Silver nanoparticle induced blood-brain barrier inflammation and increased permeability in primary rat brain microvessel endothelial cells.
The current report examines the interactions of silver nanoparticles (Ag-NPs) with the cerebral microvasculature to identify the involvement of proinflammatory mediators that can increase blood-brain barrier (BBB) permeability. Primary rat brain microvessel endothelial cells (rBMEC) were isolated from adult Sprague-Dawley rats for an in vitro BBB model. The Ag-NPs were characterized by transmission electron microscopy (TEM), dynamic light scattering, and laser Doppler velocimetry. The cellular accumulation, cytotoxicity (6.25-50 μg/cm(3)) and potential proinflammatory mediators (interleukin [IL]-1β, IL-2, tumor necrosis factor [TNF] α, and prostaglandin E(2) [PGE(2)]) of Ag-NPs (25, 40, or 80 nm) were determined spectrophotometrically, cell proliferation assay (2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide) and ELISA. The results show Ag-NPs-induced cytotoxic responses at lower concentrations for 25 and 40 nm when compared with 80-nm Ag-NPs. The proinflammatory responses in this study demonstrate both Ag-NPs size and time-dependent profiles, with IL-1B preceding both TNF and PGE(2) for 25 nm. However, larger Ag-NPs (40 and 80 nm) induced significant TNF responses at 4 and 8 h, with no observable PGE(2) response. The increased fluorescein transport observed in this study clearly indicates size-dependent increases in BBB permeability correlated with the severity of immunotoxicity. Together, these data clearly demonstrate that larger Ag-NPs (80 nm) had significantly less effect on rBMEC, whereas the smaller particles induced significant effects on all the end points at lower concentrations and/or shorter times. Further, this study suggests that Ag-NPs may interact with the cerebral microvasculature producing a proinflammatory cascade, if left unchecked; these events may further induce brain inflammation and neurotoxicity.
Trickler
William J
WJ
Neurochemistry Laboratory, Division of Neurotoxicology, National Center of Toxicological Research/Food and Drug Administration, Jefferson, Arkansas 72079, USA.
Lantz
Susan M
SM
Murdock
Richard C
RC
Schrand
Amanda M
AM
Robinson
Bonnie L
BL
Newport
Glenn D
GD
Schlager
John J
JJ
Oldenburg
Steven J
SJ
Paule
Merle G
MG
Slikker
William
W
Hussain
Saber M
SM
Ali
Syed F
SF
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001783:Blood Flow Velocity; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000098:blood supply*; D002199:Capillary Permeability / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D007249:Inflammation / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D053768:Metal Nanoparticles / Q000032:analysis / Q000633:toxicity* / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D055806:Microvessels / Q000187:drug effects* / Q000378:metabolism; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D012542:Scattering, Radiation; D012834:Silver / Q000633:toxicity*
D015415:Biomarkers; D018836:Inflammation Mediators; D012834:Silver