Different Impact of Gadopentetate and Gadobutrol on Inflammation-Promoted Retention and Toxicity of Gadolinium Within the Mouse Brain.

Autor:	Anderhalten L; From the Experimental and Clinical Research Center (ECRC), A Cooperation Between the Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin., Silva RV, Morr A; Department of Radiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin., Wang S; From the Experimental and Clinical Research Center (ECRC), A Cooperation Between the Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin., Smorodchenko A; Institute for Translational Medicine and Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg., Saatz J; Bundesanstalt für Materialforschung und -prüfung, Berlin., Traub H; Bundesanstalt für Materialforschung und -prüfung, Berlin., Mueller S, Boehm-Sturm P, Rodriguez-Sillke Y; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Flow & Mass Cytometry Core Facility, Berlin, Germany., Kunkel D; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Flow & Mass Cytometry Core Facility, Berlin, Germany., Hahndorf J; Department of Radiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin., Paul F; From the Experimental and Clinical Research Center (ECRC), A Cooperation Between the Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin., Taupitz M; Department of Radiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin., Sack I; Department of Radiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin., Infante-Duarte C; From the Experimental and Clinical Research Center (ECRC), A Cooperation Between the Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin.
Jazyk:	angličtina
Zdroj:	Investigative radiology [Invest Radiol] 2022 Oct 01; Vol. 57 (10), pp. 677-688. Date of Electronic Publication: 2022 Apr 21.
DOI:	10.1097/RLI.0000000000000884
Abstrakt:	Objectives: Using a murine model of multiple sclerosis, we previously showed that repeated administration of gadopentetate dimeglumine led to retention of gadolinium (Gd) within cerebellar structures and that this process was enhanced with inflammation. This study aimed to compare the kinetics and retention profiles of Gd in inflamed and healthy brains after application of the macrocyclic Gd-based contrast agent (GBCA) gadobutrol or the linear GBCA gadopentetate. Moreover, potential Gd-induced neurotoxicity was investigated in living hippocampal slices ex vivo. Materials and Methods: Mice at peak of experimental autoimmune encephalomyelitis (EAE; n = 29) and healthy control mice (HC; n = 24) were exposed to a cumulative dose of 20 mmol/kg bodyweight of either gadopentetate dimeglumine or gadobutrol (8 injections of 2.5 mmol/kg over 10 days). Magnetic resonance imaging (7 T) was performed at baseline as well as at day 1, 10, and 40 post final injection (pfi) of GBCAs. Mice were sacrificed after magnetic resonance imaging and brain and blood Gd content was assessed by laser ablation-inductively coupled plasma (ICP)-mass spectrometry (MS) and ICP-MS, respectively. In addition, using chronic organotypic hippocampal slice cultures, Gd-induced neurotoxicity was addressed in living brain tissue ex vivo, both under control or inflammatory (tumor necrosis factor α [TNF-α] at 50 ng/μL) conditions. Results: Neuroinflammation promoted a significant decrease in T1 relaxation times after multiple injections of both GBCAs as shown by quantitative T1 mapping of EAE brains compared with HC. This corresponded to higher Gd retention within the EAE brains at 1, 10, and 40 days pfi as determined by laser ablation-ICP-MS. In inflamed cerebellum, in particular in the deep cerebellar nuclei (CN), elevated Gd retention was observed until day 40 after last gadopentetate application (CN: EAE vs HC, 55.06 ± 0.16 μM vs 30.44 ± 4.43 μM). In contrast, gadobutrol application led to a rather diffuse Gd content in the inflamed brains, which strongly diminished until day 40 (CN: EAE vs HC, 0.38 ± 0.08 μM vs 0.17 ± 0.03 μM). The analysis of cytotoxic effects of both GBCAs using living brain tissue revealed an elevated cell death rate after incubation with gadopentetate but not gadobutrol at 50 mM. The cytotoxic effect due to gadopentetate increased in the presence of the inflammatory mediator TNF-α (with vs without TNF-α, 3.15% ± 1.18% vs 2.17% ± 1.14%; P = 0.0345). Conclusions: In the EAE model, neuroinflammation promoted increased Gd retention in the brain for both GBCAs. Whereas in the inflamed brains, efficient clearance of macrocyclic gadobutrol during the investigated time period was observed, the Gd retention after application of linear gadopentetate persisted over the entire observational period. Gadopentetate but not gadubutrol appeared to be neurotoxic in an ex vivo paradigm of neuronal inflammation. Competing Interests: Conflicts of interest and sources of funding: This work was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG), SFB1340-1 (B05 and C02), the Einstein Center for Neurosciences Berlin (ECN), and by the Hertie Foundation (medMS scholarship: P1180047). (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)
Databáze:	MEDLINE
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