Abstract
Earlier we showed that chronic administration of engineered nanoparticles (NPs) from metals, e.g., Cu, Ag, or Al (50–60 nm, 50 mg/kg, i.p. daily for 1 week) alter blood–brain barrier (BBB) disruption and induce brain pathology in adult rats (age 18 to 22 weeks). However, effects of size-dependent neurotoxicity of NPs in vivo are still largely unknown. In present investigation, we examined the effects of different size ranges of the above-engineered NPs on brain pathology in rats. Furthermore, the fact that age is also an important factor in brain pathology was also investigated in our rat model. Our results showed that small-sized NPs induced the most pronounced BBB breakdown (EBA +480 to 680 %; radioiodine +850 to 1025 %), brain edema formation (+4 to 6 %) and neuronal injuries (+30 to 40 %), glial fibrillary acidic protein upregulation (+40 to 56 % increase), and myelin vesiculation (+30 to 35 % damage) in young animals as compared to controls. Interestingly, the oldest animals (30 to 35 weeks of age) also showed massive brain pathology as compared to young adults (18 to 20 weeks old). The Ag and Cu exhibited greater brain damage compared with Al NPs in all age groups regardless of their size. This suggests that apart from the size, the composition of NPs is also important in neurotoxicity. The very young and elderly age groups exhibited greater neurotoxicity to NPs suggests that children and elderly are more vulnerable to NPs-induced brain damage. The NPs-induced brain damage correlated well with the upregulation of neuronal nitric oxide synthase activity in the brain indicating that NPs-induced neurotoxicity may be mediated via increased production of nitric oxide, not reported earlier.
Similar content being viewed by others
References
Pietroiusti A, Campagnolo L, Fadeel B (2012) Interactions of engineered nanoparticles with organs protected by internal biological barriers. Small doi:10.1002/smll.201201463. [Epub ahead of print]
van der Zande M, Vandebriel RJ, Van Doren E, Kramer E, Herrera Rivera Z, Serrano-Rojero CS, Gremmer ER, Mast J, Peters RJ, Hollman PC, Hendriksen PJ, Marvin HJ, Peijnenburg AA, Bouwmeester H (2012) Distribution, elimination, and toxicity of silver nanoparticles and silver ions in rats after 28-day oral exposure. ACS Nano 6:7427–7442
Sharma HS, Sharma A (2012) Neurotoxicity of engineered nanoparticles from metals. CNS Neurol Disord Drug Targets 11:65–80
Sharma HS, Hussain S, Schlager J, Ali SF, Sharma A (2010) Influence of nanoparticles on blood–brain barrier permeability and brain edema formation in rats. Acta Neurochir Suppl 106:359–364
Sharma HS, Ali SF, Hussain SM, Schlager JJ, Sharma A (2009) 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 Nanosci Nanotechnol 9:5055–5072
Sharma HS, Sharma A (2007) Nanoparticles aggravate heat stress induced cognitive deficits, blood–brain barrier disruption, edema formation and brain pathology. Prog Brain Res 162:245–273
Martinez LR (2012) Nitric oxide-releasing nanoparticles: challenges and future prospects. Ther Deliv 3:1139–1142
Carpenter AW, Worley BV, Slomberg DL, Schoenfisch MH (2012) Dual action antimicrobials: nitric oxide release from quaternary ammonium-functionalized silica nanoparticles. Biomacromolecules 13:3334–3342
Sharma HS, Miclescu A, Wiklund L (2011) Cardiac arrest-induced regional blood–brain barrier breakdown, edema formation and brain pathology: a light and electron microscopic study on a new model for neurodegeneration and neuroprotection in porcine brain. J Neural Transm 118:87–114
Sharma HS (2006) Hyperthermia influences excitatory and inhibitory amino acid neurotransmitters in the central nervous system. An experimental study in the rat using behavioural, biochemical, pharmacological, and morphological approaches. J Neural Transm 113:497–519
Sharma HS, Westman J, Olsson Y, Alm P (1996) Involvement of nitric oxide in acute spinal cord injury: an immunocytochemical study using light and electron microscopy in the rat. Neurosci Res 24:373–384
Sharma HS, Olsson Y, Persson S, Nyberg F (1995) Trauma-induced opening of the blood–spinal cord barrier is reduced by indomethacin, an inhibitor of prostaglandin biosynthesis. Experimental observations in the rat using [131I]-sodium, Evans blue and lanthanum as tracers. Restor Neurol Neurosci 7:207–215
Sharma HS, Westman J, Nyberg F (1998) Pathophysiology of brain edema and cell changes following hyperthermic brain injury. Prog Brain Res 115:351–412
Sharma HS, Olsson Y, Dey PK (1990) Early accumulation of serotonin in rat spinal cord subjected to traumatic injury. Relation to edema and blood flow changes. Neuroscience 36:725–730
Xu Z, Liu C, Wei J, Sun J (2012) Effects of four types of hydroxyapatite nanoparticles with different nanocrystal morphologies and sizes on apoptosis in rat osteoblasts. J Appl Toxicol 32:429–435
Naqvi S, Samim M, Abdin M, Ahmed FJ, Maitra A, Prashant C, Dinda AK (2010) Concentration-dependent toxicity of iron oxide nanoparticles mediated by increased oxidative stress. Int J Nanomedicine 5:983–989
Albanese A, Tang PS, Chan WC (2012) The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu Rev Biomed Eng 14:1–16
Das S, Mandal AK, Ghosh A, Panda S, Das N, Sarkar S (2008) Nanoparticulated quercetin in combating age related cerebral oxidative injury. Curr Aging Sci 1:169–174
Maheshwari V, Fomenko DE, Singh G, Saraf RF (2010) Ion mediated monolayer deposition of gold nanoparticles on microorganisms: discrimination by age. Langmuir 26:371–377
Chen Z, Meng H, Xing G, Yuan H, Zhao F, Liu R, Chang X, Gao X, Wang T, Jia G, Ye C, Chai Z, Zhao Y (2008) Age-related differences in pulmonary and cardiovascular responses to SiO2 nanoparticle inhalation: nanotoxicity has susceptible population. Environ Sci Technol 42:8985–9892
Andreollo NA, Santos EF, Araújo MR, Lopes LR (2012) Rat's age versus human's age: what is the relationship? Arq Bras Cir Dig 25:49–51
Saul ML, Tylee D, Becoats KT, Guerrero BG, Sweeney P, Helmreich DL, Fudge JL (2012) Long-term behavioral consequences of stress exposure in adolescent versus young adult rats. Behav Brain Res 229:226–234
Sharma HS, Badgaiyan RD, Alm P, Mohanty S, Wiklund L (2005) Neuroprotective effects of nitric oxide synthase inhibitors in spinal cord injury-induced pathophysiology and motor functions: an experimental study in the rat. Ann N Y Acad Sci 1053:422–434
Sharma HS, Sjöquist PO, Alm P (2003) A new antioxidant compound H-290151 attenuates spinal cord injury induced expression of constitutive and inducible isoforms of nitric oxide synthase and edema formation in the rat. Acta Neurochir Suppl 86:415–420
Sharma HS, Alm P, Westman J (1998) Nitric oxide and carbon monoxide in the brain pathology of heat stress. Prog Brain Res 115:297–333
Acknowledgments
This investigation is partially supported by the Air Force Office of Scientific Research (London), Air Force Material Command, USAF, under grant number FA8655-05-1-3065. The US Government is authorized to reproduce and distribute reprints for Government purpose notwithstanding any copyright notation thereon. The views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing the official policies or endorsements, either expressed or implied, of the Air Force Office of Scientific Research or the US Government. Financial support of Swedish Medical Research Council (grant no. 2710, HSS); Astra-Zeneca, Mölndal, Sweden (HSS), Alexander von Humboldt Foundation, Germany (HSS); India-EU Research Co-operation (AS/RP), Ministry of Science and Technology, govt. of India, New Delhi, India (AS/RP); and University Grants Commission, New Delhi, India (HSS); Indian Council of Medical Research, New Delhi, India (HSS) is gratefully acknowledged. The authors have no conflict of interest with any agencies mentioned above.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sharma, A., Muresanu, D.F., Patnaik, R. et al. Size- and Age-Dependent Neurotoxicity of Engineered Metal Nanoparticles in Rats. Mol Neurobiol 48, 386–396 (2013). https://doi.org/10.1007/s12035-013-8500-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-013-8500-0