Fu Jingxuan, Wang Hui, Gao Jing, Yu Mei, Wang Rubin, Yang Zhuo, Zhang Tao
College of Life Sciences and Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, 300071, Tianjin, People's Republic of China.
School of Medicine, Nankai University, 300071, Tianjin, People's Republic of China.
Mol Neurobiol. 2017 Mar;54(2):819-832. doi: 10.1007/s12035-016-9687-7. Epub 2016 Jan 15.
Our previous investigation demonstrated that autophagy significantly reduced melamine-induced cell death in PC12 cells via inhibiting the excessive generation of ROS. In the present study, we further examine if rapamycin, used as an autophagy activator, can play a significant role in protecting neurons and alleviating the impairment of spatial cognition and hippocampal synaptic plasticity in melamine-treated rats. Male Wistar rats were divided into three groups: control, melamine-treated, and melamine-treated + rapamycin. The animal model was established by administering melamine at a dose of 300 mg/kg/day for 4 weeks. Rapamycin was intraperitoneally given at a dose of 1 mg/kg/day for 28 consecutive days. The Morris water maze test showed that spatial learning and reversal learning in melamine-treated rats were considerably damaged, whereas rapamycin significantly impeded the cognitive function impairment. Rapamycin efficiently alleviated the melamine-induced impairments of both long-term potentiation (LTP) and depotentiation, which were damaged in melamine rats. Rapamycin further increased the expression level of autophagy markers, which were significantly enhanced in melamine rats. Moreover, rapamycin noticeably decreased the reactive oxygen species level, while the superoxide dismutase activity was remarkably increased by rapamycin in melamine rats. Malondialdehyde assay exhibited that rapamycin prominently reduced the malondialdehyde (MDA) level of hippocampal neurons in melamine-treated rats. In addition, rapamycin significantly decreased the caspase-3 activity, which was elevated by melamine. Consequently, our results suggest that regulating autophagy may become a new targeted therapy to relieve the damage induced by melamine.
我们之前的研究表明，自噬通过抑制活性氧的过度产生，显著降低了三聚氰胺诱导的PC12细胞死亡。在本研究中，我们进一步探究作为自噬激活剂的雷帕霉素是否能在保护神经元以及减轻三聚氰胺处理大鼠的空间认知障碍和海马突触可塑性损伤方面发挥重要作用。雄性Wistar大鼠被分为三组：对照组、三聚氰胺处理组和三聚氰胺处理+雷帕霉素组。通过以300mg/kg/天的剂量给予三聚氰胺4周来建立动物模型。雷帕霉素以1mg/kg/天的剂量连续28天腹腔注射。莫里斯水迷宫试验表明，三聚氰胺处理大鼠的空间学习和逆向学习能力受到显著损害，而雷帕霉素显著减轻了认知功能障碍。雷帕霉素有效缓解了三聚氰胺诱导的长时程增强（LTP）和去增强作用的损伤，这两种作用在三聚氰胺处理的大鼠中均受到破坏。雷帕霉素进一步提高了自噬标志物的表达水平，这些标志物在三聚氰胺处理的大鼠中显著增强。此外，雷帕霉素显著降低了活性氧水平，而在三聚氰胺处理的大鼠中，雷帕霉素显著提高了超氧化物歧化酶的活性。丙二醛检测显示，雷帕霉素显著降低了三聚氰胺处理大鼠海马神经元的丙二醛（MDA）水平。此外，雷帕霉素显著降低了三聚氰胺升高的半胱天冬酶-3活性。因此，我们的结果表明，调节自噬可能成为缓解三聚氰胺诱导损伤的一种新的靶向治疗方法。
