1Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
2Department of Toxicology and Pharmacology, Faculty of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
Silver Nanoparticles (AgNPs) have gained considerable interests during the last decade due to their excellent antimicrobial activities. Despite their extensive use, the potential toxicity of these nanoparticles and possible mechanisms by which they may induce adverse reactions have not received sufficient attention and no specific biomarker exist to describe and quantify their toxic effects. Nanoparticles, depending on their physicochemical characteristics and compositions, can interact with vital organs such as the brain and induce toxic effects. A specific concern is that any contact with AgNPs independent of the route of administration is thought to result in significant systemic uptake, internal exposure of sensitive organs, especially in the central nervous system (CNS) and different toxic responses. There are considerable evidences that AgNPs can disrupt the Blood-Brain Barrier (BBB) and induce subsequent brain edema formation. Therefore, it is essential to understand the differential effects of AgNPs on brain cell with especial emphasis on the possible mechanisms of action. Recently, biomarkers are increasingly used as surrogate indicators of toxic responses in biological monitoring due to the inaccessibility of target organs. Moreover, as the most nanoscale contaminants occur at low concentrations, physiological biomarkers may be better indicators of potential impact of nanomaterials than traditional toxicity testing. This review aims to investigate the effects of AgNPs on CNS targets of toxicity and clarify the role of existing biomarkers especially the role of dopamine levels as a potential biomarker of Ag-NPs neurotoxicity.
 Nystrom AM, Wooley KL. The importance of chemistry in creating well-defined nanoscopic embedded therapeutics: devices capable of the dual functions of imaging and therapy. Acc Chem Res. 2011; 44(10): 969-78.
 Von Maltzahn G, Park JH, Lin KY, Singh N, Schwoppe C, Mesters R, Berdel WE, Ruoslahti E, Sailor MJ, Bhatia SN. Nanoparticles that communicate in vivo to amplify tumour targeting. Nat Mater. 2011; 10(7): 545-552.
 Haase A, Rott S, Mention A, Graf P, Plendl J, Thunemann AF, Meier WP, Taubert A, Luch A, Reiser G. Effects of silver nanoparticles on primary mixed neural cell cultures: uptake, oxidative stress and acute calcium responses. Toxicol Sci. 2012; 126(2): 457-468.
 Elsaesser A, Howard CV. Toxicology of nanoparticles. Adv Drug Deliv Rev. 2012; 64(2): 129-137.
 Korani M, Rezayat SM, Arbabi Bidgoli S. Sub-chronic Dermal Toxicity of Silver Nanoparticles in Guinea Pig: Special Emphasis to Heart, Bone and Kidney Toxicities. Iran J Pharm Res. 2013; 12(3): 511-9.
 Korani M, Rezayat SM, Gilani K, Arbabi Bidgoli S, Adeli S. Acute and subchronic dermal toxicity of nanosilver in guinea pig. Int J Nanomedicine. 2011; 6(1): 855-862.
 Lee HY, Park HK, Lee YM, Kim K, Park SB. A practical procedure for producing silver nanocoated fabric and its antibacterial evaluation for biomedical applications. Chem Commun. 2007; (28): 2959-2961.
 Klaper R, Crago J, Barr J, Arndt D, Seteyowati K, Chen J. Toxicity biomarker expression in daphnids exposed to manufactured nanoparticles: changes in toxicity with functionalization. Environ Pollut. 2009; 157(4): 1152-1156.
 Comfort KK, Maurer EI, Braydich-Stolle LK, Hussain SM. Interference of silver, gold, and iron oxide nanoparticles on epidermal growth factor signal transduction in epithelial cells. ACS Nano. 2011; 5(12): 10000-10008.
 Hsin YH, Chen CF, Huang S, Shih TS, Lai PS, Chueh PJ. The apoptotic effect of nanosilver is mediated by a ROS-and JNK-dependent mechanism involving the mitochondrial pathway in NIH3T3 cells. Toxicol Lett. 2008; 179(3): 130-139.
 Panyala NR, Pena-Méndez EM, Havel J. Silver or silver nanoparticles: a hazardous threat to the environment and human health. J Appl Biomed. 2008; 6(3): 117-129.
 Trickler WJ, Lantz SM, Murdock RC, Schrand AM, Robinson BL, Newport GD, Schlager JJ, Oldenburg SJ, Paule MG, Slikker W, Hussain SM, Ali SF. Silver nanoparticle induced blood-brain barrier inflammation and increased permeability in primary rat brain microvessel endothelial cells. Toxicol Sci. 2010; kfq244
 Cha K, Hong HW, Choi YG, Lee MJ, Park JH, Chae HK, Ryu G, Myung H. Comparison of acute responses of mice livers to short-term exposure to nano-sized or micro-sized silver particles. Biotechnol Lett. 2008; 30 (11): 1893-1896.
 Liu Z, Ren G, Zhang T, Yang Z. Action potential changes associated with the inhibitory effects on voltage-gated sodium current of hippocampal CA1 neurons by silver nanoparticles. Toxicology. 2009;264(3): 179-184.
 Yin N, Liu Q, Liu J, He B, Cui L, Li Z, Yun Z, Qu G, Liu S, Zhou Q, Jiang G., Silver nanoparticle exposure attenuates the viability of rat cerebellum granule cells through apoptosis coupled to oxidative stress. Small. 2013; 9(9-10): 1831-1841.
 Curtin JF, Donovan M, Cotter TG. Regulation and measurement of oxidative stress in apoptosis. J Immunol Methods. 2002; 265(1-2): 49-72.
 Hussain SM, Javorina AK, Schrand AM, Duhart HM, Ali SF, Schlager JJ., The interaction of manganese nanoparticles with PC-12 cells induces dopamine depletion. Toxicol Sci. 2006; 92(2): 456-463.
 Lockman PR, Koziara JM, Mumper RJ, Allen DD. Nanoparticle surface charges alter blood-brain barrier integrity and permeability. J Drug Target. 2004; 12(9-10): 635-641.
 Oberdorster G, Sharp Z, Atudorei V, Elder A, Gelein R, Kreyling W, Cox C. Translocation of inhaled ultrafine particles to the brain. Inhal Toxicol. 2004; 16(6-7): 437-445.
 Elder A, Gelein R, Silva V, Feikert T, Opanashuk L, Carter J, Potter R, Maynard A, Ito Y, Finkelstein J, Oberdorster G. Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environ Health Perspect. 2006; 114(8): 1172-1178.
 Tang J, Xiong L, Zhou G, Wang S, Wang J, Liu L, Li J, Yuan F, Lu S, Wan Z, Chou L, Xi T. Silver nanoparticles crossing through and distribution in the blood-brain barrier in vitro. J Nanosci Nanotechnol. 2010; 10(10): 6313-6317.
 Yang Z, Liu ZW, Allaker RP, Reip P, Oxford J, Ahmad Z, Ren G. A review of nanoparticle functionality and toxicity on the central nervous system. J R Soc Interface. 2010; 7 (Supp4): S411-S422.
 Yokel R, Grulke E, MacPhail R. Metal-based nanoparticle interactions with the nervous system: the challenge of brain entry and the risk of retention in the organism. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2013; 5(4): 346-373.
 Azevedo FA, Carvalho LR, Grinberg LT, Farfel JM, Ferretti RE, Leite RE, Jacob Filho W, Lent R, Herculano-Houzel S. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J Comp Neurol. 2009; 513(5): 532-541.
 Hadrup N, Loeschner K, Mortensen A, Sharma AK, Qvortrup K, Larsen EH, Lam HR. The similar neurotoxic effects of nanoparticulate and ionic silver in vivo and in vitro. Neurotoxicology. 2012; 33(3): 416-423.
 Hirrlinger J, Dringen R. The cytosolic redox state of astrocytes: maintenance, regulation and functional implications for metabolite trafficking. Brain Res Rev. 2010; 63(1-2): 177-188.
 Tiffany-Castiglioni E, Hong S, Qian Y. Copper handling by astrocytes: insights into neurodegenerative diseases. Int J Dev Neurosci. 2011; 29(8): 811-818.
 Scheiber IF, Dringen R. Astrocyte functions in the copper homeostasis of the brain. Neurochem Int. 2013; 62(5): 556-565.
 Hohnholt MC, Geppert M, Luther EM, Petters C, Bulcke F, Dringen R. Handling of iron oxide and silver nanoparticles by astrocytes. Neurochem Res. 2013; 38(2): 227-239.
 Luther EM, Koehler Y, Diendorf J, Epple M, Dringen R. Accumulation of silver nanoparticles by cultured primary brain astrocytes. Nanotechnology. 2011; 22(37): 375101.
 Greulich C, Diendorf J, Simon T, Eggeler G, Epple M, Koller M. Uptake and intracellular distribution of silver nanoparticles in human mesenchymal stem cells. Acta Biomater. 2011; 7(1): 347-354.
 Weiss N, Miller F, Cazaubon S, Couraud PO. The blood-brain barrier in brain homeostasis and neurological diseases. Biochim Biophys Acta. 2009; 1788(4): 842-857.
 Entezari M, Safari M, Hekmati M, Hekmat S, Azin A. Modification of carboxylated multiwall nanotubes with benzotriazole derivatives and study of their anticancer activities. Med Chem Res. 2013; 23 (1): 487-495.
 Xu F, Piett C, Farkas S, Qazzaz M, Syed NI. Silver nanoparticles (AgNPs) cause degeneration of cytoskeleton and disrupt synaptic machinery of cultured cortical neurons. Mol Brain. 2013; 6(29): 1-15.
 Tang M, Xing T, Zeng J, Wang H, Li C, Yin S, Yan D, Deng H, Liu J, Wang M, Chen J, Ruan DY. Unmodified CdSe quantum dots induce elevation of cytoplasmic calcium levels and impairment of functional properties of sodium channels in rat primary cultured hippocampal neurons. Environ Health Perspect. 2008; 116(7): 915-922.
 Limbach LK, Wick P, Manser P, Grass RN, Bruinink A, Stark WJ. Exposure of engineered nanoparticles to human lung epithelial cells: influence of chemical composition and catalytic activity on oxidative stress. Environ Sci Technol. 2007; 41(11): 4158-4163.
 Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006; 443(7113): 787-795.
 Huang CC, Aronstam RS, Chen DR, Huang YW. Oxidative stress, calcium homeostasis, and altered gene expression in human lung epithelial cells exposed to ZnO nanoparticles. Toxicol In Vitro. 2010; 24(1): 45-55.
 Koeneman BA, Zhang Y, Westerhoff P, Chen Y, Crittenden JC, Capco DG. Toxicity and cellular responses of intestinal cells exposed to titanium dioxide. Cell Biol Toxicol. 2010; 26(3): 225-238.
 Jan E, Byrne SJ, Cuddihy M, Davies AM, Volkov Y, Gun’ko YK, Kotov NA. High-content screening as a universal tool for fingerprinting of cytotoxicity of nanoparticles. ACS Nano. 2008; 2(5): 928-938.
 Ariano P, Zamburlin P, Gilardino A, Mortera R, Onida B, Tomatis M, Ghiazza M, Fubini B, Lovisolo D. Interaction of Spherical Silica Nanoparticles with Neuronal Cells: Size-Dependent Toxicity and Perturbation of Calcium Homeostasis. Small. 2011; 7(6): 766-774.
 Wijnhoven, S.W, Peijnenburg WJ, Hereberts CA, Hagens WI, Oomen AG, Heugens EH, Roszek B, Bisschops J, Gosens I, De Mint DV, Dekkers S, De Jong WH, Zijvarden MV, Sips AJ, Geertsma RE. Nano-silver-a review of available data and knowledge gaps in human and environmental risk assessment. Nanotoxicology. 2009; 3(2): 109-138.
 Kim SH, Ko JW, Koh SK, Lee IC, Son JM, Moon C, Kim SH, Shin DH, Kim DC. Silver nanoparticles induce apoptotic cell death in cultured cerebral cortical neurons. Molecular & Cellular Toxicology. 2014; 10(2): 173-179.
 Grosse S, Evje L, Syversen T. Silver nanoparticle-induced cytotoxicity in rat brain endothelial cell culture. Toxicol In Vitro. 2013; 27(1): 305-313.
 Esposito P, Gheorghe D, Kandere K, Pang X, Connolly R, Jacobson S, Theoharides TC. Acute stress increases permeability of the blood–brain-barrier through activation of brain mast cells. Brain Res. 2001; 888(1): 117-127.
 Sharma HS, Hussain S, Schlager J, Ali SF, Sharma A. Influence of nanoparticles on blood–brain barrier permeability and brain edema formation in rats. Acta Neurochir Suppl. 2010; 106: 359-364.
 Rogers EJ, Bello D, Hsieh S. Oxidative stress as a screening metric of potential toxicity by nanoparticles and ariborne particulate matter. Inhal Toxicol. 2008; 20(9): 895.
 Sharma, H., Effect of captopril (a converting enzyme inhibitor) on blood-brain barrier permeability and cerebral blood flow in normotensive rats. Neuropharmacology. 1987; 26(1): 85-92.
 Cramer S, Tacke S, Bornhorst J, Klingauf J, Schwerdtle T, Galla HJ. The Influence of Silver Nanoparticles on the Blood-Brain and the Blood-Cerebrospinal Fluid Barrier in vitro. J Nanomed Nanotechnol. 2014; 5(5): 1-12.
 Hanada S, Fujioka K, Inoue Y, Kanaya F, Manome Y, Yamamoto K. Cell-Based in Vitro Blood–Brain Barrier Model Can Rapidly Evaluate Nanoparticles’ Brain Permeability in Association with Particle Size and Surface Modification. Int J Mol Sci. 2014; 15(2): 1812-1825.
 Tang J, Xiong L, Wang S, Wang J, Liu L, Li J, Yuan F, Xi T. Distribution, translocation and accumulation of silver nanoparticles in rats. J Nanosci Nanotechnol. 2009; 9(8): 4924-4932.
 Zielhuis RL, Henderson PT. Definitions of monitoring activities and their relevance for the practice of occupational health. Int Arch Occup Environ Health. 1986; 57(4): 249-257.
 Manno M, Viau C, Cocker J, Colosio C, Lowry L, Mutti A, Nordberg M, Wang S. Biomonitoring for occupational health risk assessment (BOHRA). Toxicol Lett. 2010; 192(1): 3-16.
 Wang J, Rahman MF, Duhart HM, Newport GD, Patterson TA, Murdock RC, Hussain SM, Schlager JJ, Ali SF. Expression changes of dopaminergic system-related genes in PC12 cells induced by manganese, silver, or copper nanoparticles. Neurotoxicology. 2009; 30(6): 926-933.
 Floyd RA, Hensley K. Oxidative stress in brain aging: implications for therapeutics of neurodegenerative diseases. Neurobiol Aging. 2002; 23(5): 795-807.
 Siddiqi NJ, Abdelhalim MA, El-Ansary AK, Alhomida AS, Ong WY. Identification of potential biomarkers of gold nanoparticle toxicity in rat brains. J Neuroinflammation. 2012; 9: 123.
 Drechsel DA, Patel M. Role of reactive oxygen species in the neurotoxicity of environmental agents implicated in Parkinson’s disease. Free Radic Biol Med. 2008; 44(11): 1873-1886.
 Xu L, Li X, Takemura T, Hanagata N, Wu G, Chou LL. Genotoxicity and molecular response of silver nanoparticle (NP)-based hydrogel. J Nanobiotechnology. 2012; 10(16): 1-11.
 AshaRani PV, Low Kah Mun G, Hande MP, Valiyaveettil S. Cytotoxicity and genotoxicity of silver nanoparticles in human cells. ACS Nano. 2009; 3(2): 279-290.
 Panda KK, Achary VM, Krishnaveni R, Padhi BK, Sarangi SN, Sahu SN, Panda BB. In vitro biosynthesis and genotoxicity bioassay of silver nanoparticles using plants. Toxicol In Vitro. 2011; 25(5): 1097-1105.
 Rim KT, Song SW, Kim HY. Oxidative DNA damage from nanoparticle exposure and its application to workers’ health: a literature review. Saf Health Work. 2013; 4(4): 177-186.
 Dziendzikowska K, Gromadzka-Ostrowska J, Lankoff A, Oczkowski M, Krawczynska A, Chwastowska J, Sadowska-Bratek M, Chajduk E, Wojewodzka M, Dusinska M, Kruszewski M. Time-dependent biodistribution and excretion of silver nanoparticles in male Wistar rats. J Appl Toxicol. 2012; 32(11): 920-928.
 Rahman MF, Wang J, Patterson TA, Saini UT, Robinson BL, Newport GD, Murdock RC, Schlager JJ, Hussain SM, Ali SF. Expression of genes related to oxidative stress in the mouse brain after exposure to silver-25 nanoparticles. Toxicol Lett. 2009; 187(1): 15-21.
 Koike S, Ogasawara Y, Shibuya N, Kimura H, Ishii K. Polysulfide exerts a protective effect against cytotoxicity caused by t-buthylhydroperoxide through Nrf2 signaling in neuroblastoma cells. FEBS Lett. 2013; 587(21): 3548-3555.
 Huang CL, Hsiao IL, Lin HC, Wang CF, Huang YJ, Chuang CY. Silver nanoparticles affect on gene expression of inflammatory and neurodegenerative responses in mouse brain neural cells. Environ Res. 2015; 136: 253-63.
 Liu Y, Guan W, Ren G, Yang Z. The possible mechanism of silver nanoparticle impact on hippocampal synaptic plasticity and spatial cognition in rats. Toxicol Lett. 2012; 209(3): 227-231.
 Hritcu L, Stefan M, Ursu L, Neagu A, Mihasan M, Tartau L, Melnig V. Exposure to silver nanoparticles induces oxidative stress and memory deficits in laboratory rats. Open Life Sci. 2011; 6(4): 497-509.
 Cereda C, Gabanti E, Corato M, de Silvestri A, Alimonti D, Cova E, Malaspina A, Ceroni M. Increased incidence of FMO1 gene single nucleotide polymorphisms in sporadic amyotrophic lateral sclerosis. ALS. 2006; 7(4): 233-240.
 dos Santos AP, Mateus ML, Carvalho CM, Batoréu MC. Biomarkers of exposure and effect as indicators of the interference of selenomethionine on methylmercury toxicity. Toxicol Lett. 2007; 169(2): 121-128.
 Gohil K, Azzi A. Drug Insight: antioxidant therapy in inherited ataxias. Nat Clin Pract Neurol. 2008; 4 (7): E1.
 Yin N, Yao X, Zhou Q, Faiola F, Jiang G. Vitamin E attenuates silver nanoparticle-induced effects on body weight and neurotoxicity in rats. Biochem Biophys Res Commun. 2015; 458(2): 405-410.
 Wang Y, Wang B, Zhu MT, Li M, Wang HJ, Wang M, Ouyang H, Chai ZF, Feng WY, Zhao YL. Microglial activation, recruitment and phagocytosis as linked phenomena in ferric oxide nanoparticle exposure. Toxicol Lett. 2011; 205(1): 26-37.
 Dong Y, Benveniste EN. Immune function of astrocytes. Glia. 2001; 36(2): 180-190.
 Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007; 10(11): 1387-1394.
 Didier N, Romero IA, Créminon C, Wijkhuisen A, Grassi J, Mabondzo A. Secretion of interleukin-1â by astrocytes mediates endothelin-1 and tumour necrosis factor-á effects on human brain microvascular endothelial cell permeability. J Neurochem. 2003; 86(1): 246-254.
 Elsabahy M, Wooley KL. Cytokines as biomarkers of nanoparticle immunotoxicity. Chem Soc Rev. 2013; 42(12): 5552-5576.
 Zhang T, Wang L, Chen Q, Chen C. Cytotoxic potential of silver nanoparticles. Yonsei Med j. 2014; 55(2): 283-291.
 Tashkhourian, J, Hormozi Nezhad MR , Khodavesi J, Javadi S. Silver nanoparticles modified carbon nanotube paste electrode for simultaneous determination of dopamine and ascorbic acid. J Electroanal Chem. 2009; 633(1): 85-91.
 Anderson K, Kuruvilla A, Uretsky N, Miller DD. Synthesis and pharmacological evaluation of sulfonium analogs of dopamine: nonclassical dopamine agonists. J Med Chem. 1981; 24(6): 683-687.
 Lavoie J, Illiano P, Sotnikova TD, Gainetdinov RR, Beaulieu JM, Hébert M. The electroretinogram as a biomarker of central dopamine and serotonin: potential relevance to psychiatric disorders. Biol Psychiatry. 2014; 75(6): 479-486.
 Rahman MF, Wang J, Patterson TA, Saini UT, Robinson BL, Newport GD, Murdock RC, Schlager JJ, Hussain SM, Ali F. Expression of genes related to oxidative stress in the mouse brain after exposure to silver-25nanoparticles. Toxicol Lett. 2009; 187(1): 15-21.
 Chandra SV, Shukla GS, Saxena DK. Manganese-induced behavioral dysfunction and its neurochemical mechanism in growing mice. J Neurochem. 1979; 33(6): 1217-1221.
 Savitt JM, Dawson VL, Dawson TM. Diagnosis and treatment of Parkinson disease: molecules to medicine. J Clin Invest. 2006; 116(7): 1744-1754.
 Meisler MH, Kearney JA., Sodium channel mutations in epilepsy and other neurological disorders. J Clin Invest. 2005; 115(8): 2010-2017.
 Manzo L, Artigas F, Martinez E, Mutti A, Bergamaschi E, Nicotera P, Tonini M, Candura SM, Ray DE, Costa LG. Biochemical markers of neurotoxicity. A review of mechanistic studies and applications. Hum Exp Toxicol. 1996; 15: S20-35.