Ferritin, a protein containing iron nanoparticles, induces reactive oxygen species formation and inhibits glutamate uptake in rat brain synaptosomes.
Nanoparticles are currently used in medicine as agents for targeted drug delivery and imaging. However it has been demonstrated that nanoparticles induce neurodegeneration in vivo and kill neurons in vitro. The cellular and molecular bases of this phenomenon are still unclear. We have used the protein ferritin as a nanoparticle model. Ferritin contains iron particles (Fe(3+)) with size 7 nm and a protein shell. We investigated how ferritin influences uptake and release of [(14)C]glutamate and free radical formation as monitored by fluorescent dye DCFDA in rat brain synaptosomes. We found that even a high concentration of ferritin (800 microg/ml) did not induce spontaneous [(14)C]glutamate release. In contrast the same concentration of this protein inhibited [(14)C]glutamate uptake two fold. Furthermore ferritin induced intrasynaptosomal ROS (reactive oxygen species) formation in a dose-dependent manner. This process was insensitive to 30 microM DPI, an inhibitor of NADPH oxidase and to 10 microM CCCP, a mitochondrial uncoupler. These results indicate that iron-based nanoparticles can cause ROS and decreased glutamate uptake, potentially leading to neurodegeneration.
Institute of Biophysics and Cell Engineering, National Academy of Sciences of Belarus, Akademicheskaya Street, 27, Minsk 220072, Belarus.
Alexandra V
AV
Alekseenko
Tatyana V
TV
Waseem
Sergei V
SV
Fedorovich
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002250:Carbon Radioisotopes; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005293:Ferritins / Q000737:chemistry / Q000633:toxicity*; D005609:Free Radicals / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D009249:NADP / Q000037:antagonists & inhibitors / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D014475:Uncoupling Agents / Q000494:pharmacology
D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D005609:Free Radicals; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D018698:Glutamic Acid; D009249:NADP; D005293:Ferritins