Evaluation of toxicity of gadolinium-based contrast agents on neuronal cells

Abstract

Background Gadolinium-based contrast agents (GBCAs) are widely used in magnetic resonance imaging (MRI). Recently, increased signal intensity has been reported in specific brain areas after repeated administrations of GBCAs. Purpose To investigate the toxic effects of GBCAs on neuronal cells by using SH-SY5Y neuroblastoma cell cultures. Material and Methods For toxicity assays, SH-SY5Y cells were incubated with different doses (0–1000 µM) of several macrocyclic (gadoterate meglumine and gadobutrol) and linear GBCAs (gadoversetamide, gadopentetate dimeglumine, gadodiamide, and gadoxetate disodium) for 48 h. Cell viability and proliferation capacity were evaluated by using MTS assay, LDH assay, and colony-forming assay. In addition, Western blotting of Bcl-2 and Bax proteins and nuclear Hoechst 33258 staining were performed to evaluate apoptotic cell death. The results were expressed as mean ± SEM. The data were analyzed using Student’s t-test. A P value < 0.05 was accepted as statistically significant. Results Both macrocyclic and linear GBCAs significantly and dose-dependently reduced cell viability in neuronal cells compared to control. Cell viability was measured between 89.5% ± 4% and 61% ± 0.7% in GBCA-treated groups. In addition, neurotoxicity was more prominent in linear GBCA-treated cultures ( P < 0.0005). Bax protein levels were increased in GBCA-treated cells particularly with linear agents whereas Bcl-2 expression was decreased concomitantly. Conclusion The results of the present study indicated that exposure to specific GBCAs, even at low micro-molar concentrations, may have detrimental effects on neuronal survival. Further investigations are required to clarify the molecular mechanism underlying GBCA-induced cell death.