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

Abstract

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.

Experimentally Created Magnetic Force in Microbiological Space and On-Earth Studies: Perspectives and Restrictions

“…However, when using these systems, potential toxic effects of the gadolinium salts should be considered as well as effects of the strong magnetic field and its gradient that are described above. Gadolinium derivatives are widely used as contrast agents in magnetic resonance imaging (MRI) techniques so their toxicity has been extensively studied [61][62][63]. An ability of the Gd 3+ to compete with Ca 2+ in active centers of Ca 2+ -binding enzymes underlies gadolinium toxicity because Ca 2+ substitution with Gd 3+ can interrupt critically important Ca 2+ -dependent pathways [61].…”

“…To decrease toxicity, gadolinium-based substances, which are used in MRI, enclose Gd 3+ in the complex that is expected to remain chelated in the human body and be excreted intact. Fast and almost unchanged excretion was demonstrated for FDA approved contrast agents such as gadobutrol [62,63]. In bacteria, although Ca 2+ ions do not play such a critical role as in mammals, Ca 2+ dependent proteins take part in such cellular functions as motility and chemotaxis, virulence, and maintenance of membrane integrity [64][65][66].…”

A New Era in Magnetic Resonance Contrast Media

“…This includes profibrotic responses in the skin 21,22 and increased gadolinium retention (accompanied by neurotoxicity, due to linear chelate administration) in the brain with neuroinflammation. 23 Stunning new work has measured high gadolinium concentrations in specific subregions and layers of the brain, with distinct spatial patterns of deposition making possible tailored functional neurological testing (looking for effects in patients). 24 An excellent example is the very high gadolinium concentration measured after gadodiamide administration in the superior olivary complex and inferior colliculus, structures central to the auditory system.…”

“…In recent years, additional information has come forth regarding other possible problems associated with gadolinium deposition, in addition to the original concerns (due to brain and bone deposition). This includes profibrotic responses in the skin 21,22 and increased gadolinium retention (accompanied by neurotoxicity, due to linear chelate administration) in the brain with neuroinflammation 23 . Stunning new work has measured high gadolinium concentrations in specific subregions and layers of the brain, with distinct spatial patterns of deposition making possible tailored functional neurological testing (looking for effects in patients) 24 .…”

Pharmacokinetics, Safety, and Tolerability of the Novel Tetrameric, High-Relaxivity, Macrocyclic Gadolinium-Based Contrast Agent Gadoquatrane in Healthy Adults

“…Both observations can be attributed to the lower stability of the linear GBCAs compared with the macrocyclic GBCAs, yielding in prolonged presence of gadolinium (Gd) in the central nervous system and other body regions, as shown in nonclinical and clinical studies. [4][5][6] But despite the favorable properties of the macrocyclic GBCAs, there are ongoing concerns about a prolonged presence of Gd in the brain and other body areas. 1,6,7 Thus, calls for next-generation contrast agents, that is, contrast agents with improved relaxivity that would allow lowering the Gd dose, have been voiced.…”