纳米金属氧化物的神经毒性效应研究进展

摘要/Abstract

摘要： 人造纳米金属氧化物材料因其独特理化特性，已被广泛应用于生物医药、细胞标记分选、药物载体和临床治疗等领域，其对人类健康和环境安全日益受到关注。研究表明，纳米金属氧化物进入神经系统后，引起活性氧与细胞因子释放，导致血脑屏障损伤和中枢神经系统功能紊乱，但其毒性作用机制仍不清楚。本文综述了纳米金属氧化物的神经毒性效应及作用机制的相关研究进展。

关键词: 纳米金属氧化物, 神经系统, 毒性效应及机制

Abstract: Manufactured metal oxide nanomaterials are utilized in a wide variety of applications including in diagnostic devices, cell tracking, drug targeting and regenerative medicine, and their potential adverse effects on both the environment and human health have been concerned. It has been reported that metal oxide nanomaterials-induced reactive oxygen species (ROS) generation and cytokine release play important roles in the blood-brain barrier damage and central nervous system (CNS) dysfunction. However, the mechanism underlying metal oxide nanomaterials-related neurotoxicity has not been fully elucidated. Here, the neurotoxic effects of metal oxide nanoparticles on central nervous system are reviewed.

Key words: metal oxide nanoparticles, nervous system, oxidative stress

王洁婷, 张芳, 丁文军. 纳米金属氧化物的神经毒性效应研究进展[J]. 神经药理学报, 2013, 3(3): 39-47.

WANG1 Jie-ting, ZHANG Fang, DING Wen-jun. Neurotoxic Effects of Metal Oxide Nanomaterials[J]. Acta Neuropharmacologica, 2013, 3(3): 39-47.

参考文献

[1] Takahiro Kaida, Kota Kobayashi, Maoya Adachi, et al. Optical characteristics of titanium oxide interference film and the film laminated with oxides and their applications for cosmetics [J]. J Cosmet Sci, 2004, 55(2): 219-220.

[2] Nohyun Lee, Hyoungsu Kim, Seung Hong Choi, et al. Magnetosome-like ferrimagnetic iron oxide nanocubes for highly sensitive MRI of single cells and transplanted pancreatic islets [J]. Proc Natl Acad Sci USA, 2011, 108(7): 2662-2667.

[3] Eva Tysiak, Patrick Asbach, Orhan Aktas, et al. Beyond blood brain barrier breakdown - in vivo detection of occult neuroinflammatory foci by magnetic nanoparticles in high field MRI [J]. J Neuroinflammation, 2009, 6: 20.

[4] Hu Yu-lan, Gao Jian-qing. Potential neurotoxicity of nanoparticles [J]. Int J Pharm, 2010, 394(1-2): 115-121.

[5] W M Burch, Passage of inhaled particles into the blood circulation in humans [J]. Circulation, 2002, 106(20): E141-E141.

[6] Annette Peters, Bellina Veronesi, Lilian Calderon-Garciduenas, et al. Translocation and potential neurological effects of fine and ultrafine particles a critical update [J]. Part Fibre Toxicol, 2006, 3: 13.

[7] Alpesh Mistry, Snjezana Stolnik, Lisbeth Illum. Nanoparticles for direct nose-to-brain delivery of drugs [J]. Int J Pharm, 2009, 379(1): 146-157.

[8] Paul J A Borm, David Robbins, Stephan Haubold, et al. The potential risks of nanomaterials: a review carried out for ECETOC [J]. Part Fibre Toxicol, 2006, 3: 11.

[9] William S Beckett, David F Chalupa, Andrea Pauly-Brown, et al. Comparing inhaled ultrafine versus fine zinc oxide particles in healthy adults: a human inhalation study [J]. Am J Respir Crit Care Med, 2005, 171(10): 1129-1135.

[10] Gunter Oberdorster, Zachary Sharp, Viorel Atudorei, et al. Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats [J]. J Toxicol Environ Health A, 2002. 65(20): 1531-1543.

[11] Elder A, Gelein R, Silva V, et al. Translocation of inhaled ultrafine manganese oxide particles to the central nervous system [J]. Environ Health Perspect, 2006, 114(8): 1172-1178.

[12] Wang Bing, Feng Wei Y, Wang Meng, et al. Transport of intranasally instilled fine Fe2O3 particles into the brain: micro-distribution, chemical states, and histopathological observation [J]. Biol Trace Elem Res, 2007, 118(3): 233-243.

[13] Kwon Jung-Taek, Hwang Soon-Kyung, Jin Hua, et al. Body distribution of inhaled fluorescent magnetic nanoparticles in the mice [J]. J Occup Health, 2008, 50(1): 1-6.

[14] Kao Yi-yun, Cheng Tsun-Jen, Yang De-ming, et al. Demonstration of an olfactory bulb-brain translocation pathway for ZnO nanoparticles in rodent cells in vitro and in vivo [J]. J Mol Neurosci, 2012, 48(2): 464-471.

[15] Hari S Sharma, Syed F Ali, Saber M Hussain, et al. Influence of engineered nanoparticles from metals on the blood-brain barrier permeability, cerebral blood flow, brain edema and neurotoxicity. An experimental study in the rat and mice using biochemical and morphological approaches [J]. J Nanosci Nanotechnol, 2009, 9(8): 5055-5072.

[16] E Barbu, E Molnar, J Tsibouklis, et al. The potential for nanoparticle-based drug delivery to the brain: overcoming the blood-brain barrier [J]. Expert Opin Drug Deliv, 2009, 6(6): 553-565.

[17] Kewal K Jain. Nanobiotechnology-based strategies for crossing the blood-brain barrier [J]. Nanomedicine (Lond), 2012, 7(8): 1225-1233.

[18] G Oberdorster, Z Sharp, V Atudorei, et al. Translocation of inhaled ultrafine particles to the brain [J]. Inhalation Toxicology, 2004, 16(6-7): 437-445.

[19]吉俊伟, 唐仕川, 白茹, 等. 纳米氧化铝对小鼠血脑屏障通透性的影响 [J]. 毒理学杂志, 2012, 5: 321-326.

[20] Hari S Sharma, Saber Hussain, John Schlager, et al. Influence of nanoparticles on blood-brain barrier permeability and brain edema formation in rats [J]. Acta Neurochir Suppl, 2010, 106: 359-364.

[21] Ma Ling-lan, Liu Jie, Li Na, et al. Oxidative stress in the brain of mice caused by translocated nanoparticulate TiO2 delivered to the abdominal cavity [J]. Biomaterials, 2010, 31(1): 99-105.

[22] Wang Jiang-xue, Liu Ying, Jiao Fang, et al. Time-dependent translocation and potential impairment on central nervous system by intranasally instilled TiO(2) nanoparticles [J]. Toxicology, 2008, 254(1-2): 82-90.

[23] Wang Bing, Feng Wei-yue, Zhu Mo-tao, et al. Neurotoxicity of low-dose repeatedly intranasal instillation of nano- and submicron-sized ferric oxide particles in mice [J]. J Nanoparticle Res, 2009, 11(1): 41-53.

[24] Rahman M F, Wang J, Patterson T A, et al. Expression of genes related to oxidative stress in the mouse brain after exposure to silver-25 nanoparticles [J]. Toxicol Lett, 2009, 187(1): 15-21.

[25] Masahiro Kawahara. Effects of aluminum on the nervous system and its possible link with neurodegenerative diseases [J]. J Alzheimers Dis, 2005, 8(2): 171-182, 209-215.

[26] Li Xiao-bo, Zheng Hao, Zhang Zhi-ren, et al. Glia activation induced by peripheral administration of aluminum oxide nanoparticles in rat brains [J]. Nanomedicine, 2009, 5(4): 473-479.

[27] Han Da-dong, Tian Yu-tao, Zhang Tao, et al. Nano-zinc oxide damages spatial cognition capability via over-enhanced long-term potentiation in hippocampus of Wistar rats [J]. Int J Nanomedicine, 2011, 6: 1453-1461.

[28] An Lei, Liu Shi-chang, Yang Zhuo, et al. Cognitive impairment in rats induced by nano-CuO and its possible mechanisms [J]. Toxicol Lett, 2012, 213(2): 220-227.

[29] Xie Yong-ling, Wang Yi-yi, Zhang Tao, et al. Effects of nanoparticle zinc oxide on spatial cognition and synaptic plasticity in mice with depressive-like behaviors [J]. J Biomed Sci, 2012, 19(1): 14.

[30] Akiko Yamamoto, Rieko Honma, Masae Sumita, et al. Cytotoxicity evaluation of ceramic particles of different sizes and shapes [J]. J Biomed Mater Res A, 2004, 68(2): 244-256.

[31] Liu Zhao-wei, Ren Guo-gang, Zhang Tao, et al. Action potential changes associated with the inhibitory effects on voltage-gated sodium current of hippocampal CA1 neurons by silver nanoparticles [J]. Toxicology, 2009, 264(3): 179-184.

[32] Liu Z, Liu S, Ren G, et al. Nano-CuO inhibited voltage-gated sodium current of hippocampal CA1 neurons via reactive oxygen species but independent from G-proteins pathway [J]. J Appl Toxicol, 2011, 31(5): 439-445.

[33] Xu L J, Zhao J X, Zhang T, et al. In vitro study on influence of nano particles of CuO on CA1 pyramidal neurons of rat hippocampus potassium currents [J]. Environ Toxicol, 2009, 24(3): 211-217.

[34] Thomas R Pisanic, Jennifer D Blackwell, Veronica I Shubayev, et al. Nanotoxicity of iron oxide nanoparticle internalization in growing neurons [J]. Biomaterials, 2007, 28(16): 2572-2581.

[35] Diana M Stefanescu, Ali Khoshnan, Paul H Patterson, et al. Neurotoxicity of manganese oxide nanomaterials [J]. J Nanoparticle Res, 2009, 11(8): 1957-1969.

[36] Mark R Pickard, Divya M Chari. Robust uptake of magnetic nanoparticles (MNPs) by central nervous system (CNS) microglia: implications for particle uptake in mixed neural cell populations [J]. Int J Mol Sci, 2010, 11(3): 967-981.

[37] Thomas C Long, Julianne Tajuba, Preethi Sama, et al. Nanosize titanium dioxide stimulates reactive oxygen species in brain microglia and damages neurons in vitro [J]. Environ Health Perspect, 2007, 115(11): 1631-1637.

[38] Wu Jie, Sun Jiao, Xue Yang. Involvement of JNK and P53 activation in G2/M cell cycle arrest and apoptosis induced by titanium dioxide nanoparticles in neuron cells [J]. Toxicol Lett, 2010, 199(3): 269-276.

[39] Liu Shi-chang, Xu Lan-ju, Zhang Tao, et al. Oxidative stress and apoptosis induced by nanosized titanium dioxide in PC12 cells [J]. Toxicology, 2010, 267(1-3): 172-177.

[40] Vanessa Valdiglesias, Carla Costa, Vyom Sharma, et al. Comparative study on effects of two different types of titanium dioxide nanoparticles on human neuronal cells [J]. Food Chem Toxicol, 2013, 57: 352-361.

[41] Thomas C Long, Navid Saleh, Robert D Tilton, et al. Titanium dioxide (P25) produces reactive oxygen species in immortalized brain microglia (BV2): implications for nanoparticle neurotoxicity [J]. Environ Sci Technol, 2006, 40(14): 4346-4352.

[42] Xue Y, Wu J, Sun J. Four types of inorganic nanoparticles stimulate the inflammatory reaction in brain microglia and damage neurons in vitro [J]. Toxicol Lett, 2012, 214(2): 91-98.

[43] Deng Xiao-yong, Luan Qi-xia, Chen Wen-ting, et al. Nanosized zinc oxide particles induce neural stem cell apoptosis [J]. Nanotechnology, 2009, 20(11): 115101.

[44] Yin Yi-xia, Lin Qiang, Sun Hai-ming, et al. Cytotoxic effects of ZnO hierarchical architectures on RSC96 Schwann cells [J]. Nanoscale Res Lett, 2012, 7: 439.

[45] Zhao Jing-xia, Xu Lan-ju, Zhang Tao, et al. Influences of nanoparticle zinc oxide on acutely isolated rat hippocampal CA3 pyramidal neurons [J]. Neurotoxicology, 2009, 30(2): 220-230.

[46] Vanessa Valdiglesias, Carla Costa, Gozde Kilic, et al. Neuronal cytotoxicity and genotoxicity induced by zinc oxide nanoparticles [J]. Environ Int, 2013, 55: 92-100.

[47] Huei-wang Anna Jeng, James Swanson. Toxicity of metal oxide nanoparticles in mammalian cells [J]. J Environ Sci Health A Tox Hazard Subst Environ Eng, 2006, 41(12): 2699-2711.

[48] Wang Jie-ting, Deng Xiao-bei, Zhang Fang, et al. ZnO nanoparticle-induced oxidative stress triggers apoptosis by activating JNK signaling pathway in cultured primary astrocytes [J]. Nanoscale Res Lett, 2014, 9(1): 117.

[49] Andre Nel, Tian Xia, Lutz Madler, et al. Toxic potential of materials at the nanolevel [J]. Science, 2006, 311(5761): 622-627.

[50] Congcong He, Daniel J Klionsky. Regulation mechanisms and signaling pathways of autophagy [J]. Annu Rev Genet, 2009, 43: 67-93.

[51] Chen Yong, Lisong Yang, Feng Chao, et al., Nano neodymium oxide induces massive vacuolization and autophagic cell death in non-small cell lung cancer NCI-H460 cells [J]. Biochem Biophys Res Commun, 2005, 337(1): 52-60.

[52] L Yu, Y Lu, N Man, et al. Rare earth oxide nanocrystals induce autophagy in HeLa cells [J]. Small, 2009, 5(24): 2784-2787.

[53] Zhang Ying, Yu Chen-guang, Huang Guan-yi, et al. Nano rare-earth oxides induced size-dependent vacuolization: an independent pathway from autophagy [J]. Int J Nanomedicine, 2010, 5: 601-609.

[54] Hilary Afeseh Ngwa, Arthi Kanthasamy, Yan Gu, et al. Manganese nanoparticle activates mitochondrial dependent apoptotic signaling and autophagy in dopaminergic neuronal cells [J]. Toxicol Appl Pharmacol, 2011, 256(3): 227-240.

[55] Zhao Jing-xia, Yao Yang, Liu Shi-chang, et al. Involvement of reactive oxygen species and high-voltage-activated calcium currents in nanoparticle zinc oxide-induced cytotoxicity in vitro [J]. J Nanoparticle Res, 2012, 14(11): 1-14.

[56] Catherine Au, Lysette Mutkus, Allison Dobson, et al. Effects of nanoparticles on the adhesion and cell viability on astrocytes [J]. Biol Trace Elem Res, 2007, 120(1-3): 248-256.

[57] Gunter Oberdorster, Alison Elder, Amber Rinderknecht, Nanoparticles and the brain: cause for concern? [J]. J Nanosci Nanotechnol, 2009, 9(8): 4996-5007.

[58] Skaper S D, Floreani M, Ceccon M, et al. Excitotoxicity, oxidative stress, and the neuroprotective potential of melatonin [J]. Ann N Y Acad Sci, 1999, 890: 107-118.

[59] Li Xue-feng, Wang Hui-jun, Qiu Ping-ming, et al. Proteomic profiling of proteins associated with methamphetamine-induced neurotoxicity in different regions of rat brain [J]. Neurochem Int, 2008, 52(1-2): 256-264.

[60] David Butler, Ben A Bahr, Oxidative stress and lysosomes: CNS-related consequences and implications for lysosomal enhancement strategies and induction of autophagy [J]. Antioxid Redox Signal, 2006, 8(1-2): 185-196.

[61] Li Xue-feng, Wang Hui-jun, Qiu Ping-ming, et al. Proteomic profiling of proteins associated with methamphetamine-induced neurotoxicity in different regions of rat brain [J]. Neurochem Int, 2008, 52(1-2): 256-264.

[61] Wang Bing, Feng Wei-yue, Zhu Mo-tao, et al. Neurotoxicity of low-dose repeatedly intranasal instillation of nano- and submicron-sized ferric oxide particles in mice [J]. Journal of Nanoparticle Research, 2008. 11(1): 41-53.

[62] Christina M Powers, Appala R Badireddy, Ian T Ryde, et al. Silver nanoparticles compromise neurodevelopment in PC12 cells: critical contributions of silver ion, particle size, coating, and composition [J]. Environ Health Perspect, 2011, 119(1): 37-44.

[63] Paul Borm, Frederick C Klaessig, Timothy D Landry, et al. Research strategies for safety evaluation of nanomaterials, part V: role of dissolution in biological fate and effects of nanoscale particles [J]. Toxicol Sci, 2006, 90(1): 23-32.

[64] Tobias J Brunner, Peter Wick, Pius Manser, et al. In vitro cytotoxicity of oxide nanoparticles: comparison to asbestos, silica, and the effect of particle solubility [J]. Environ Sci Technol, 2006, 40(14): 4374-4381.

[65] Song Wen-hua, Zhang Jin-yang, Guo Jing, et al. Role of the dissolved zinc ion and reactive oxygen species in cytotoxicity of ZnO nanoparticles [J]. Toxicol Lett, 2010, 199(3): 389-397.

[66] Syed K Sohaebuddin, Paul T Thevenot, David Baker, et al. Nanomaterial cytotoxicity is composition, size, and cell type dependent [J]. Part Fibre Toxicol, 2010, 7: 22.

[67] Yin Hong, Philip S Casey, Maxine J McCall, et al. Effects of surface chemistry on cytotoxicity, genotoxicity, and the generation of reactive oxygen species induced by ZnO nanoparticles [J]. Langmuir, 2010, 26(19): 15399-15408.

[68] Chen Yung-chu, Hsieh Wen-yuan, Lee Wen-fu, et al. Effects of surface modification of PLGA-PEG-PLGA nanoparticles on loperamide delivery efficiency across the blood-brain barrier [J]. J Biomater Appl, 2013, 27(7): 909-922.