Gao Jing, Zhang Xiaochen, Yu Mei, Ren Guogang, Yang Zhuo
College of Medicine, State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Nankai University, Tianjin 300071, China.
College of Life Science, Nankai University, Tianjin 300071, China.
Toxicology. 2015 Nov 4;337:21-9. doi: 10.1016/j.tox.2015.08.011. Epub 2015 Sep 7.
Multi-walled carbon nanotubes (MWCNTs) have shown potential applications in many fields, especially in the field of biomedicine. Several studies have reported that MWCNTs induce apoptosis and oxidative damage in nerve cells during in vitro experiments. However, there are few studies focused on the neurotoxicity of MWCNTs used in vivo. Many studies have reported that autophagy, a cellular stress response to degrade damaged cell components, can be activated by diverse nanoparticles. In this study, we investigated the neurotoxic effects of MWCNTs on hippocampal synaptic plasticity and spatial cognition in rats. Then, we used an inhibitor of autophagy called chloroquine (CQ) to examine whether autophagy plays an important role in hippocampal synaptic plasticity, since this was damaged by MWCNTs. In this study, adult male Wister rats were randomly divided into three groups: a control group, a group treated with MWCNTs (2.5mg/kg/day) and a group treated with MWCNTs+CQ (20mg/kg/day). After two-weeks of intraperitoneal (i.p.) injections, rats were subjected to the Morris water maze (MWM) test, and the long-term potentiation (LTP) and other biochemical parameters were determined. Results showed that MWCNTs could induce cognitive deficits, histopathological alteration and changes of autophagy level (increased the ratio of LC3 II /LC3 I and the expression of Beclin-1). Furthermore, we found that CQ could suppress MWCNTs-induced autophagic flux and partly rescue the synapse deficits, which occurred with the down-regulation of NR2B (a subunit of NMDA receptor) and synaptophysin (SYP) in the hippocampus. Our results suggest that MWCNTs could induce cognitive deficits in vivo via the increased autophagic levels, and provide a potential strategy to avoid the adverse effects of MWCNTs.
多壁碳纳米管（MWCNTs）已在许多领域显示出潜在应用，尤其是在生物医学领域。多项研究报告称，在体外实验中，MWCNTs可诱导神经细胞凋亡和氧化损伤。然而，很少有研究关注体内使用的MWCNTs的神经毒性。许多研究报告称，自噬作为一种降解受损细胞成分的细胞应激反应，可被多种纳米颗粒激活。在本研究中，我们调查了MWCNTs对大鼠海马突触可塑性和空间认知的神经毒性作用。然后，我们使用一种名为氯喹（CQ）的自噬抑制剂来研究自噬是否在海马突触可塑性中起重要作用，因为海马突触可塑性已被MWCNTs破坏。在本研究中，成年雄性Wister大鼠被随机分为三组：对照组、接受MWCNTs（2.5mg/kg/天）治疗的组和接受MWCNTs+CQ（20mg/kg/天）治疗的组。腹腔注射两周后，对大鼠进行莫里斯水迷宫（MWM）测试，并测定长时程增强（LTP）和其他生化参数。结果表明，MWCNTs可诱导认知缺陷、组织病理学改变和自噬水平变化（增加LC3 II /LC3 I的比率和Beclin-1的表达）。此外，我们发现CQ可抑制MWCNTs诱导的自噬流，并部分挽救海马中NR2B（N-甲基-D-天冬氨酸受体的一个亚基）和突触素（SYP）下调所导致的突触缺陷。我们的结果表明，MWCNTs可通过提高自噬水平在体内诱导认知缺陷，并提供了一种避免MWCNTs不良反应的潜在策略。
