受处理。对3个处理组分别以（50、100和200毫克/公斤）浓度腹腔内注射丙泊酚，脂肪乳剂组组腹腔注射脂肪乳剂（10%，10毫升/公斤）。FJB染色、免疫组织化学分析用于研究神经细胞核抗原，透射电子显微镜用于检测神经元细胞凋亡和结构变化。MWM测试检查长期的空间学习和记忆障碍。PKA、pCREB和BDNF的表达是用蛋白免疫印迹来量化的。
结果：在P7大鼠的未成熟的大脑中，丙泊酚引起了FJB-阳性细胞的显著增加，并减少了PKA、pCREB和BDNF蛋白质水平。利用MWM测试，丙泊酚处理过的大鼠表现出长期的空间学习和记忆障碍。此外，还发现了海马体神经元核抗原阳性细胞消亡、神经元和突触的长期超微结构异常，以及成熟海马体中PKA、pCREB和BDNF蛋白质表达的长期下调。
结论：我们的研究结果表明，新生大鼠丙泊酚处理会显著地导致成年期的长期学习和记忆障碍。与此相关的神经细胞凋亡可能机制与PKA-CREB-BDNF信号通路的下调有关。
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.
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